Understanding general practitioner and pharmacist preferences for pharmacogenetic testing in primary care: a discrete choice experiment.

Pharmacogenetic testing in the United Kingdom's National Health Service (NHS) has historically been reactive in nature, undertaken in the context of single gene-drug relationships in specialist settings. Using a discrete choice experiment we aimed to identify healthcare professional preferences for development of a pharmacogenetic testing service in primary care in the NHS. Respondents, representing two professions groups (general practitioners or pharmacists), completed one of two survey versions, asking them to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or joint pain. Responses from 235 individuals were included. All respondents preferred pharmacogenetic testing over no testing, though preference heterogeneity was identified. Both professional groups, but especially GPs, were highly sensitive to service design, with uptake varying depending on the service offered. This study demonstrates uptake of a pharmacogenetic testing service is impacted by service design and highlights key areas which should be prioritised within future initiatives.

Pharmacogenetics Clinical Decision Support Systems for Primary Care in England: Co-Design Study.

BACKGROUND: Pharmacogenetics can impact patient care and outcomes through personalizing the selection of medicines, resulting in improved efficacy and a reduction in harmful side effects. Despite the existence of compelling clinical evidence and international guidelines highlighting the benefits of pharmacogenetics in clinical practice, implementation within the National Health Service in the United Kingdom is limited. An important barrier to overcome is the development of IT solutions that support the integration of pharmacogenetic data into health care systems. This necessitates a better understanding of the role of electronic health records (EHRs) and the design of clinical decision support systems that are acceptable to clinicians, particularly those in primary care. OBJECTIVE: Explore the needs and requirements of a pharmacogenetic service from the perspective of primary care clinicians with a view to co-design a prototype solution. METHODS: We used ethnographic and think-aloud observations, user research workshops, and prototyping. The participants for this study included general practitioners and pharmacists. In total, we undertook 5 sessions of ethnographic observation to understand current practices and workflows. This was followed by 3 user research workshops, each with its own topic guide starting with personas and early ideation, through to exploring the potential of clinical decision support systems and prototype design. We subsequently analyzed workshop data using affinity diagramming and refined the key requirements for the solution collaboratively as a multidisciplinary project team. RESULTS: User research results identified that pharmacogenetic data must be incorporated within existing EHRs rather than through a stand-alone portal. The information presented through clinical decision support systems must be clear, accessible, and user-friendly as the service will be used by a range of end users. Critically, the information should be displayed within the prescribing workflow, rather than discrete results stored statically in the EHR. Finally, the prescribing recommendations should be authoritative to provide confidence in the validity of the results. Based on these findings we co-designed an interactive prototype, demonstrating pharmacogenetic clinical decision support integrated within the prescribing workflow of an EHR. CONCLUSIONS: This study marks a significant step forward in the design of systems that support pharmacogenetic-guided prescribing in primary care settings. Clinical decision support systems have the potential to enhance the personalization of medicines, provided they are effectively implemented within EHRs and present pharmacogenetic data in a user-friendly, actionable, and standardized format. Achieving this requires the development of a decoupled, standards-based architecture that allows for the separation of data from application, facilitating integration across various EHRs through the use of application programming interfaces (APIs). More globally, this study demonstrates the role of health informatics and user-centered design in realizing the potential of personalized medicine at scale and ensuring that the benefits of genomic innovation reach patients and populations effectively.

The Implementation of Pharmacogenetics in the United Kingdom.

There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to introduce pharmacogenetics in the NHS, highlighting key challenges related to scale, informatics, and education.

Identification of Rodent Husbandry Refinement Opportunities through Benchmarking and Collaboration.

Expanding the use of methods that refine, reduce, and replace (3Rs) the use of animals in research is fundamental for both ethical and scientific reasons. The mission of the 3Rs Translational and Predictive Sciences Leadership Group (3Rs TPS LG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) is to promote sharing and integration of science and technology to advance the 3Rs in the discovery and development of new medicines, vaccines, medical devices, and health care products for humans and animals. The 3Rs TPS LG is dedicated to identifying opportunities for member companies to share practices, enhance learning, promote discussions, and advance the 3Rs across the industry. One such opportunity was a benchmarking survey, conducted by the Contract Research Organization (CRO) Outreach Working Group, designed to share practices in rodent husbandry for drug safety research and to identify potential opportunities for refinement. IQ member companies and CROs in Asia, North America, and Europe were surveyed. Areas identified for potential alignment included provision of corncob bedding and wire-grid flooring, management of the nest at cage change, approaches to social housing for male mice, evidence-based enrichment strategies, and evaluating the effects of the timing of studies in relation to the animals' circadian rhythm and light-cycle, with consideration for how such extrinsic factors influence animal welfare and scientific outcomes. This manuscript presents the results of the benchmarking survey, including general trends in mouse and rat husbandry practices in toxicology studies, considerations for social housing, enrichment selection, and potential effects of bedding substrate, emphasizing opportunities for collaboration that can help to identify refinements to rodent husbandry practices.

Efficacy of soaking in 70% isopropyl alcohol on aerobic bacterial decontamination of surgical instruments and gloves for serial mouse laparotomies.

Rodent surgeries in biomedical research facilities are often performed in series. This practice presents many challenges to maintaining aseptic technique between animals. Here, we examined using soaking in 70% isopropyl alcohol for aerobic bacterial decontamination of surgical instruments and gloves used in a series of as many as 10 mouse laparotomy surgeries. These surgeries were performed on mice that were euthanized immediately prior to the procedure. Instruments and gloves were cultured before and after each procedure to determine the presence of aerobic bacterial contamination. To assess the efficacy of the decontamination protocol, culture results were grouped by procedure and then paired (before soak and after soak) for analysis using McNemar test at an α level of 0.05. In addition, by using the Fisher exact test, this modified aseptic method was compared with strict aseptic technique, for which autoclaved instruments and sterile surgical gloves were used for each procedure. In this study, we observed that the modified aseptic technique using 70% isopropyl alcohol soaks pre- vented aerobic bacterial contamination of instruments and gloves for as many as 5 mice.

Real-time PCR assay for rapid detection and analysis of PfCRT haplotypes of chloroquine-resistant Plasmodium falciparum isolates from India.

Chloroquine-resistant Plasmodium falciparum (CRPF) malaria isolates in Southeast Asia and sub-Saharan Africa share the same Plasmodium falciparum chloroquine resistance transporter (PfCRT) haplotype (CVIET; amino acids 72 to 76). It is believed that CRPF malaria emerged in Southeast Asia and spread to sub-Saharan Africa via the Indian subcontinent. Based on this assumption, we hypothesized that CRPF isolates in India should possess the same drug resistance haplotype (PfCRT haplotype CVIET) as P. falciparum isolates in Southeast Asia and Africa and that the prevalence of CRPF may be higher and more widespread in India than appreciated. To test this postulate, we utilized a standardized real-time PCR assay to assess the prevalence and distribution of PfCRT haplotypes in P. falciparum isolates (n = 406) collected from Western, Central, and Eastern states in India and compared them to isolates from South America and Africa. Based on the proportion of isolates possessing the molecular marker K76T, the prevalence of chloroquine resistance was high in all five regions of India studied (91%), as well as in Uganda (98%) and Suriname (100%). All isolates from Suriname contained the chloroquine-resistant SVMNT haplotype typical of South American isolates, and 98% of isolates from Uganda possessed the chloroquine-resistant CVIET haplotype characteristic of Southeast Asian/African strains. However, of 246 P. falciparum isolates from across India that contained the molecular marker for chloroquine resistance, 81% contained the SVMNT haplotype. In conclusion, the prevalence of CRPF malaria was high in geographically dispersed regions of India, and the primary haplotype observed, SVMNT, did not support a presumed geographic spread from contiguous Southeast Asia.

HIV impairs opsonic phagocytic clearance of pregnancy-associated malaria parasites.

BACKGROUND: Primigravid (PG) women are at risk for pregnancy-associated malaria (PAM). Multigravid (MG) women acquire protection against PAM; however, HIV infection impairs this protective response. Protection against PAM is associated with the production of IgG specific for variant surface antigens (VSA-PAM) expressed by chondroitin sulfate A (CSA)-adhering parasitized erythrocytes (PEs). We hypothesized that VSA-PAM-specific IgG confers protection by promoting opsonic phagocytosis of PAM isolates and that HIV infection impairs this response. METHODS AND FINDINGS: We assessed the ability of VSA-PAM-specific IgG to promote opsonic phagocytosis of CSA-adhering PEs and the impact of HIV infection on this process. Opsonic phagocytosis assays were performed using the CSA-adherent parasite line CS2 and human and murine macrophages. CS2 PEs were opsonized with plasma or purified IgG subclasses from HIV-negative or HIV-infected PG and MG Kenyan women or sympatric men. Levels of IgG subclasses specific for VSA-PAM were compared in HIV-negative and HIV-infected women by flow cytometry. Plasma from HIV-negative MG women, but not PG women or men, promoted the opsonic phagocytosis of CSA-binding PEs (p < 0.001). This function depended on VSA-PAM-specific plasma IgG1 and IgG3. HIV-infected MG women had significantly lower plasma opsonizing activity (median phagocytic index 46 [interquartile range (IQR) 18-195] versus 251 [IQR 93-397], p = 0.006) and levels of VSA-PAM-specific IgG1 (mean fluorescence intensity [MFI] 13 [IQR 11-20] versus 30 [IQR 23-41], p < 0.001) and IgG3 (MFI 17 [IQR 14-23] versus 28 [IQR 23-37], p < 0.001) than their HIV-negative MG counterparts. CONCLUSIONS: Opsonic phagocytosis may represent a novel correlate of protection against PAM. HIV infection may increase the susceptibility of multigravid women to PAM by impairing this clearance mechanism.