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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, acuterespiratory-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article brings together a number of key issues that emerge in research around the problem of teacher shortages in hard-to-staff schools. It offers a broad overview of the hard-to-staff schooling sector as discussed in recent academic literature and provides a context-specific overview of the literature around workforce shortages in hard-to-staff schools with relevancy for high poverty contexts. In line with Williams et al. (2022) position on "Local Strategies, Global Inspiration," this paper focuses on the problem of teacher shortages in hard-to-staff schools in Australia while looking to both Australian and broader Anglosphere literature (p.120) to reconsider responses to teacher recruitment and retention. The paper begins with a survey of the current state of this issue of workforce shortages in hard-to-staff schools in Australia. Turning our attention to literature from both Australia and Anglosphere countries, the summary then focuses on the specific initiatives and mechanisms employed for recruiting and retaining teachers in hard-to-staff schools, particularly the organisational contributions of Initial Teacher Education that support recruitment into hard-to-staff schools. The article concludes by highlighting limitations and critiques of hard-to-staff initiatives in the literature to inform policy and organisational considerations when addressing the issue of teacher shortages going forward. [ABSTRACT FROM AUTHOR]

This paper describes the aims, origins and principles of the Australian National Exceptional Teaching for Disadvantaged Schools programme and reflects on findings from its first eight years. As a well-established, mainstream university-based initial teacher-education programme designed to prepare social justice teachers for low socio-economic or high-poverty schools, NETDS has had significant impact on recruiting and retaining high-performing teachers in the schools that need them most. In this paper we discuss how it works, but also outline some of the complexities that arose in trying to design a teacher-education programme with equity at the centre and some of the changes we made along the way. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the working lives of three Australian teachers in the hardest-to-staff schools as they tell their stories of how teacher attrition has impacted them and others. Drawing on Zavelevsky & Shapira-Lishchinsky's ecological framework (2020) we analyse their work-stories to better understand issues impacting the teaching workforce in a time of extreme teaching shortages. Part of a larger study on teachers who remain in hard-to-staff schools, here we focus not only on the challenges facing the education workforce but also on the insights that may lead to better strategies to retain teachers in the schools that need them most. [ABSTRACT FROM AUTHOR]

Dementia and cognitive impairment have become the major concerns worldwide due to a significantly aging population, increasing life span and lack of effective pharmacotherapy. In light of limited pharmaceutical drug choices and the socioeconomic implications of these conditions, the search for safe and effective alternatives from natural sources has gained many attractions within the medical food and dietary supplement industry. Two polyphenol extracts derived from roots of Scutellaria baicalensis and heartwoods of Acacia catechu containing free-B-ring flavonoids and flavans, respectively, were combined into a proprietary blend called UP326. A similar bioflavonoid composition, UP446, has been reported with modulation of pathways related to systemic inflammation. To test the effect of UP326 on memory and learning, a radial arm water maze (RAWM) and contextual fear conditioning (CF) were utilized in aged F344 rats fed with UP326 at doses of 3, 7, and 34 mg/kg for 11 weeks. The 7 and 34 mg/kg dosage groups had significantly fewer errors than aged vehicle control animals and their performance was equivalent to young animal controls. In a separate human clinical trial, test subjects orally given 300 mg of UP326 BID for 30 days showed marked improvement in speed and accuracy of processing complex information in computer tasks and reduced their standard deviation of performance compared to baseline and the placebo group. This data suggest that UP326 may help maintain memory, sustain speed of processing, and reduce the number or memory errors as we age. [ABSTRACT FROM AUTHOR]

While teaching is largely a White, middle-class profession, some teachers, including White teachers, come from low socio-economic backgrounds. This paper examines how one working-class pre-service teacher in Australia experiences studying in a predominantly middle-class teacher-education program. Drawing on the work of Bourdieu, this paper seeks to explore what we can learn from the reflections of a female pre-service teacher who is a member of this much smaller group of working-class teachers and who brings to her teaching the habitus and life history that aligns with many of her students and the low socio-economic communities in which she teaches. [ABSTRACT FROM AUTHOR]

Oral immunoglobulin (Ig) preparations are prime examples of medicinal nutrition from natural sources. Plasma products containing Ig have been used for decades in animal feed for intestinal disorders to mitigate the damaging effects of early weaning. These preparations reduce overall mortality and increase feed utilization in various animal species leading to improved growth. Oral administration of Ig preparations from human serum as well as bovine colostrum and serum have been tested and proven to be safe as well as effective in human clinical trials for a variety of enteric microbial infections and other conditions which cause diarrhea. In infants, children, and adults, the amount of intact IgG recovered in stool ranges from trace amounts up to 25% of the original amount ingested. It is generally understood that IgG can only bind to antigens within the GI tract if the Fab structure is intact and has not been completely denatured through acidic pH or digestive proteolytic enzymes. This is a comprehensive review of human studies regarding the survivability of orally-administered Ig preparations, with a focus on IgG. This review also highlights various biochemical studies on IgG which potentially explain which structural elements are responsible for increased stability against digestion. [ABSTRACT FROM AUTHOR]

A variety of human disease conditions are associated with chronic intestinal disorders or enteropathies that are characterized by intestinal inflammation, increased gut permeability, and reduced capacity to absorb nutrients. Such disruptions in the homeostasis of the gastrointestinal (GI) tract can lead to symptoms of abdominal pain and discomfort, bloating, abnormal bowel function, and malabsorption of nutrients. While significant advances have been made in understanding the factors that influence the complex and fragile balance between the gut microbiota, intestinal epithelial cell integrity, and the underlying immune system, effective therapies for restoring intestinal balance during enteropathy are still not available. Numerous studies have demonstrated the ability of oral immunoglobulins to improve weight gain, support gut barrier function, and reduce the severity of enteropathy in animals. More recently, studies in humans provide evidence that serum-derived bovine immunoglobulin/protein isolate is safe and improves nutritional status and GI symptoms in patients with enteropathy associated with irritable bowel syndrome or infection with the human immunodeficiency virus. This review summarizes studies showing the impact of enteropathy on nutritional status and how specially formulated bovine immunoglobulins may help restore intestinal homeostasis and nutritional status in patients with specific enteropathies. Such protein preparations may provide distinct nutritional support required for the dietary management of patients who, because of therapeutic or chronic medical needs, have limited or impaired capacity to digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or other special medically determined nutrient requirements that cannot be satisfied by changes to the normal diet alone. [ABSTRACT FROM AUTHOR]

AIM: Chronic diarrhea with fecal incontinence (FI) is a severe, underreported, and intractable problem in many patients for which limited pharmaceutical options exist. METHODS: A retrospective case history was collected after the administration of a prescription medical food composed of serum-derived bovine immunoglobulin/protein isolate (SBI) at 5 g once daily in a patient with chronic mesenteric ischemia (CMI) for chronic loose, frequent, and urgent stools. The patient was an 84-year-old white male with a 20-year history of progressively worsening chronic diarrhea with six to eight watery stools per day (Bristol Stool Form Scale, Type 7), urgency, nocturnal diarrhea, FI, and postprandial abdominal discomfort before administration of SBI. RESULTS: After four weeks of SBI administration, the patient had two to three soft, semi-formed stools (Bristol Stool Form Scale, Types 4 and 5) per day with no nocturnal diarrhea, urgency, or FI, as well as full resolution of abdominal discomfort. In addition, the patient expressed an enhanced quality of life (QoL): able to travel, attend social events, and perform tasks not possible before therapy. CONCLUSION: This case underscores how a safe, nutritional therapy may offer a new modality for physicians to address chronic loose, frequent stools with FI in patients with CMI in this difficult to manage gastrointestinal population. [ABSTRACT FROM AUTHOR]

An FDA-regulated, prescription medical food (Fosteum; 27 mg natural genistein, 200IU cholecalciferol, 20 mg citrated zinc bisglycinate (4 mg elemental zinc) per capsule) and an over-the-counter (OTC) supplement (Citracal Plus Bone Density Builder; 27 mg synthetic genistein, 600 mg elemental calcium (calcium citrate), 400 IU vitamin D3, 50 mg magnesium, 7.5 mg zinc, 1 mg copper, µg 75 molybdenum, 250 µg boron per two tablets) were compared to a clinically proven bone formulation (27 mg natural genistein, 400 IU cholecalciferol, 500 mg elemental calcium (calcium carbonate) per tablet; the Squadrito formulation) in an 8-day steady-state pharmacokinetic (PK) study of healthy postmenopausal women (n = 30) randomized to receive 54 mg of genistein per day. Trough serum samples were obtained before the final dose on the morning of the ninth day followed by sampling at 1,2,4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hrs. Total serum genistein, after ß-glucuronidase/sulfatase digestion, was measured by time-resolved fluorometric assay. Maximal time (Tmax), concentration (Cmax), half-life (T1/2), and area under the curve (AUC) were determined for genistein in each formulation. Fosteum and the Squadrito study formulation were equivalent for genistein Tmax (2 hrs), Cmax (0.7 µM), T1/2 (18±6.9 versus 21 ± 4.9 hrs), and AUC (9221 ± 413 versus 9818± 1370 ng-hr/mL). The OTC supplement's synthetically derived genistein, however, showed altered Tmax (6 hrs), Cmax (0.57 µM), T1/2 (8.3 ± 1.9 hrs), and AUC (6474 ± 287 ng-hr/mL). Differences in uptake may be due to multiple ingredients in the OTC supplement which interfere with genistein absorption. [ABSTRACT FROM AUTHOR]

Australia has a long and sometimes turbulent relationship with the migrant Other. This paper examines a component of this relationship via the window of contemporary multicultural policy. The paper begins with an analysis of the political and social conditions that enabled a national and bipartisan policy of multiculturalism to emerge as formalised federal policy during the late 1960s and early 1970s. The paper re-problematises the influences that helped shape Australia's articulation of race and ethnicity and argues that multiculturalism, within a post-September 11 environment, can no longer be framed solely within its traditional framework of social justice. The paper positions education for sustainable development (ESD) as an emerging discursive field that provides educators with an alternative road map for critiquing Australia's fluid relationship with the migrant Other. By linking the tenets of multiculturalism with ESD, this paper suggests pre-service teacher educators are presented with a productive, and at the same time politically palatable, means for regaining pedagogical traction for a semi-dormant agenda of social inclusion. [ABSTRACT FROM AUTHOR]

The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA2) (IC50 = 60µg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC50 = 12.3) and COX-2 (IC50 = 11.3µg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC50 = 110µg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC50 = 38µg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS). [ABSTRACT FROM AUTHOR]

A combined extract containing primarily baicalin from Scutellaria baicalensis and (+ )-catechin from Acacia catechu used in both joint supplements and a prescription medical food was tested for safety. Cytotoxicity testing in THP-1 monocytes showed limited cell death compared to nonsteroidal anti-inflammatory drugs (NSAIDs). Acute and subchronic toxicity testing demonstrated no abnormalities in any toxicological end points examined including animal body weights, gross organ pathology and tissue histology, and blood chemistries or serology. The extract, when dosed in Fischer 344 rats, a model for gastric toxicity of NSAIDs, showed no evidence of ulceration. No mutagenicity or drug interactions were seen by AMES and cytochrome P450 enzyme inhibition, respectively. When the extract was compared with placebo after administration to a healthy human population, no changes in blood chemistry or serology were observed. Based on these findings, the combined extract with baicalin and catechin appears to possess a safety profile that justifies further testing in humans. PRACTICAL APPLICATIONS A specific ratio of Scutellaria baicalensis and Acacia catechu metabolically balances the inhibition of cyclooxygenase-1 and cyclooxygenase-2 (COX-2) enzymes and provides a comparable amount of 5-lipoxygenase (5-LOX) enzyme inhibition in the conversion of arachidonic acid (AA) to inflammatory metabolites. This mechanism of action may yield fewer side effects than traditional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors produced by their generally specific inhibition of either COX enzyme. Simultaneous inhibition of 5-LOX may also avoid a “shunt” of arachidonic acid metabolism down the LOX pathway, thus reducing side effects related to excess, unopposed production of inflammatory vasoconstrictive as well as chemoattractive leukotrienes. The net result should be an effective anti-inflammatory metabolic product for the management of osteoarthritis with an improved toxicity profile and lower requirement for use with gastroprotective therapies. [ABSTRACT FROM AUTHOR]

This article serves as a provocation to researchers to refuse the apparent 'safety' of the objective and a-political, and to continue to work on the 'how-to' of culturally sensitive research. This provocation works by means of an investigation into the uses to which narrative was employed in research into identity and difference in Japan. The research explores narrative as a means of generating, disciplining, dismantling and displaying difference-as-data, a process which insists on the difference that cultural difference makes for representing the Other -- in this case the problematics of female Japanese university students being re/presented by their male Anglo-Australian lecturer. The writing/displaying of this data pushed narrative form to offer up fresh notions of ethnicity and identity -- fresh accounts of a resistant Other. The study is therefore as much an exploration of narrative as a cross-disciplinary tool used to evoke the defiant speech of the Other, as it is a re-theorising of Japanese gender, resistance and power. [ABSTRACT FROM AUTHOR]

Looks at a study concerning posttranscriptional modification of retroviral primers and their relationship with the later stages of DNA replication. Reverse transcription of retroviral synthesis of (-) strand DNA; Materials and methods used in the study; Details on the results of experiments.

Describes the DNase protection studies to understand better the interactions of duplex DNA with the RecA nucleoprotein filaments. Conditions for blocking the re-formation of joint molecules and selective examination of distal joints; Materials and methods listed; Results; Discussion of results.

Discusses the effects of a series of carboxy-terminal deletions in vivo at haploid copy number on the essential requirement of GroEL for cell growth in Escherichia coli. Focus on Arg substitution and deletion; Phenotypic defects; Implications of substitution-deletion mutation in oligomeric assembly; Correlation with crystal structure of GroEL.

The article reports that the concept of collaboration in medical care is a dynamic process that requires relationship building and shared decision making. Partners in a collaborative process acknowledge their shared values and interact constructively to solve problems. The collaborative process is enhanced by mutual confidence, trust, and respect. Forming a new collaborative relationship may be difficult if the individuals involved are not aware of each other's competence in practice. Collaboration brings about continuity in care that can enhance compliance and improve health care for everyone involved.

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. [ABSTRACT FROM AUTHOR]

Background: Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. Results: From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9–152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25. Conclusions: This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trialregistration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420 [ABSTRACT FROM AUTHOR]

An FDA-regulated, prescription medical food (Fosteum; 27 mg natural genistein, 200 IU cholecalciferol, 20 mg citrated zinc bisglycinate (4 mg elemental zinc) per capsule) and an over-the-counter (OTC) supplement (Citracal Plus Bone Density Builder; 27 mg synthetic genistein, 600 mg elemental calcium (calcium citrate), 400 IU vitamin D3, 50 mg magnesium, 7.5 mg zinc, 1 mg copper, 75 ¿ g molybdenum, 250 ¿ g boron per two tablets) were compared to a clinically proven bone formulation (27 mg natural genistein, 400 IU cholecalciferol, 500 mg elemental calcium (calcium carbonate) per tablet; the Squadrito formulation) in an 8-day steady-state pharmacokinetic (PK) study of healthy postmenopausal women (n = 30) randomized to receive 54 mg of genistein per day. Trough serum samples were obtained before the final dose on the morning of the ninth day followed by sampling at 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hrs. Total serum genistein, after ß -glucuronidase/sulfatase digestion, was measured by time-resolved fluorometric assay. Maximal time (Tmax), concentration (Cmax), half-life (T1/2), and area under the curve (AUC) were determined for genistein in each formulation. Fosteum and the Squadrito study formulation were equivalent for genistein Tmax (2 hrs), Cmax (0.7 ¿M), T1/2 (18 ± 6.9 versus 21 ± 4.9 hrs), and AUC (9221 ± 413 versus 9818 ± 1370 ng·hr/mL). The OTC supplement's synthetically derived genistein, however, showed altered Tmax (6 hrs), Cmax (0.57 ¿ M), T1/2 (8.3 ± 1.9 hrs), and AUC (6474 ± 287 ng·hr/mL). Differences in uptake may be due to multiple ingredients in the OTC supplement which interfere with genistein absorption. [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]

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]

Current retroviral replication models propose that during (+) strand synthesis, the initial (−) strand tRNA primer is partially replicated to reproduce the 18 nt primer-binding site (PBS). Subsequent removal of the tRNA primer from the (−) strand template exposes the PBS, which anneals to complementary sequences on a DNA acceptor template to enable (+) strand transfer. We used model templates composed of primed (−) strand DNA covalently linked with post-transcriptionally modified tRNA3lys along with natural sequence human immunodeficiency virus (HIV) acceptor DNA to study the generation of the (+) strand strong stop intermediate and the subsequent (+) strand transfer reaction. The rate of formation of the (+) strand transfer reaction products was modestly increased (threefold) by inclusion of nucleocapsid protein, suggesting an ancillary role for this protein in this stage of retroviral replication. In addition to the well-known stop site opposite G59 of the tRNA primer, we detected two additional stop sites opposite ψ55 and at A38. Kinetic analysis showed that only the intermediates formed by stops opposite G59 and ψ55 were active in the subsequent (+) strand transfer reaction. The surprising discovery of the longer, viable (+) strand interaction intermediate prompted us to survey retroviral sequences for a region complementary to the additional donor DNA nucleotides involved in this over-extension. Indeed, complementary sequences that could support this over-extension were found. A strong consensus sequence is immediately adjacent to and downstream of the PBS in lentiviruses and spumaviruses. This consensus sequence was not found in other genera of retroviruses. We have named this element the “primer over-extension sequence” (POS), and propose that it provides a complementary sequence for strand transfer reactions proceeding from intermediates that extend beyond the standard 18 nt complement of the PBS. [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: 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]

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: Nonvalvular atrial fibrillation (AF) is a common ongoing health problem that places patients at risk of stroke. Whether and how a patient addresses this risk depends on each patient's goals, context, and values. Consequently, leading cardiovascular societies recommend using shared decision making (SDM) to individualize antithrombotic treatment in patients with AF. The aim of this study is to assess the extent to which the ANTICOAGULATION CHOICE conversation tool promotes high-quality SDM and influences anticoagulation uptake and adherence in patients with AF at risk of strokes.Methods: This study protocol describes a multicenter, encounter-level, randomized trial to assess the effect of using the ANTICOAGULATION CHOICE conversation tool in the clinical encounter, compared to usual care. The participating centers include an academic hospital system, a suburban community group practice, and an urban safety net hospital, all in Minnesota, USA. Patients with ongoing nonvalvular AF at risk of strokes (CHA2DS2-VASc score ≥ 1 in men, or ≥ 2 in women) will be eligible for participation. We aim to include 999 patients and their clinicians. The primary outcome is the quality of SDM as perceived by participants, and as assessed by a post-encounter survey that ascertains (a) knowledge transfer, (b) concordance of the decision made, (c) quality of communication, and (d) satisfaction with the decision-making process. Recordings of encounters will be reviewed to assess the extent of patient involvement and how participants use the tool (fidelity). Anticoagulant use, choice of agent, and adherence will be drawn from patients' medical and pharmacy records. Strokes and bleeding events will be drawn from patient records.Discussion: This study will provide a valid and precise measure of the effect of the ANTICOAGULATION CHOICE conversation tool on SDM quality and processes, and on the treatment choices and adherence to therapy among AF patients at risk of stroke.Trial Registration: ClinicalTrials.gov, NCT02905032 . Registered on 9 September 2016. [ABSTRACT FROM AUTHOR]

The article explores the institutional policies created by the Duke University Medical Center that assist the research community with meeting clinical trials disclosure obligations mandated by the Food and Drug Administration Amendments Act of 2007 (FDAAA 2007) . A centralized resource group was also created, with three full time staff members ensuring compliance with FDAAA 2007. Also discussed is the operational plan that improved investigator compliance with these federal requirements.

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]

A standardized, combined flavonoid extracts of Scutellaria baicalensis and Acacia catechu, UP446, demonstrates favorable anti-inflammatory properties. In this study, DNA microarray, quantitative polymerase chain reaction (QPCR), and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of UP446 on the lipopolysaccharide (LPS)-induced pro-inflammatory gene regulation of both animal and human immortalized cell lines and also primary human cells. One consistent result from microarray was that the gene expression levels stimulated or suppressed by LPS were returned to normal levels by the UP446 co-treatment. This normalization effect from UP446 was also shown for pro-inflammatory genes cyclooxygenase (COX)-2, tissue necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 using QPCR, and TNF-α using ELISA. The controlling transcriptional factor of these genes, NFκB, was also down-regulated by UP446 in the LPS-induced cell models. Microarray analysis for numerous genes, including cytokines, chemokines, receptors, transcriptional factors, caspase, growth factors, and phosphatases, suggests not only a genomic anti-inflammatory activity for UP446 but also signaling pathways of cell proliferation, cell death, and lipid metabolism demonstrated on different types of cells. [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]

Purpose: This study highlights Warning Letter (WL) findings issued to sponsor-investigators (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]