Objectives
Patient and public involvement (PPI) in clinical research has a well-established infrastructure in the UK, and while there has been good progress within pharmaceutical-industry-sponsored ...research, further improvements are still needed. This review aims to share learnings from quality assessments of historical PPI projects within Pfizer UK to inform future projects and drive PPI progress in the pharmaceutical industry.
Design and setting
Internal assessments of Pfizer UK PPI projects were conducted to identify all relevant projects across the medicines development continuum between 2017 and 2021. Five sample projects were developed into case studies.
Outcome measure
Retrospective quality assessments were performed using the Patient Focused Medicines Development (PFMD) Patient Engagement Quality Guidance (PEQG) tool. Recommendations for improvement were developed.
Results
Retrospective case study analysis and quality framework assessment revealed benefits of PPI to both Pfizer UK and to external partners, as well as challenges and learnings to improve future practice. Recommendations for improvement based on these findings focused on processes and procedures for PPI, group dynamics and diversity for PPI activities, sharing of expertise, the importance of bidirectional and timely feedback, and the use of understandable language in materials.
Conclusions
PPI in medicines development is impactful and beneficial but is still being optimised in the pharmaceutical industry. Using the PFMD PEQG tool to define gaps, share learnings and devise recommendations for improvement helps to ensure that PPI is genuine and empowering, rather than tokenistic. Ultimately, these recommendations should be acted on to further embed PPI as an integral part of medicines development and health research within the pharmaceutical industry. This article includes a plain language summary in the supplement.
Learning how to interpret and enter data into the EHR are essential skills, and navigating poorly developed EHRs can be a cause of work-related stress and burnout.5 New challenges are emerging; NHS ...England have announced plans for all adult patients in England to have online access to all new information entered into their primary care record.6 With the increasing digitisation of hospital records,7 this is also likely to happen in secondary care. Investigating the pedagogical approaches being used to integrate EHRs into curricula and their outcomes shows that teaching alongside EHRs positively impacts student confidence, preparedness for clinical practice and improved communications skills.10 We believe that such work will not only equip students and clinicians to put data in the record to better use and write entries benefiting their colleagues and patients, but also inspire them to consider how electronic medical records and systems could evolve in the future beyond their current functions to become a collaborative tool to enhance and encourage better patient-centred care. Pharmacy students’ perspectives on the initial implementation of a teaching electronic medical record: results from a mixed-methods assessment.
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► A new life cycle lineage for a century-old Microsporidian taxon is described. ► The new lineage displays extreme morphological variation from that published previously. ► Molecular ...phylogenetic data is utilised to demonstrate synonymy between life cycle variants. ► The new data presents a taxonomic conundrum that widely implicates other taxa within the phylum.
Investigations to determine whether juvenile gnathiid isopods are vectors of haemogregarines between coral reef fishes were undertaken at Lizard Island, Australia. Haemogregarina balistapi parasitaemias in triggerfish, Rhinecanthus aculeatus, decreased under gnathiid-free, laboratory conditions, compared with those in tagged R. aculeatus returned to the reef. Gnathia aureamaculosa juveniles were common ectoparasites of reef R. aculeatus and laboratory reared specimens of this gnathiid were fed on R. aculeatus infected with H. balistapi. Subsequent squashes of this gnathiid contained haemogregarine gamonts similar to those seen in blood films of R. aculeatus, and haemogregarine developmental stages, including oocysts, sporozoites, meronts and merozoites. Biological transmission of H. balistapi and a second haemogregarine species, Haemogregarina bigemina, using laboratory reared gnathiids to several species of triggerfishes and surgeonfishes raised from larvae was then attempted. Investigations involved recipient fish ingesting, or being bitten by, G. aureamaculosa juveniles fed on donor fish with haemogregarines; control fish were exposed to gnathiids fed on uninfected donor fish. Subsequently, no haemogregarines were detected in recipient triggerfishes and controls were negative. However, a recipient surgeonfish, Acanthurus xanthopterus, which had ingested gnathiids likely infected with donor fish H. balistapi, carried H. bigemina-like stages. A second recipient surgeonfish, which had ingested gnathiids presumed to be infected with H. bigemina, also carried haemogregarine stages. Finally, a third surgeonfish apparently carried haemogregarines after gnathiids presumed to be infected with H. bigemina had bitten this fish, although not all gnathiids were recovered during the trials and the third infected surgeonfish may have also ingested gnathiids. The study provides strong evidence that G. aureamaculosa is the definitive host of H. balistapi, to our knowledge the first such observation from a coral reef environment. Although transmission of H. balistapi has not yet been demonstrated, laboratory trials tend to support the view that G. aureamaculosa is also a potential vector of H. bigemina between surgeonfish.
Bortezomib, a small-molecule proteasome inhibitor, has activity in lung cancer both as a single agent and in combination with
agents commonly used in lung cancer. The ability of bortezomib to ...favorably modulate the expression of apoptosis-associated
proteins, along with its moderate toxicity as a single agent, provides the basis for its combination with cytotoxic agents
in the treatment of lung cancer. In non–small cell lung cancer, bortezomib as a single agent has limited activity but in combination
with chemotherapy has shown encouraging activity without significantly adding to toxicity. Bortezomib as a single agent has
shown minimal activity in small cell lung cancer. Although the role of bortezomib in lung cancer is uncertain, it is likely
to have its greatest clinical benefit when given in combination with other therapeutics. Ongoing studies are focused on optimizing
the scheduling of bortezomib with chemotherapy, investigating its combination with targeted agents and radiation, and examining
its efficacy in a specific subgroup, bronchioloalveolar carcinoma.
Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS), experienced by more than 80% of people with MS. FACETS (Fatigue: Applying Cognitive Behavioral and Energy ...Effectiveness Techniques to Lifestyle) is an evidence-based, face-to-face, 6-session group fatigue management program for people with MS. Homework tasks are an integral part of FACETS and are currently undertaken in a paper-based form. Feedback from a consultation undertaken with FACETS attendees and health care professionals with experience in delivering the FACETS program suggested that being able to complete the homework tasks digitally would be desirable, potentially enhancing engagement and adherence and enabling on-the-go access to fit into busy lifestyles. Relative to other long-term conditions, there are few apps specifically for MS and, of those available, many have been developed with little or no input from people with MS.
The purpose of this mixed methods study was to create a digital toolkit comprising the homework tasks (eg, activity diary, goal planner, thought diary) of the FACETS program for people with MS, considering end users' unique requirements throughout the design, build, prototyping, and testing stages.
Phase 1 involved the elicitation of detailed user requirements for the toolkit via 2 focus groups with previous attendees of FACETS (n=3 and n=6) and wireframing. Phase 2 involved supervised usability testing with people with MS (n=11) with iterative prototyping. The usability sessions involved going through test scenarios using the FACETS toolkit on an Android test phone with video capture and concurrent think-aloud followed by completion of the System Usability Scale (SUS) and a semistructured interview collecting feedback about design, content, and functionality.
The mean SUS score for the digital toolkit was 74.3 (SD 16.8, 95% CI 63.2-85.6; range 37.5-95), which equates to an adjective rating of good and a B grade (70th-79th percentile range) on the Sauro-Lewis curved grading scale. A number of usability and design issues (such as simplifying overall screen flow to better meet users' needs) and suggestions for improvements (such as using location-based services and displaying personalized information and progress via a central dashboard) were addressed and implemented during the usability testing cycle.
This work highlights the importance of the participation of people with MS across the entire development cycle, working to a human-centered design methodology to enable a considered and MS-centered solution to be developed. Continued horizon scanning for emergent technological enhancements will enable us to identify opportunities for further improvements to the FACETS toolkit prior to launch. The toolkit supports self-monitoring and management of fatigue and has potential applicability to other long-term conditions where fatigue is a significant issue.
Research was undertaken to clarify the true taxonomic position of the terrestrial tortoise apicomplexan, Haemogregarina fitzsimonsi (Dias, 1953). Thin blood films were screened from 275 wild and ...captive South African tortoises of 6 genera and 10 species between 2009–2011. Apicomplexan parasites within films were identified, with a focus on H. fitzsimonsi. Ticks from wild tortoises, especially Amblyomma sylvaticum and Amblyomma marmoreum were also screened, and sporogonic stages were identified on dissection of adult ticks of both species taken from H. fitzsimonsi infected and apparently non-infected tortoises. Parasite DNA was extracted from fixed, Giemsa-stained tortoise blood films and from both fresh and fixed ticks, and PCR was undertaken with two primer sets, HEMO1/HEMO2, and HepF300/HepR900, to amplify parasite 18S rDNA. Results indicated that apicomplexan DNA extracted from tortoise blood films and both species of tick had been amplified by one or both primer sets. Haemogregarina fitzsimonsi 18S rDNA sequences from tortoise blood aligned with those of species of Hepatozoon, rather than those of species of Haemogregarina or Hemolivia. It is recommended therefore that this haemogregarine be re-assigned to the genus Hepatozoon, making Hepatozoon fitzsimonsi (Dias, 1953) the only Hepatozoon known currently from any terrestrial chelonian. Ticks are its likely vectors.
Cyclic AMP (cAMP)-dependent protein kinase/protein kinase A (PKA) is the major transducer of cAMP signalling in eukaryotic cells. Here, using laser scanning confocal microscopy and 'smart' ...anti-phospho PKA antibodies that exclusively detect activated PKA, we provide a detailed in situ analysis of PKA signalling in intact adult Schistosoma mansoni, a causative agent of debilitating human intestinal schistosomiasis. In both adult male and female worms, activated PKA was consistently found associated with the tegument, oral and ventral suckers, oesophagus and somatic musculature. In addition, the seminal vesicle and gynaecophoric canal muscles of the male displayed activated PKA whereas in female worms activated PKA localized to the ootype wall, the ovary, and the uterus particularly around eggs during expulsion. Exposure of live worms to the PKA activator forskolin (50 µM) resulted in striking PKA activation in the central and peripheral nervous system including at nerve endings at/near the tegument surface. Such neuronal PKA activation was also observed without forskolin treatment, but only in a single batch of worms. In addition, PKA activation within the central and peripheral nervous systems visibly increased within 15 min of worm-pair separation when compared to that observed in closely coupled worm pairs. Finally, exposure of adult worms to forskolin induced hyperkinesias in a time and dose dependent manner with 100 µM forskolin significantly increasing the frequency of gross worm movements to 5.3 times that of control worms (P≤0.001). Collectively these data are consistent with PKA playing a central part in motor activity and neuronal communication, and possibly interplay between these two systems in S. mansoni. This study, the first to localize a protein kinase when exclusively in an activated state in adult S. mansoni, provides valuable insight into the intricacies of functional protein kinase signalling in the context of whole schistosome physiology.
Learning Objectives
After completing this course, the reader will be able to:
Describe the currently recommended dose adjustments for common chemotherapeutics in oncology patients with organ ...dysfunction.
Explain the rationale for using phase I dose‐escalation studies to determine appropriate chemotherapy dosing in patients with organ dysfunction.
Discuss the limitations of the currently available studies to guide chemotherapy dose adjustment in patients with organ dysfunction.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
There are few prospective data regarding the pharmacokinetics and clinical toxicity of commonly used chemotherapeutics in cancer patients with organ dysfunction. Although increasing numbers of studies are investigating newer chemotherapeutics in patients with liver or kidney dysfunction, most guidelines for dosing, especially for established agents, remain empiric. This review describes the available data (both prospective and case study) evaluating the impact of renal and hepatic dysfunction on toxicity and dosing of commonly used chemotherapeutics and provides a practical summary for their use in this setting.
BACKGROUND/AIMThe therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, ...although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML). MATERIALS AND METHODSCo-clinical modeling involves taking the patient's biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG-EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%). RESULTSResults from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with >60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively). CONCLUSIONThese findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously ...identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR).
We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors.
ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts.
Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.
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