Drug development for major chronic health conditions-aligning with growing public health needs: Proceedings from a multistakeholder think tank.

The global pharmaceutical industry portfolio is skewed towards cancer and rare diseases due to more predictable development pathways and financial incentives. In contrast, drug development for major chronic health conditions that are responsible for a large part of mortality and disability worldwide is stalled. To examine the processes of novel drug development for common chronic health conditions, a multistakeholder Think Tank meeting, including thought leaders from academia, clinical practice, non-profit healthcare organizations, the pharmaceutical industry, the Food and Drug Administration (FDA), payors as well as investors, was convened in July 2022. Herein, we summarize the proceedings of this meeting, including an overview of the current state of drug development for chronic health conditions and key barriers that were identified. Six major action items were formulated to accelerate drug development for chronic diseases, with a focus on improving the efficiency of clinical trials and rapid implementation of evidence into clinical practice.

Evaluation of setting kinetics, mechanical strength, ion release, and cytotoxicity of high-strength glass ionomer cement contained elastomeric micelles.

BACKGROUND: Low mechanical properties are the main limitation of glass ionomer cements (GICs). The incorporation of elastomeric micelles is expected to enhance the strength of GICs without detrimentally affecting their physical properties and biocompatibility. This study compared the chemical and mechanical properties, as well as the cytotoxicity, of elastomeric micelles-containing glass ionomer cement (DeltaFil, DT) with commonly used materials, including EQUIA Forte Fil (EF), Fuji IX GP Extra (F9), and Ketac Molar (KT). METHOD: Powder particles of GICs were examined with SEM-EDX. Setting kinetics were assessed using ATR-FTIR. Biaxial flexural strength/modulus and Vickers surface microhardness were measured after immersion in water for 24 h and 4 weeks. The release of F, Al, Sr, and P in water over 8 weeks was analyzed using a fluoride-specific electrode and ICP-OES. The toxicity of the material extract on mouse fibroblasts was also evaluated. RESULTS: High fluoride levels in the powder were detected with EF and F9. DT demonstrated an initial delay followed by a faster acid reaction compared to other cements, suggesting an improved snap set. DT also exhibited superior flexural strength than other materials at both 24 h and 4 weeks but lower surface microhardness (p < 0.05). EF and F9 showed higher release of F, Al, and P than DT and KT. There was no statistically significant difference in fibroblast viability among the tested materials (p > 0.05). CONCLUSIONS: Elastomeric micelles-containing glass ionomer cement (DT) exhibited satisfactory mechanical properties and cytocompatibility compared with other materials. DT could, therefore, potentially be considered an alternative high-strength GIC for load-bearing restorations.

ICAM-1-mediated osteoblast-T lymphocyte direct interaction increases mineralization through TGF-ß1 suppression.

Modulation of osteoblast functions by T lymphocytes is important in inflammation-associated mineralized tissue diseases. The study aimed to determine whether direct interaction between these two cell types affects osteoblast functions and mineralization. The results showed that direct contact between the two cell types was evident by scanning electron microscopy and transmission electron microscopy. Under osteogenic induction, higher hydroxyapatite precipitation was observed in cocultures with direct contact with T lymphocytes compared with that by osteoblasts cultured alone. Cocultures without direct cell contact caused a decrease in mineralization. Direct cell contact also upregulated intercellular adhesion molecule (ICAM)-1 and simultaneously downregulated transforming growth factor (TGF)-ß1 in osteoblasts. However, the downregulation of TGF-ß1 was reversed by ICAM-1 blocking. Exogenously added TGF-ß1 in cocultures with direct cell contact suppressed mineralization. In conclusion, studies are consistent with ICAM-1-mediated direct contact between osteoblasts and T lymphocytes increasing mineralization via downregulation of TGF-ß1 in osteoblasts in vitro. This suggests a possible unexpected, but crucial, role of T lymphocytes in enhancing matrix mineralization during the repair process in vivo. The study identifies ICAM-1/TGF-ß1 as possible novel therapeutic targets for the treatment and prevention of inflammation-associated mineralized tissue diseases.

Assessment of Mechanical/Chemical Properties and Cytotoxicity of Resin-Modified Glass Ionomer Cements Containing Sr/F-Bioactive Glass Nanoparticles and Methacrylate Functionalized Polyacids.

This study prepared low-toxicity, elemental-releasing resin-modified glass ionomer cements (RMGICs). The effect of 2-hydroxyethyl methacrylate (HEMA, 0 or 5 wt%) and Sr/F-bioactive glass nanoparticles (Sr/F-BGNPs, 5 or 10 wt%) on chemical/mechanical properties and cytotoxicity were examined. Commercial RMGIC (Vitrebond, VB) and calcium silicate cement (Theracal LC, TC) were used as comparisons. Adding HEMA and increasing Sr/F-BGNPs concentration decreased monomer conversion and enhanced elemental release but without significant effect on cytotoxicity. Rising Sr/F-BGNPs reduced the strength of the materials. The degree of monomer conversion of VB (96%) was much higher than that of the experimental RMGICs (21-51%) and TC (28%). The highest biaxial flexural strength of experimental materials (31 MPa) was significantly lower than VB (46 MPa) (p < 0.01) but higher than TC (24 MPa). The RMGICs with 5 wt% HEMA showed higher cumulative fluoride release (137 ppm) than VB (88 ppm) (p < 0.01). Unlike VB, all experimental RMGICs showed Ca, P, and Sr release. Cell viability in the presence of extracts from experimental RMGICs (89-98%) and TC (93%) was significantly higher than for VB (4%). Experimental RMGICs showed desirable physical/mechanical properties with lower toxicity than the commercial material.

Experiences of viewing self in the mirror for men and women with dementia as perceived by their caregivers: A phenomenological study.

AIM: To explore and discuss the perceptions and experiences of caregivers who rendered care to persons with dementia who viewed themselves in the mirror. BACKGROUND: Considerations must be given to caring for those with dementia due to the steady rise of adults 65 and older living with dementia. A literature review revealed limited experiential knowledge concerning aspects of mirror-viewing for persons with dementia. METHODS: This phenomenological hermeneutic study was analyzed using Ricoeur's theory of interpretation. Eighteen participants who cared for individuals with dementia in the home, and long-term care facilities took part in the study. A semi-structured interview guide with open- ended questions facilitated an open dialogue about their experiences while caring for persons with dementia when they view themselves in the mirror. Two questions guiding the study were: 1) What are caregivers' perceptions of what they see and believe when they observe dementia patients whom they care view themselves in a mirror? 2) How do the caregivers' perceptions of that experience change over time as the dementia worsens? RESULTS: The structural analysis uncovered a considerable difference between the numbers of mirrors available in the homes as compared to the long-term care facilities. Two phenomenological findings were uncovered: 1) decision to look in the mirror and 2) viewing self in the mirror. Six subsequent subthemes; mirror as a tool, wanting to look presentable, self- recognition, self-confirmation seeing another and the latent stage were revealed. CONCLUSION: A mirror assessment is needed for individuals who have dementia.

Scoping review of trials evaluating adhesive strategies in pediatric dentistry: where do simplified strategies lie?

BACKGROUND: Adhesive restorations allow a conservative approach to caries management and are increasingly used as a restorative option in pediatric dentistry. Placement can be difficult in children because of the cooperation required for multiple bonding steps. Due to this, it is vital to assess if novel, simpler strategies have been featured in clinical trials and if clinical trials are researching the different existing adhesive strategies. METHODS: This review followed Preferred Reporting Items for Systematic Reviews and Meta-analysis adapted for Scoping Reviews (PRISMA-ScR) guidelines. PubMed/Medline, Cochrane Central, Scopus and EMBASE were used for systematic search, using free keywords and controlled search terms. Clinical trials of children requiring a restorative intervention which featured adhesive strategies were included. Only peer-reviewed trials of primary teeth restored with resin composites, published in the last 10-year period were eligible. Data charting was accomplished independently by two reviewers, and studies were summarized according to their date, type, intervention, sample size, observation period, outcomes and conclusions. Quality assessment was performed using Cochrane's Risk of Bias 2.0 tool. RESULTS: 700 potentially relevant references were found, which after a rigorous inclusion scheme, resulted in a total of 8 eligible clinical trials. Out of these, 7 were randomized clinical trials. Most trials featured a split-mouth design and the observation period ranged from 12 to 36 months. The trials evaluated interventions of two self-adhesive composites, two bulk-fill composites, two novel composites, one compomer and eight adhesives from different strategies. Most studies (4/8) included were judged to raise some concerns regarding risk of bias, while two were classified as high risk and two as low. CONCLUSION: Few studies comparing adhesive strategies were found, especially adhesives in sound substrates. The existing studies do not reflect all current approaches that could be used in pediatric dentistry. Further studies addressing bioactive composites and contemporary adhesives are necessary.

A School Nurse-Led Asthma Intervention for School-Age Children: A Randomized Control Trial to Improve Self-Management.

Asthma is a common disease in children, and obtaining basic knowledge and skills to manage asthma symptoms is critically important. This study examined the effectiveness of a theoretically based school nurse-led asthma intervention on asthma symptoms, self-management, peak flow meter usage, daily activities, and school absences in children 7-12 years old. A randomized controlled, two-group, repeated measures design was conducted in eight public schools. Data collection occurred at three time points. The treatment group had statistically significant differences in reported symptoms (p < .001), asthma control with a peak flow meter usage (p < .001), and daily activities (p < .001) at 6 weeks and at 12 weeks. Although difference in school absences was not statistically significant, the treatment group missed fewer school days than the control group. Self-management is a complex process, and school nurses can provide essential learning steps and continuity of care for school-age children living with asthma.

Sex may influence motor phenotype in a novel rodent model of cerebral palsy.

Cerebral palsy (CP) is the most common cause of childhood motor disability, manifesting most often as spasticity and/or dystonia. Spasticity and dystonia are often co-morbid clinically following severe injury at term gestation. Currently available animal CP models have not demonstrated or differentiated between these two motor phenotypes, limiting their clinical relevance. We sought to develop an animal CP model displaying objectively identifiable spasticity and dystonia. We exposed rat pups at post-natal day 7-8 (equivalent to human 37 post-conceptional weeks) to global hypoxia. Since spasticity and dystonia can be difficult to differentiate from each other in CP, objective electrophysiologic markers of motor phenotypes were assessed. Spasticity was inferred using an electrophysiologic measure of hyperreflexia: soleus Hoffman reflex suppression with 2 Hz tibial nerve stimulation. Dystonia was assessed during voluntary isometric hindlimb withdrawal at different levels of arousal by calculating tibialis anterior and triceps surae electromyographic co-activation as a surrogate of overflow muscle activity. Hypoxia affected spasticity and dystonia measures in a sex-dependent manner. Males had attenuated Hoffman reflex suppression suggestive of spasticity but no change in antagonist muscle co-activation. In contrast, females demonstrated increased co-activation suggestive of dystonia but no change in Hoffman reflex suppression. Therefore, there was an unexpected segregation of electrophysiologically-defined motor phenotypes based on sex with males predominantly demonstrating spasticity and females predominantly demonstrating dystonia. These results require human clinical confirmation but suggest that sex could play a critical role in the motor manifestations of neonatal brain injury.

A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors.

Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16-25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14-120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.

Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia.

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

The choice not to undergo genetic testing for Huntington disease: Results from the PHAROS study.

Rates of genetic testing in Huntington disease (HD) are lower than was predicted before direct DNA testing became available. Clinicians often do not have in-depth conversations with people at risk who chose not to test. We queried 733 research subjects who chose not to learn their HD gene status when enrolling in the Prospective Huntington At-Risk Observational Study, carried out between 1999 and 2008. Lack of an effective cure or treatment (66% of subjects) and inability to undo knowledge (66%) were the major reasons cited for choosing not to undergo HD DNA testing. Most subjects were not concerned about the length or burden of the testing process (61% and 59%, respectively). Subjects were optimistic that a treatment to improve symptoms or postpone onset would be developed within the next 10 years (56% and 53%, respectively), but they had less certainty about the prospects to prevent HD onset (36%). This is the first large, systematic study of why people at risk for HD choose not to undergo genetic testing. Attitudes about how people at risk for HD approach this life-altering choice should be reassessed as new treatments develop, and as clinical trials now require genetic testing at entry.

Clinical educators' skills and qualities in allied health: a systematic review.

BACKGROUND: The skills and qualities of effective clinical educators are linked to improved student learning and ultimately patient care; however, within allied health these have not yet been systematically summarised in the literature. AIMS: To identify and synthesise the skills and qualities of clinical educators in allied health and their effect on student learning and patient care. METHOD: A systematic search of the literature was conducted across five electronic databases in November 2017. Study identification, data extraction and quality appraisal were performed in duplicate. Qualitative and quantitative data were extracted separately but analysed together using a thematic analysis approach whereby items used in quantitative surveys and themes from qualitative approaches were interpreted together. RESULTS: Data revealed seven educator skills and qualities: (i) intrinsic and personal attributes of clinical educators; (ii) provision of skillful feedback; (iii) teaching skills; (iv) fostering collaborative learning; (v) understanding expectations; (vi) organisation and planning; and (vii) clinical educators in their professional role. Across all themes was the concept of taking time to perform the clinical educator role. No studies used objective measurements as to how these skills and qualities affect learning or patient care. DISCUSSION AND CONCLUSION: Despite much primary evidence of clinical educator skills and qualities, this review presents the first synthesis of this evidence in allied health. There is a need to examine clinical education from new perspectives to develop deeper understanding of how clinical educator qualities and skills influence student learning and patient care.

Assessing Executive Nurse Leaders' Financial Literacy Level: A Mixed-Methods Study.

OBJECTIVES: To evaluate the reliability and validity of the Financial Management Competency Self-assessment (FMCA) in executive nurse leaders (ENLs) and to determine how ENLs develop and apply financial knowledge. BACKGROUND: Financial literacy (FL) helps in planning, implementing, and evaluating fiscal decisions, but many ENLs report weaknesses in this core competency. METHODS: An explanatory-sequential mixed-methods study was conducted to psychometrically test the FMCA and explore how ENLs with different levels of FL develop and apply financial knowledge. Eligible participants (n = 178) were recruited from a population of ENLs across the United States. RESULTS: The test-retest reliability of the FMCA was good (mean difference, 6.80; 95% confidence interval). Correlations between domain scores (P < .01) and the overall score (Cronbach's α = .99) demonstrated the reliability and validity of the instrument. The cutoff scores were fair indicators of different levels of FL in ENLs (P < .001). Self-awareness, gaps in hospital and graduate nursing education, application of financial knowledge, and a micro versus macro view emerged as important themes in the qualitative analysis. CONCLUSION: FMCA reliability and validity were established. FMCA cutoff scores were established to determine FL level, and the ENL lived experience described in financial knowledge development and application.

The Influence of Race and Gender on Nursing Care Decisions: A Pain Management Intervention.

BACKGROUND: Understanding whether a patient's race or gender and/or the nurse's race or gender influence how nurses form care decisions can contribute to exploration of methods that can positively affect disparate treatment. AIMS: This research examined how the variables of race and gender of both the nurse and the patient influence nurses' decision making about pain management. DESIGN: A randomized four-group post-test-only experimental design was used to examine the variables and variable interactions. SETTINGS: An investigator-developed case vignette tool hosted online was used to obtain data about nursing pain management decisions. The vignette intervention was developed to simulate four exact patient scenarios that differed only by patient race and gender. Participants/Subjects: A quota sample of 400 nurses was recruited using a self-selected face-to-face recruitment technique. METHODS: A four-way between-groups analysis of variance assessed whether the gender of the nurse, race of the nurse, gender of the patient, or race of the patient made any differences in the dose intensity of pain medications selected by the nurse sample. RESULTS: No significant interactions were noted between any combinations of the four independent variables. A significant main effect was noted in medication intensity for nurse gender (F [1,384] = 9.75, p = .002). CONCLUSIONS: Data trends suggested that gender stereotypes about how patients managed pain played a role in dose intensity decisions because female patients on average were given higher doses of pain medication than male patients were by all the nurses in the study. Further research is needed in this complex area of study.

Forensic nursing science knowledge and competency: the use of simulation.

Forensic nursing is a nursing specialty that provides services to a variety of patient populations who have experienced violence, including interpersonal violence, sudden or unexpected death, and motor vehicle collisions. However, many critical care nurses have received the background knowledge or practical skills required to provide the level of care required by many forensic patients. The purpose of this study was to determine whether differences in knowledge or practical competence exist between participants using 2 different learning modalities: medium fidelity simulation versus face-to-face lecture. Participants who were enrolled in an elective online forensic nursing science course were randomly assigned to an intervention or control group. The 18 intervention group participants were given three 2-hour forensic simulation sessions in the laboratory. The 17 control group participants attended 3 face-to-face lectures covering forensic science topics. All study participants also received the same forensic course content via the online Blackboard platform. No significant differences were found between the 2 groups in either knowledge or practical competency. The lack of results may have been heavily influenced by the small sample size, which resulted in insufficient power to detect possible differences.

Hydroxyapatite, fluor-hydroxyapatite and fluorapatite produced via the sol-gel method: dissolution behaviour and biological properties after crystallisation.

Hydroxyapatite (HA), fluor-hydroxyapatite (FHA) with varying levels of fluoride ion substitution and fluorapatite (FA) were synthesised by the sol-gel method as possible implant coating or bone-grafting materials. Calcium nitrate and triethyl phosphite were used as precursors under an ethanol-water based solution. Different amounts of ammonium fluoride were incorporated for the preparation of the FHA and FA sol-gels. After heating and powdering the sol-gels, dissolution behaviour was assessed using ion chromatography to measure Ca(2+) and PO4 (3-) ion release. Biological behaviour was assessed using cellular proliferation with human osteosarcoma cells and alamarBlue™ assay. Statistical analysis was performed with a two way analysis of variance and post hoc testing with a Bonferroni correction. Increasing fluoride substitution into an apatite structure decreased the dissolution rate. Increasing the firing temperature of the HA, FHA and FA sol-gels up to 1,000 °C decreased the dissolution rate. There was significantly higher cellular proliferation on highly substituted FHA and FA than on HA or Titanium. The properties of an implant coating or bone grafting material can be tailored to meet specific requirements by altering the amount of fluoride that is incorporated into the original apatite structure. The dissolution behaviour can further be altered by the temperature at which the sol-gel is fired.

Afghanistan and Iraq war veterans' health care needs and their underuse of health care resources: implications for psychiatric-mental health nurses.

U.S. Veterans who have served in the Afghanistan and Iraq wars have combat-related medical and mental health issues, notably posttraumatic stress disorder and traumatic brain injury, but underuse health care resources. To better understand their health care needs, resource use, and facilitators and barriers to seeking health care, a literature review was conducted. The results suggest high prevalence of mental and medical health issues and disproportionate use of quantitative research design that lacked approaches to understanding the psychosocial, cultural, and contextual factors that affect help-seeking by Veterans. Strategies to increase the likelihood that Veterans will seek needed health care, gaps in the literature, and the need for further research are discussed.

Resin tags formation by modified Renewal MI formulations in a carious dentine model.

Objectives: To determine which components in a new restorative material (Renewal MI) improve its ability to form resin tags within demineralized dentine. Methods: Varied components included polylysine (PLS), monocalcium phosphate (MCP), powder to liquid ratio (PLR), 4-methacryloyloxyethyl trimellitate anhydride (4META), and polypropylene glycol dimethacrylate (PPGDMA). Urethane dimethacrylate (UDMA), containing PPGDMA (24 wt%) and 4META (3 wt%), was mixed with glass filler with MCP (8 wt%) and PLS (5 wt%). PLR was 3:1 or 5:1. Reducing MCP and/or PLS to 4 and 2 wt% respectively or fully removing MCP, PLS, 4META or PPGDMA gave 16 formulations in total. Renewal MI, Z250 (with or without Scotchbond Universal adhesive) and Activa were used as commercial comparators. Collagen discs were obtained by totally demineralizing 2 mm thick, human, premolar, coronal dentine discs by immersion in formic acid (4M) for 48 h. The restorative materials were then applied on top (n = 3), before dissolving the collagen in sodium hypochlorite (15%). SEM/EDX was employed to determine resin tags length, composition, and surface coverage. Results: Tags were >400, 20 and 200 µm and covered 62, 55 and 39% of the adhesion interface for Renewal MI, Scotchbond and Activa, respectively. With experimental formulations, they were 200 and >400 µm long with high vs. low PLR and composed primarily of polymerized monomers. Percentages of the adhesion interface covered varied between 35 and 84%. Reducing PLS or MCP caused a decline in coverage that was linear with their concentrations. Reducing MCP had lesser effect when PLS or PLR were low. Removal of 4META caused a greater reduction in coverage than PPGDMA removal. Conclusion: PLS, MCP, 4META, PPGDMA and low PLR together enhance Renewal MI tags formation in, and thereby sealing of, demineralized dentine.