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The article attempts to examine two contradictory notions of student resistance. The first being the traditional neomarxist Western understandings of student resistance such as those premised on an informal, disorganized and apolitical notion of agency. The second being the paradigm of postwar Japanese student resistance which grew from the ashes of World War II into at a series of splinter terrorist groups. A profusion of literature generated during the 1970s sought to demystify the role of educational institutions in promoting inequalities in society, by highlighting how they authenticated specific cultural and institutional provisions. Researchers refer to a general desire to analyze and interrogate the relationship between schools and their specific cultural and historical contexts, and to comprehend the roles of schools in terms of the ideological structures which they helped to sustain and reproduce. Education, for the first time was scrutinized under a series of new lens that enabled a relationship to be viewed between schooling, power and the "subject."

Objectives To develop an epirubicin-loaded, water-soluble mucoadhesive gels that have the correct rheological properties to facilitate their delivery into the bladder via a catheter, while allowing for their spread across the bladder wall with limited expansion of the bladder and increasing the retention of epirubicin in the bladder and flushing with urine. Methods Epirubicin-loaded hydroxyl ethyl cellulose ( HEC) and hydroxy propyl methyl cellulose ( HPMC) gels were manufactured and tested for their rheological properties. Their ability to be pushed through a catheter was also assessed as was their in-vitro drug release, spreading in a bladder and retention of epirubicin after flushing with simulated urine. Key findings Epirubicin drug release was viscosity-dependent. The 1 and 1.5% HEC gels and the 1, 1.5 and 2% HPMC gels had the correct viscosity to be administered through a model catheter and spread evenly across the bladder wall under the pressure of the detrusor muscle. The epirubicin-loaded gels had an increased retention time in the bladder when compared with a standard intravesical solution of epirubicin, even after successive flushes with simulated urine. Conclusion The increased retention of epirubicin in the bladder by the HEC and HPMC gels warrant further investigation, using an in-vivo model, to assess their potential for use as treatment for non-muscle-invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Background: Trial recruitment of Black, indigenous, and people of color (BIPOC) is key for interventions that interact with socioeconomic factors and cultural norms, preferences, and values. We report on our experience enrolling BIPOC participants into a multicenter trial of a shared decision-making intervention about anticoagulation to prevent strokes, in patients with atrial fibrillation (AF).Methods: We enrolled patients with AF and their clinicians in 5 healthcare systems (three academic medical centers, an urban/suburban community medical center, and a safety-net inner-city medical center) located in three states (Minnesota, Alabama, and Mississippi) in the United States. Clinical encounters were randomized to usual care with or without a shared decision-making tool about anticoagulation.Analysis: We analyzed BIPOC patient enrollment by site, categorized reasons for non-enrollment, and examined how enrollment of BIPOC patients was promoted across sites.Results: Of 2247 patients assessed, 922 were enrolled of which 147 (16%) were BIPOC patients. Eligible Black participants were significantly less likely (p < .001) to enroll (102, 11%) than trial-eligible White participants (185, 15%). The enrollment rate of BIPOC patients varied by site. The inclusion and prioritization of clinical practices that care for more BIPOC patients contributed to a higher enrollment rate into the trial. Specific efforts to reach BIPOC clinic attendees and prioritize their enrollment had lower yield.Conclusions: Best practices to optimize the enrollment of BIPOC participants into trials that examined complex and culturally sensitive interventions remain to be developed. This study suggests a high yield from enrolling BIPOC patients from practices that prioritize their care.Trial Registration: ClinicalTrials.gov (NCT02905032). [ABSTRACT FROM AUTHOR]

Drug stability and compatibility are critical factors influencing the cost and logistics of treatment delivery, therapeutic effectiveness, and patient safety. This is particularly significant in the realm of cancer chemotherapeutics, where stability and compatibility studies play a vital role in ensuring rational and safe medicine administration. Oxaliplatin, fluorouracil, and irinotecan, commonly used in various combinations for gastrointestinal cancers, are complemented by co-administration of folinic acid in certain protocols. Notably, some folinic acid preparations include trometamol as an excipient, potentially impacting the stability of the chemotherapeutic agents if infused concomitantly. This study seeks to establish guidelines for oncology multidisciplinary teams, addressing potential risks associated with the combination of trometamol-containing folinic acid and chemotherapeutics. To achieve this, a quantitative questionnaire was distributed to members of the British Oncology Pharmacy Association (BOPA) and non-BOPA members through an online survey. Nineteen healthcare professionals with oncology experience, comprising 18 pharmacists and one nurse, completed the questionnaires. Each participant rated the validity and clarity of statements on a 5-point scale. The Delphi process concluded after the fourth round, consolidating the findings and recommendations from the multidisciplinary team. Twelve recommendations for safe practice have been made. [ABSTRACT FROM AUTHOR]

Background Conventional itraconazole (CI) absorption from capsules even under fed conditions is suboptimal (~55%), let alone when fasted. SUBA-itraconazole (SI) is ~1.8x's more bioavailable than CI at steady-state in a fed condition. There are, however, no data comparing these formulations under a fasted state. A single-dose PK study was performed comparing bioavailability of 65mg SI to 100mg CI under fasted or fed conditions. Methods This was an open-label, single-dose, randomized, four-period, four-treatment, four-sequence, crossover bioequivalence study under fasted and fed conditions in healthy adults. Subjects were administered a single dose of SI (1 × 65 mg) and CI (1 × 100 mg). Under fasted condition, subjects were administered SI or CI following an overnight fast of at least 10 hours. Subjects under fed condition were administered SI or CI after 30 minutes of consuming a standardized high fat breakfast preceded by an overnight fast of at least 10 hours. After dosing, all subjects fasted for at least 4 hours post-dose in all periods. Blood samples were collected prior to dosing and then from 1 to 120 hours. Analysis of itraconazole (IZ) and hydoxyitraconazole (HIZ) serum levels was by least-squares-geometric means of PK parameters. Results Under fasted condition, Cmax and AUCtau of IZ for SI were substantially higher compared with CI (Table, Figure 1). Under fed conditions, however, the Cmax and AUCtau of IZ for SI was 20% and 10% lower, respectively (table, Figure 2). Similar results were found for HIZ. The Tmax for IZ and HIZ of SI and CI were similar under a fasted condition but extended by over 2 hours for SI vs. CI under fed conditions. Study drugs were well-tolerated under fasted and fed conditions. All TEAEs were mild and resolved at the end of the study. Fifty of 52 subjects enrolled completed the study. Two subjects did not complete the study due to not being able to finish a high fat meal and noncompliance. No SAEs were reported. Conclusion Total and peak IZ/HIZ exposure was substantially higher for SI under fasted conditions compared with CI, but slightly lower under fed conditions with similar safety profiles. This study demonstrates the unique nature of the SI formulation compared with CI under fasted conditions and may lead to less variability if patients are not adherent to dietary requirements when taking itraconazole. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background: Shared decision making (SDM) implementation remains challenging. The factors that promote or hinder implementation of SDM tools for use during the consultation, including contextual factors such as clinician burnout and organizational support, remain unclear. We explored these factors in the context of a practical multicenter randomized trial evaluating the effectiveness of an SDM conversation tool for patients with atrial fibrillation considering anticoagulation therapy.Methods: In this cross-sectional study, we recruited clinicians who were regularly involved in conversations with patients regarding anticoagulation for atrial fibrillation. Clinicians reported their characteristics and burnout symptoms using the two-item Maslach Burnout Inventory. Clinicians were trained in using the SDM tool, and they recorded their perceptions of the tool's normalization potential using the Normalization MeAsure Development (NoMAD) survey instrument and verbally reflected on their answers to these survey questions. When possible, the training sessions and clinicians' verbal responses to the conversation tool were recorded.Results: Our study comprised 183 clinicians recruited into the trial (168 with survey responses and 112 with recordings). Overall, clinicians gave high scores to the normalization potential of the intervention; they endorsed all domains of normalization to the same extent, regardless of site, clinician characteristics, or burnout ratings. In interviews, clinicians paid significant attention to making sense of the tool. Tool buy-in seemed to depend heavily on their ability to see the tool as accurate and "evidence-based" and their perceptions of having time in the consultation to use it.Conclusions: While time in the consultation remains a barrier, we did not find a significant association between burnout symptoms and normalization of an SDM conversation tool. Possible areas for improving the normalization of SDM conversation tools in clinical practice include enabling collaboration among clinicians to implement the tool and reporting how clinicians elsewhere use the tool. Direct measures of normalization (i.e., observing how often clinicians access the tool in practice outside of the clinical trial) may further elucidate the role that contextual factors, such as clinician burnout, play in the implementation of SDM.Trial Registration: ClinicalTrials.gov, NCT02905032. Registered on 9 September 2016. [ABSTRACT FROM AUTHOR]

This paper provides three case studies of initiatives developed to improve educational opportunities in vulnerable urban communities. The cities in the three countries involved, Australia, the United States, and Spain, are different in many ways; however, each has persistent and entrenched inequalities between the educational opportunities and outcomes of historically marginalised students and their mainstream counterparts. Here, we focus on conceptualising and describing urban examples of poverty from three different countries, and reporting on programs and strategies aimed at enhancing the quality of teaching in schools in high-poverty areas. By providing and comparing the three cases, we aim to contribute to broader understandings of poverty in three locations and how teachers and schools in high-poverty urban settings can re-think their practices. [ABSTRACT FROM AUTHOR]

Purpose: This study highlights Warning Letter (WL) findings issued to sponsorinvestigators (S-Is) by the Food and Drug Administration (FDA). Methods: The online index of WLs issued from October 1, 2007 through September 30, 2012 was reviewed [1]. Through a manual screening process, letters were evaluated if specifically issued to 'clinical investigators', 'sponsors' or 'sponsor-investigators'. A particular focus was given to S-Is at Academic Health Centres (AHCs). Each letter was scored for the presence of violations in 40 general regulatory categories. Results: A review of FDA WLs issued over a five-year period (FDA Fiscal Years 2008-2012) revealed that WLs to S-Is represent half of the WLs issued to all sponsors (16 of 32 letters). A review of these letters indicates that S-Is are not aware of, or simply do not meet, their regulatory responsibilities as either investigators or sponsors. In comparing total sponsor letters to those of S-Is, the most cited violation was the same: a lack of monitoring. A review of publicly available inspection data indicates that these 16 letters merely represent the tip of the iceberg. Conclusion: This review of the WL database reveals the potential for serious regulatory violations among S-Is at AHCs. Recent translational funding initiatives may serve to increase the number of S-Is, especially among Academic Health Centres (AHCs) [2]; thus, AHCs must become aware of this S-I role and work to support investigators who assume both roles in the course of their research. [ABSTRACT FROM AUTHOR]

First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity. [ABSTRACT FROM AUTHOR]

We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. [ABSTRACT FROM AUTHOR]

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression. [ABSTRACT FROM AUTHOR]

In Asian epidemiological studies, health benefits, including reduced incidence of breast and prostate cancers, are attributed to soy food and isoflavone consumption. The recent increased intake of soy foods and supplements in the American diet has raised concerns about the possible estrogen-like effects of natural isoflavones and possible promotion or propagation of estrogen-sensitive cancers. These concerns are primarily based on in vitro and rodent data which suggest that genistein aglycone can stimulate tumor cell proliferation and growth in mice having deficient immune systems. In contrast, a recent nested case-control study and meta-analysis of numerous epidemiological studies show an inverse correlation between genistein intake and breast cancer risk. Furthermore, clinical studies in osteopenic and osteoporotic, postmenopausal women support the breast and uterine safety of purified naturally derived genistein administered for up to 3 years. In this review, we summarize the in vitro, preclinical and clinical evidence for the safety of natural genistein. [ABSTRACT FROM AUTHOR]

Abstract: Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P ≤ .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups. [Copyright &y& Elsevier]

Abstract: We used a propagation-defective, single-cycle, alphavirus replicon vector system to produce virus-like replicon particles (VRP) expressing the hemagglutinin (HA) and neuraminidase (NA) proteins from influenza A/Wyoming/03/2003 (H3N2). Efficient production methods were scaled to produce pilot lots of HA VRP and NA VRP and clinical lots of HA VRP. HA VRP-induced high-titered antibody responses in mice, rabbits and rhesus macaques, as measured by ELISA or hemagglutination inhibition (HI) assays, and robust cellular immune responses in mice and rhesus macaques, as measured by IFN-γ ELISPOT. NA VRP also induced cellular immune responses in mice. A toxicology study with HA VRP and NA VRP in rabbits showed no adverse effects in any parameter. These studies support clinical testing of alphavirus replicon vaccines for influenza. [Copyright &y& Elsevier]

Abstract: We used a replication-incompetent, single-cycle, alphavirus replicon vector system to produce virus-like replicon particles (VRP) expressing the extracellular domain of human cytomegalovirus (CMV) glycoprotein B or a pp65/IE1 fusion protein. Efficient production methods were scaled to produce pilot lots and clinical lots of each alphavirus replicon vaccine component. The vaccine induced high-titered antibody responses in mice and rabbits, as measured by ELISA and CMV neutralization assays, and robust T-cell responses in mice, as measured by IFN-γ ELISPOT assay. A toxicity study in rabbits showed no adverse effects in any toxicology parameter. These studies support clinical testing of this novel CMV alphavirus replicon vaccine in humans. [Copyright &y& Elsevier]

In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward's hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed (p = 0.998). For HC, no significant classes were found (p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (β), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes (p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07-0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients., (© 2024. The Author(s).)

Purpose: Public health measures instituted at the onset of the COVID-19 pandemic in the UK in 2020 had profound effects on the cancer patient pathway. We hypothesise that this may have affected analgesic prescriptions for cancer patients in primary care., Methods: A whole-nation retrospective, observational study of opioid and antineuropathic analgesics prescribed in primary care for two cohorts of cancer patients in Wales, using linked anonymised data to evaluate the impact of the pandemic and variation between different demographic backgrounds., Results: We found a significant increase in strong opioid prescriptions during the pandemic for patients within their first 12 months of diagnosis with a common cancer (incidence rate ratio (IRR) 1.15, 95% CI: 1.12-1.18, p < 0.001 for strong opioids) and significant increases in strong opioid and antineuropathic prescriptions for patients in the last 3 months prior to a cancer-related death (IRR = 1.06, 95% CI: 1.04-1.07, p < 0.001 for strong opioids; IRR = 1.11, 95% CI: 1.08-1.14, p < 0.001 for antineuropathics). A spike in opioid prescriptions for patients diagnosed in Q2 2020 and those who died in Q2 2020 was observed and interpreted as stockpiling. More analgesics were prescribed in more deprived quintiles. This differential was less pronounced in patients towards the end of life, which we attribute to closer professional supervision., Conclusions: We demonstrate significant changes to community analgesic prescriptions for cancer patients related to the UK pandemic and illustrate prescription patterns linked to patients' demographic background., (© 2023. The Author(s).)

It is unclear how medication use evolved before diagnosis of dementia (DoD). This study aims to identify varied patterns of polypharmacy before DoD, their prevalence and possible complications. We collected primary care e-health records for 33,451 dementia patients in Wales from 1990 to 2015. The medication uses in every 5-year period along with 20-years prior to dementia diagnosis were considered. Exploratory factor analysis was used to identify clusters of medicines for every 5-year period. The prevalence of patients taking three or more medications was 82.16%, 69.7%, 41.1% and 5.5% in the Period 1 (0-5 years before DoD) ~ Period 4 (16-20 years before DoD) respectively. The Period 1 showed 3 clusters of polypharmacy - medicines for respiratory/urinary infections, arthropathies and rheumatism, and cardio-vascular disease (CVD) (66.55%); medicines for infections, arthropathies and rheumatism (AR), cardio-metabolic disease (CMD) and depression (22.02%); and medicines for arthropathies, rheumatism and osteoarthritis (2.6%). The Period 2 showed 4 clusters of polypharmacy - medicines for infections, arthropathies, and CVD (69.7%); medicines for CVD and depression (3%); medicines for CMD and arthropathies (0.3%); and medicines for AR, and CVD (2,5%). The Period 3 showed 6 clusters of polypharmacy - medicines for infections, arthropathies, and CVD (41.1%); medicines for CVD, acute-respiratory-infection (ARI), and arthropathies (1.25%); medicines for AR (1.16%); medicines for depression, anxiety (0.06%); medicines for CMD (1.4%); and medicines for dermatologic disorders (0.9%). The Period 4 showed 3 main clusters of polypharmacy - medicines for infections, arthropathy, and CVD (5.5%); medicines for anxiety, ARI (2.4%); and medicines for ARI and CVD (2.1%). As the development towards dementia progressed, the associative diseases tended to cluster with a larger prevalence in each cluster. Farther away before DoD, the clusters of polypharmacy tended to be clearly distinct between each other, resulting in an increasing number of patterns, but in a smaller prevalence., (copyright: © 2022 Longo et al.)

The inclusion of machine-learning-derived models in systematic reviews of risk prediction models for colorectal cancer is rare. Whilst such reviews have highlighted methodological issues and limited performance of the models included, it is unclear why machine-learning-derived models are absent and whether such models suffer similar methodological problems. This scoping review aims to identify machine-learning models, assess their methodology, and compare their performance with that found in previous reviews. A literature search of four databases was performed for colorectal cancer prediction and prognosis model publications that included at least one machine-learning model. A total of 14 publications were identified for inclusion in the scoping review. Data was extracted using an adapted CHARM checklist against which the models were benchmarked. The review found similar methodological problems with machine-learning models to that observed in systematic reviews for non-machine-learning models, although model performance was better. The inclusion of machine-learning models in systematic reviews is required, as they offer improved performance despite similar methodological omissions; however, to achieve this the methodological issues that affect many prediction models need to be addressed.

Objectives: To estimate the level of contamination in an encounter-randomized trial evaluating a shared decision-making (SDM) tool., Study Design and Setting: We assessed contamination at three levels: (1) tool contamination (whether the tool was physically present in the usual care encounter), (2) functional contamination (whether components of the SDM tool were recreated in the usual care encounters without directly accessing the tool), and (3) learned contamination (whether clinicians "got better at SDM" in the usual care encounters as assessed by the OPTION-12 score). For functional and learned contamination, the interaction with the number of exposures to the tool was assessed., Results: We recorded and analyzed 830 of 922 randomized encounters. Of the 411 recorded encounters randomized to usual care, the SDM tool was used in nine (2.2%) encounters. Clinicians discussed at least one patient-important issue in 377 usual care encounters (92%) and the risk of stroke in 214 encounters (52%). We found no significant interaction between number of times the SDM tool was used and subsequent functional or learned contamination., Conclusion: Despite randomly assigning clinicians to use an SDM tool in some and not other encounters, we found no evidence of contamination in usual care encounters., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background Guidelines promote shared decision-making (SDM) for anticoagulation in patients with atrial fibrillation. We recently showed that adding a within-encounter SDM tool to usual care (UC) increases patient involvement in decision-making and clinician satisfaction, without affecting encounter length. We aimed to estimate the extent to which use of an SDM tool changed adherence to the decided care plan and clinical safety end points. Methods and Results We conducted a multicenter, encounter-level, randomized trial assessing the efficacy of UC with versus without an SDM conversation tool for use during the clinical encounter (Anticoagulation Choice) in patients with nonvalvular atrial fibrillation considering starting or reviewing anticoagulation treatment. We conducted a chart and pharmacy review, blinded to randomization status, at 10 months after enrollment to assess primary adherence (proportion of patients who were prescribed an anticoagulant who filled their first prescription) and secondary adherence (estimated using the proportion of days for which treatment was supplied and filled for direct oral anticoagulant, and as time in therapeutic range for warfarin). We also noted any strokes, transient ischemic attacks, major bleeding, or deaths as safety end points. We enrolled 922 evaluable patient encounters (Anticoagulation Choice=463, and UC=459), of which 814 (88%) had pharmacy and clinical follow-up. We found no differences between arms in either primary adherence (78% of patients in the SDM arm filled their first prescription versus 81% in UC arm) or secondary adherence to anticoagulation (percentage days covered of the direct oral anticoagulant was 74.1% in SDM versus 71.6% in UC; time in therapeutic range for warfarin was 66.6% in SDM versus 64.4% in UC). Safety outcomes, mostly bleeds, occurred in 13% of participants in the SDM arm and 14% in the UC arm. Conclusions In this large, randomized trial comparing UC with a tool to promote SDM against UC alone, we found no significant differences between arms in primary or secondary adherence to anticoagulation or in clinical safety outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: clinicaltrials.gov. Identifier: NCT02905032.

Conventional itraconazole (C-ITZ) suffers from absorption variability. SUBA-itraconazole (S-ITZ) is more bioavailable than C-ITZ at steady state in a fed condition, but there are no data comparing the two under a fasted state. An open-label, single-dose, randomized, bioequivalence study was performed comparing S-ITZ to C-ITZ capsules under fasted and fed conditions in healthy adults measuring itraconazole and hydroxyitraconazole plasma levels. This study demonstrated less variability of S-ITZ compared to C-ITZ capsules under fasted conditions.

Importance: Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear., Objective: To assess the extent to which the use of an SDM tool affects the quality of SDM and anticoagulant treatment decisions in at-risk patients with AF., Design, Setting, and Participants: This encounter-randomized trial recruited patients with nonvalvular AF who were considering starting or reviewing anticoagulant treatment and their clinicians at academic, community, and safety-net medical centers between January 30, 2017 and June 27, 2019. Encounters were randomized to either the standard care arm or care that included the use of an SDM tool (intervention arm). Data were analyzed from August 1 to November 30, 2019., Interventions: Standard care or care using the Anticoagulation Choice Shared Decision Making tool (which presents individualized risk estimates and compares anticoagulant treatment options across issues of importance to patients) during the clinical encounter., Main Outcomes and Measures: Quality of SDM (which included quality of communication, patient knowledge about AF and anticoagulant treatment, accuracy of patient estimates of their own stroke risk [within 30% of their estimate], decisional conflict, and satisfaction), decisions made during the encounter, duration of the encounter, and clinician involvement of patients in the SDM process., Results: The clinical trial enrolled 922 patients (559 men [60.6%]; mean [SD] age, 71 [11] years) and 244 clinicians. A total of 463 patients were randomized to the intervention arm and 459 patients to the standard care arm. Participants in both arms reported high communication quality, high knowledge, and low decisional conflict, demonstrated low accuracy in their risk perception, and would similarly recommend the approach used in their encounter. Clinicians were significantly more satisfied after intervention encounters (400 of 453 encounters [88.3%] vs 277 of 448 encounters [61.8%]; adjusted relative risk, 1.49; 95% CI, 1.42-1.53). A total of 747 of 873 patients (85.6%) chose to start or continue receiving an anticoagulant medication. Patient involvement in decision-making (as assessed through video recordings of the encounters using the Observing Patient Involvement in Decision Making 12-item scale) scores were significantly higher in the intervention arm (mean [SD] score, 33.0 [10.8] points vs 29.1 [13.1] points, respectively; adjusted mean difference, 4.2 points; 95% CI, 2.8-5.6 points). No significant between-arm difference was found in encounter duration (mean [SD] duration, 32 [16] minutes in the intervention arm vs 31 [17] minutes in the standard care arm; adjusted mean between-arm difference, 1.1; 95% CI, -0.3 to 2.5 minutes)., Conclusion and Relevance: The use of an SDM encounter tool improved several measures of SDM quality and clinician satisfaction, with no significant effect on treatment decisions or encounter duration. These results help to calibrate expectations about the value of implementing SDM tools in the care of patients with AF., Trial Registration: ClinicalTrials.gov Identifier: NCT02905032.

Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered three times daily for 3 days and once on day 4 ( n  = 15). For the steady-state administration study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered twice daily for 14 days and a last dose was administered 30 min after a meal on day 15 ( n  = 16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares geometric means were used to compare the maximum peak concentration of drug after administration at steady state prior to administration of the subsequent dose ( C max&#95;ss ), the minimum drug level after administration prior to the subsequent dose ( C trough ), and the area under the curve over the dosing interval (AUC tau ) of each formulation. The ratios of itraconazole (ITZ) and OH-ITZ for S-ITZ to C-ITZ were between 107% and 118% in both studies for C max&#95;ss , C trough , and AUC tau , which were within the U.S. FDA-required bioequivalence range of 80% to 125%. At the end of the steady-state administration study, 13 of 16 volunteers obtained higher mean ITZ blood C trough levels of >1,000 ng/ml when they were administered S-ITZ (81%) than when they were administered C-ITZ (44%). The study drugs were well tolerated in both studies, with similar adverse events (AEs). All treatment-emergent AEs resolved after study completion. One volunteer receiving C-ITZ discontinued due to a treatment-unrelated AE in the steady-state administration study. No serious AEs were reported. Total, trough, and peak ITZ and OH-ITZ exposures were similar between the two formulations. Therefore, SUBA-ITZ, which has 35% less drug than C-ITZ, was bioequivalent to C-ITZ in healthy adult volunteers and exhibited a safety profile similar to that of C-ITZ., (Copyright © 2020 Thompson et al.)

Patient-centered care requires that treatments respond to the problematic situation of each patient in a manner that makes intellectual, emotional, and practical sense, an achievement that requires shared decision making (SDM). To implement SDM in practice, tools-sometimes called conversation aids or decision aids-are prepared by collating, curating, and presenting high-quality, comprehensive, and up-to-date evidence. Yet, the literature offers limited guidance for how to make evidence support SDM. Herein, we describe our approach and the challenges encountered during the development of Anticoagulation Choice, a conversation aid to help patients with atrial fibrillation and their clinicians jointly consider the risk of thromboembolic stroke and decide whether and how to respond to this risk with anticoagulation., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Medical foods in the United States, and foods for special medical purposes in other countries, are food formulations used to manage specific chronic diseases or conditions under medical or physician supervision. The process of reviewing and approving food claims for health benefits varies widely from country to country., Recent Findings: CODEX Alimentarius, a 187-country and one-member (European Union) organization, has standardized not only nutrition labeling and food safety worldwide but has also recently taken on a prominent role in analyzing therapeutic and health claims for food in member countries by providing a framework to study these issues. Two recent activities at CODEX - analyzing foods for special dietary uses and foods for special medical purposes therapeutic food claims - have focused on both how these food categories are formulated for patients with specific conditions and diseases., Summary: Food and specially formulated foods can play a role in preventing or mitigating disease and other health-related conditions. This article will examine the means by which regulatory authorities across the globe address health claims for foods and food-derived products to alter human physiology and disease outcome.

Background: Oral immunotherapy (OIT) is an investigational therapeutic approach for the treatment of food allergies. Characterization of the drug product used in oral immunotherapy trials for peanut allergy has not been reported., Objective: To quantify relative amounts of the major peanut allergens and microbial load present in peanut flour used in OIT trials and assess whether these parameters change over a 12-month period. We also anticipate that this report will serve as a guide for investigators seeking to conduct OIT trials under Food and Drug Administration-approved Investigational New Drug applications., Methods: Densitometric scanning of Ara h 1 and Ara h 2 resolved on SDS-PAGE gels was used to assess allergen content in peanut flour extracts. Microbial testing was conducted on peanut flour under US Pharmacopeia guidelines for the presence of Escherichia coli, salmonella, yeast, mold, and total aerobic bacteria. In addition, aflatoxin was quantified in peanut flour. Reported results were obtained from 4 unique lots of peanut flour., Results: Relative amounts of the major peanut allergens were similar between different lots of peanut flour and remained stable over a 12-month period. E coli and salmonella were absent from all lots of flour. Yeast, mold, total aerobic bacteria, and aflatoxin were within established US Pharmacopeia guidelines on all lots tested and remained within the criteria over a 12-month period., Conclusions: Peanut flour used as a drug product contains the major peanut allergens and has low levels of potentially harmful microbes. Both these parameters remain stable over a 12-month period., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Ideal therapeutics have low toxicity and can effectively manage condition(s) or disease(s). The Food & Drug Administration (FDA) marketing category of therapeutics called “medical foods” (MFs) meets such a definition. Medical foods have existed in Federal law since passage the Orphan Drug Act in 1988, which created a category of nutritional therapeutics separate from drugs. Unfortunately, MFs are not widely understood by the medical community or utilized in all patients who need them due to lack of a FDA-approval process, unclear and contradictory guidance especially with regard for need for an investigational new drug (IND) application, and no clear regulations regarding their development and marketing. The goals of this article are to propose “Best Practices” to guide the medical food industry in the development and marketing of products as well as to serve as a starting point for suggestions regarding further FDA regulation so that therapeutics which are shown to be generally recognized as safe (GRAS), provide food ingredients to meet a distinctive nutritional requirement for a specific condition/disease and are proven effective for the management for that condition/disease can be used to benefit patients who need them.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.