A Practical Tool for Risk-Based In-use Compatibility Assessments.

In drug development, in-use compatibility studies are crucial steps to ensure that the critical quality attributes of the drug product are maintained when in contact with administration components. But once the drug is in clinical trials, unanticipated variations in these components can stretch limited resources and lengthen timelines to market, as these changes must be assessed and approved to ensure continued patient safety. It's desirable to use a science-based risk evaluation to determine the extent of data and testing needed in these situations, but there is no standard for how such evaluations are done. We have developed an Excel™-based semi-quantitative risk assessment tool to determine whether in-use testing is needed when drug delivery sites or components are changed during a clinical trial. We developed the tool based on our multi-company experience with compatibility studies for many types of drug products targeted for various geographic regions. We have employed the tool as a means to expedite decision-making and, if appropriate, reduce testing in low-risk situations. The tool can save significant time and effort (our estimate is approximately at least 6-9 months off the development cycle) and can minimize pitfalls in clinical administration. While we have designed the tool for our drug products and for use with parenteral dosing regimens, the tool can be adapted for other situations as needed. It will be especially useful for companies with more limited resources.

Public perceptions of advance care planning (ACP) from an international perspective: a scoping review.

BACKGROUND: Advance Care Planning (ACP) helps people discuss personal values, goals and priorities regarding future care with family and professionals. It can support care coordination and guide decision-making as health deteriorates. However, uptake remains low internationally. Poor communication and information due to Covid-19 pressures exacerbated public and professional criticism and concerns. Recent recommendations highlight the importance of understanding and addressing public perceptions about ACP combined with person-centred approaches to ACP conversations. OBJECTIVES: To explore public perceptions of ACP to inform increased public engagement and empowerment. METHODS: Joanna Briggs Institute methodology was applied in a rapid scoping review. Three databases (Embase, MEDLINE, APA PsycInfo) were searched for English language reviews and primary or secondary research studies from 2015 to 2021. Following title and abstract review, two researchers screened full-text articles and performed data extraction independently using Covidence. Charted data were analysed for themes and subthemes starting with two recent published reviews. Emerging findings were added and data synthesis reviewed by the research team, including public-patient representatives, to achieve consensus. RESULTS: Of 336 studies, 20 included reviews and research papers represented diverse public views, situations and contexts. Studies found poor public knowledge of ACP and widespread perceptions of confusing or accessible information. Multiple reports described little personal relevance, perceived risks of emotional distress, fears, mistrust and misconceptions about the purpose and scope of ACP. Studies identified public concerns stemming from reluctance to discuss death and dying despite this being just one aspect of ACP. Research with minority communities and marginalised groups found intensified concerns. Some studies cited people who valued maintaining autonomy by expressing their goals and preferences. CONCLUSIONS: Studies reviewed found many members of the public had negative or unclear perceptions of ACP. Improved knowledge and understanding appeared to influence perceptions of ACP but were not considered sufficient to change behaviours. The research provided valuable insights from members of the public that could inform current professional and societal debates about the future of ACP. Findings point to a need for novel approaches to ACP public information and involvement whilst bearing in mind societal norms, diverse cultures and contexts.

Online public information about advance care planning: An evaluation of UK and international websites.

Introduction: Healthcare information is increasingly internet-based. Standards require websites to be 'perceivable, operable, understandable and robust' with relevant content for citizens in appropriate language. This study examined UK and international websites offering public healthcare information on advance care planning (ACP) using current recommendations for website accessibility and content and informed by a public engagement exercise. Methods: Google searches identified websites in English from health service providers, governmental or third sector organisations based in the UK and internationally. Target keywords that would be used by a member of the public informed the search terms. Data extraction used criterion-based assessment and web content analysis of the first two pages of each search result. Public patient representatives as key members of the multidisciplinary research team guided the development of the evaluation criteria. Results: A total of 1158 online searches identified 89 websites, reduced to 29 by inclusion/exclusion criteria. Most sites met international recommendations for knowledge/understanding about ACP. Differences in terminology, lack of information about ACP limitations and non-adherence to recommended reading levels, accessibility standards and translation options were apparent. Sites targeting members of the public used more positive, non-technical language than those for both professional and lay users. Conclusions: Some websites met accepted standards required to facilitate understanding and public engagement in ACP. Others could be improved significantly. Website providers have important roles and responsibilities in increasing people's understanding of their health conditions, future care options and ability to take an active role in planning for their health and care.

"Selecting the right tool for the job" a narrative overview of experimental methods used to measure or estimate active and passive drag in competitive swimming.

Free-swimming performance depends strongly on the ability to develop propulsive force and minimise resistive drag. Therefore, estimating resistive drag (passive or active) may be important to understand how free-swimming performance can be improved. The purpose of this narrative overview was to describe and discuss experimental methods of measuring or estimating active and passive drag relevant to competitive swimming. Studies were identified using a mixed-model approach comprising a search of SCOPUS and Web of Science data bases, follow-up of relevant studies cited in manuscripts from the primary search, and additional studies identified by the co-authors based on their specific areas of fluid dynamics expertise. The utility and limitations of active and passive drag methods were critically discussed with reference to primary research domains in this field, 'swimmer morphology' and 'technique analysis'. This overview and the subsequent discussions provide implications for researchers when selecting an appropriate method to measure resistive forces (active or passive) relevant to improving performance in free-swimming.

The role of the biomechanics analyst in swimming training and competition analysis.

Swimming analysts aid coaches and athletes in the decision-making by providing evidence-based recommendations. The aim of this narrative review was to report the best practices of swimming analysts that have been supporting high-performance athletes. It also aims to share how swimming analysts can translate applied research into practice. The role of the swimming analyst, as part of a holistic team supporting high-performance athletes, has been expanding and is needed to be distinguished from the job scope of a swimming researcher. As testing can be time-consuming, analysts must decide what to test and when to conduct the evaluation sessions. Swimming analysts engage in the modelling and forecast of the performance, that in short- and mid-term can help set races target-times, and in the long-term provide insights on talent and career development. Races can be analysed by manual, semi-automatic or fully automatic video analysis with single or multi-cameras set-ups. The qualitative and quantitative analyses of the swim strokes, start, turns, and finish are also part of the analyst job scope and associated with race performance goals. Land-based training is another task that can be assigned to analysts and aims to enhance the performance, prevent musculoskeletal injuries and monitor its risk factors.

Advance care planning in primary care for patients with gastrointestinal cancer: feasibility randomised trial.

BACKGROUND: Advance (anticipatory) care planning (ACP) requires discussions between patients and healthcare professionals about planning for future deterioration in health. ACP improves care coordination but uptake is limited and often deferred. AIM: To assess the feasibility and acceptability to patients, carers, and GPs of a primary care ACP intervention for people with incurable oesophageal, gastric, or pancreatic cancer. DESIGN AND SETTING: A 12-month feasibility randomised controlled trial (RCT) in a Scottish Cancer Network. METHOD: Patients aged ≥18 years starting palliative oncology treatment were randomised 1:1 to an ACP intervention or standard care. Patients in the intervention group received an oncologist letter supporting them to request a GP review along with a patient information leaflet about ACP. Pre-specified analyses with masking included trial recruitment and retention, ACP completion, and quality-of-life questionnaires (EuroQol EQ-5D-5L and ICECAP Supportive Care Measure) at baseline, 6, 12, 24, and 48 weeks. Qualitative interviews with purposive sampling explored patient, carer, and GP experiences. RESULTS: Of 99 eligible participants (269 screened), 46% were recruited (n = 46) and randomised; 25 to intervention and 21 to control. By 12 weeks, 45% (n = 9/20) of the individuals in the intervention and 59% (n = 10/17) in the control group had a documented ACP plan. By 24 weeks, 30% (n = 14) had died; in the remaining participants quality of life was maintained at 24 weeks except for physical symptoms. Social norms associating ACP with dying were prevalent among 23 participants interviewed. No psychological or clinical harms were identified. CONCLUSION: An RCT of ACP for people with incurable cancer in primary care is feasible. Patient, carer, and GP attitudes and behaviours determined acceptability and timing of care planning.

Integrating lived experiences of out-of-hours health services for people with palliative and end-of-life care needs with national datasets for people dying in Scotland in 2016: A mixed methods, multi-stage design.

BACKGROUND: Unscheduled care is used increasingly during the last year of life by people known to have significant palliative care needs. AIM: To document the frequency and patterns of use of unscheduled healthcare by people in their last year of life and understand the experiences and perspectives of patients, families and professionals about accessing unscheduled care out-of-hours. DESIGN: A mixed methods, multi-stage study integrating a retrospective cohort analysis of unscheduled healthcare service use in the last year of life for all people dying in Scotland in 2016 with qualitative data from three regions involving service users, bereaved carers and general practitioners. SETTING: Three contrasting Scottish Health Board regions and national datasets for the whole of Scotland. RESULTS: People who died in Scotland in 2016 (n = 56,407) had 472,360 unscheduled contacts with one of five services: telephone advice, primary care, ambulance service, emergency department and emergency hospital admission. These formed 206,841 individual continuous unscheduled care pathways: 65% starting out-of-hours. When accessing healthcare out-of-hours, patients and carers prioritised safety and a timely response. Their choice of which service to contact was informed by perceptions and previous experiences of potential delays and whether the outcome might be hospital admission. Professionals found it difficult to practice palliative care in a crisis unless the patient had previously been identified. CONCLUSION: Strengthening unscheduled care in the community, together with patient and public information about how to access these services could prevent hospital admissions of low benefit and enhance community support for people living with advanced illness.

Core Outcome Measures for Palliative and End-of-Life Research After Severe Stroke: Mixed-Method Delphi Study.

Background and Purpose: Stroke is the second commonest cause of death worldwide and a leading cause of severe disability, yet there are no published trials of palliative care in stroke. To design and evaluate palliative care interventions for people with stroke, researchers need to know what measurable outcomes matter most to patients and families, stroke professionals, and other service providers. Methods: A multidisciplinary steering group of professionals and laypeople managed the study. We synthesized recommendations from respected United Kingdom and international consensus documents to generate a list of outcome domains and then performed a rapid scoping literature review to identify potential outcome measures for use in future trials of palliative care after stroke. We then completed a 3-round, online Delphi survey of professionals, and service users to build consensus about outcome domains and outcome measures. Finally, we held a stakeholder workshop to review and finalize this consensus. Results: We generated a list of 36 different outcome domains from 4 key policy documents. The rapid scoping review identified 43 potential outcome measures that were used to create a shortlist of 16 measures. The 36 outcome domains and 16 measures were presented to a Delphi panel of diverse healthcare professionals and lay service users. Of 48 panelists invited to take part, 28 completed all 3 rounds. Shared decision-making and quality of life were selected as the most important outcome domains for future trials of palliative care in stroke. Additional comments highlighted the need for outcomes to be feasible, measurable, and relevant beyond the initial, acute phase of stroke. The stakeholder workshop endorsed these results. Conclusions: Future trials of palliative care after stroke should include pragmatic outcome measures, applicable to the evolving patient and family experiences after stroke and be inclusive of shared decision-making and quality of life.

Unscheduled and out-of-hours care for people in their last year of life: a retrospective cohort analysis of national datasets.

OBJECTIVES: To analyse patterns of use and costs of unscheduled National Health Service (NHS) services for people in the last year of life. DESIGN: Retrospective cohort analysis of national datasets with application of standard UK costings. PARTICIPANTS AND SETTING: All people who died in Scotland in 2016 aged 18 or older (N=56 407). MAIN OUTCOME MEASURES: Frequency of use of the five unscheduled NHS services in the last 12 months of life by underlying cause of death, patient demographics, Continuous Unscheduled Pathways (CUPs) followed by patients during each care episode, total NHS and per-patient costs. RESULTS: 53 509 patients (94.9%) had at least one contact with an unscheduled care service during their last year of life (472 360 contacts), with 34.2% in the last month of life. By linking patient contacts during each episode of care, we identified 206 841 CUPs, with 133 980 (64.8%) starting out-of-hours. People with cancer were more likely to contact the NHS telephone advice line (63%) (χ2 (4)=1004, p<0.001) or primary care out-of-hours (62%) (χ2 (4)=1924,p<0.001) and have hospital admissions (88%) (χ2 (4)=2644, p<0.001). People with organ failure (79%) contacted the ambulance service most frequently (χ2 (4)=584, p<0.001). Demographic factors associated with more unscheduled care were older age, social deprivation, living in own home and dying of cancer. People dying with organ failure formed the largest group in the cohort and had the highest NHS costs as a group. The cost of providing services in the community was estimated at 3.9% of total unscheduled care costs despite handling most out-of-hours calls. CONCLUSIONS: Over 90% of people used NHS unscheduled care in their last year of life. Different underlying causes of death and demographic factors impacted on initial access and subsequent pathways of care. Managing more unscheduled care episodes in the community has the potential to reduce hospital admissions and overall costs.

Studying the effects of asymmetry on freestyle swimming using smoothed particle hydrodynamics.

The use of asymmetrical strokes is common in freestyle swimming because of breathing and strength laterality. In this study, the asymmetrical freestyle swimming performance of a male elite level swimmer who breathed every second arm stroke (unilaterally) was investigated. A laser body scan and multi-angle video footage of the athlete were used to generate a swimming biomechanical model. This model was then used in a Smoothed Particle Hydrodynamics (SPH) fluid simulation of swimming through a virtual pool. The results from this study enabled the kinematic asymmetry to be related to the consequential fluid dynamic asymmetry. The intra-cyclic fluctuations in the streamwise forces and speed were also examined. Hand angles of attack were compared along with the lift and drag contributions of the hands to generating the streamwise thrust. From this study, connections between asymmetry and the resultant swimming performance were identified.

Analytical artifacts in characterization of recombinant monoclonal antibody therapeutics.

A battery of analytical methods is used to analyze recombinant monoclonal antibodies for lot release to ensure consistent product quality, safety, and efficacy. Additionally, state-of-the-art analytical methods have been used to thoroughly characterize various post-translational modifications and degradation pathways of those molecules. Scientifically sound and robust analytical methods are essential to providing reliable results for defining control strategy, including setting phase-appropriate specifications. Analytical artifacts can substantially impact analytical method performance, causing either overestimation or underestimation of the impacted attributes. However, these artifacts are often overlooked due to lack of the fundamental understanding of analytical methods. This review discusses several regularly encountered artifacts and provides a guidance on assessment and prevention of these artifacts. Understanding and preventing artifacts can help establish scientifically sound and robust methods with reliable performance throughout the method life cycle.

Disrupted biographies and balancing identities: A qualitative study of cancer patients' communication with healthcare professionals about dependent children.

OBJECTIVE: About 14% of cancer patients live with dependent children. Healthcare professionals are well placed to help patients support their children as part of a patient-centred practice. Children tend to appreciate open communication during the course of illness, but patients often find this difficult. However, research is unclear about patients' preferences and their willingness to talk with healthcare professionals about their dependent children. METHODS: We conducted 15 in-depth interviews with patients from haematological (N = 11) and gynaecological oncology (N = 4). The interviews and subsequent analysis focused on patients' communicative preferences, taking the theoretical framework of "biographical disruption" as a starting point and using Jenkins' concept of identity as a social, relational and dynamic process. RESULTS: We identified two overall identities at stake for seriously ill patients with parental responsibility: "patient identity" and "parent identity." As "patients," patients were ambivalent about relating to their children, but as "parents" they wanted healthcare professionals to talk about their children. CONCLUSION: In order to be patient-centred, clinicians should, we suggest, acknowledge that patients have these conflicting perspectives and identities, which surface at various times and situations throughout their illness trajectories. Research is needed to further explore these findings in different illness groups and cultures.

Structure, heterogeneity and developability assessment of therapeutic antibodies.

Increasing attention has been paid to developability assessment with the understanding that thorough evaluation of monoclonal antibody lead candidates at an early stage can avoid delays during late-stage development. The concept of developability is based on the knowledge gained from the successful development of approximately 80 marketed antibody and Fc-fusion protein drug products and from the lessons learned from many failed development programs over the last three decades. Here, we reviewed antibody quality attributes that are critical to development and traditional and state-of-the-art analytical methods to monitor those attributes. Based on our collective experiences, a practical workflow is proposed as a best practice for developability assessment including in silico evaluation, extended characterization and forced degradation using appropriate analytical methods that allow characterization with limited material consumption and fast turnaround time.

Analytical comparability study of recombinant monoclonal antibody therapeutics.

Process changes are inevitable in the life cycle of recombinant monoclonal antibody therapeutics. Products made using pre- and post-change processes are required to be comparable as demonstrated by comparability studies to qualify for continuous development and commercial supply. Establishment of comparability is a systematic process of gathering and evaluating data based on scientific understanding and clinical experience of the relationship between product quality attributes and their impact on safety and efficacy. This review summarizes the current understanding of various modifications of recombinant monoclonal antibodies. It further outlines the critical steps in designing and executing successful comparability studies to support process changes at different stages of a product's lifecycle.

Computer screening for palliative care needs in primary care: a mixed-methods study.

BACKGROUND: Though the majority of people could benefit from palliative care before they die, most do not receive this approach, especially those with multimorbidity and frailty. GPs find it difficult to identify such patients. AIM: To refine and evaluate the utility of a computer application (AnticiPal) to help primary care teams screen their registered patients for people who could benefit from palliative care. DESIGN AND SETTING: A mixed-methods study of eight GP practices in Scotland, conducted in 2016-2017. METHOD: After a search development cycle the authors adopted a mixed-methods approach, combining analysis of the number of people identified by the search with qualitative observations of the computer search as used by primary care teams, and interviews with professionals and patients. RESULTS: The search identified 0.8% of 62 708 registered patients. A total of 27 multidisciplinary meetings were observed, and eight GPs and 10 patients were interviewed. GPs thought the search identified many unrecognised patients with advanced multimorbidity and frailty, but were concerned about workload implications of assessment and care planning. Patients and carers endorsed the value of proactive identification of people with advanced illness. CONCLUSION: GP practices can use computer searching to generate lists of patients for review and care planning. The challenges of starting a conversation about the future remain. However, most patients regard key components of palliative care (proactive planning, including sharing information with urgent care services) as important. Screening for people with deteriorating health at risk from unplanned care is a current focus for quality improvement and should not be limited by labelling it solely as 'palliative care'.

Contribution of uncertainty in estimation of active drag using assisted towing method in front crawl swimming.

Active drag force in swimming can be calculated from a function of five different variables: swim velocity, tow velocity, belt force, power output and exponent of velocity. The accuracy of the drag force value is dependent on the accuracy of each variable, and on the contribution of each variable to drag estimation. To calculate uncertainty in drag value, first the derivatives of the active drag equation with respect to each variable were obtained. Second, these were multiplied by the uncertainty of that variable. Twelve national age and open level swimmers were recruited to complete four free swimming and five active drag trials. The uncertainties for the free and the tow swim velocities, and for the belt force, contributed approximately 5-6% and 2-3% error, respectively, in calculation of drag. The result of the uncertainty of the velocity exponent (1.8-2.6) indicated a contribution of about 6% error in active drag. The contribution of unequal power output showed that if a power changed 7.5% between conditions, it would lead to about 30% error in calculated drag. Consequently, if a swimmer did not maintain constant power output between conditions, there would be substantial errors in the calculation of active drag.

Forced degradation of recombinant monoclonal antibodies: A practical guide.

Forced degradation studies have become integral to the development of recombinant monoclonal antibody therapeutics by serving a variety of objectives from early stage manufacturability evaluation to supporting comparability assessments both pre- and post- marketing approval. This review summarizes the regulatory guidance scattered throughout different documents to highlight the expectations from various agencies such as the Food and Drug Administration and European Medicines Agency. The various purposes for forced degradation studies, commonly used conditions and the major degradation pathways under each condition are also discussed.

Reliability of estimating active drag in swimming using the assisted towing method with fluctuating speed.

The reliability of active drag values was examined using a method that compared free swim speed with measurements taken by towing swimmers slightly faster than their maximum swim speed, while allowing their intra-stroke speed fluctuations. Twelve national age and open level swimmers were tested on two alternate days (Day 1 and Day 2). All participants completed four maximum swim speed, three passive drag and five active drag trials on each of the days. The reliability was determined using within-participant intra-class correlation coefficients (ICC) within each day and between the days. The ICCs for Day 1 and Day 2 were 0.82 and 0.85, respectively, while the comparison of the mean active drag values between days was 0.93. The data showed that the assisted towing method (ATM) with fluctuating speed was only moderately reliable within a single test. However, this method was more reliable when using the average value of active drag from both days (ICC = 0.93). This study identified that the ATM method with fluctuating speed had moderate reliability within-participant trials on values in a single day but high reliability for the average active drag values across different days.

The threatened self: Considerations of time, place, and uncertainty in advanced illness.

OBJECTIVES: Loss of self and the transition to patient-hood have been widely discussed in relation to the experience of advanced illness. Individuals however often maintain identities or selves beyond those demanded by the circumstances of being a patient. This study explores the presentation of this personal identity and interactions between intrinsic and extrinsic elements that support or threaten its maintenance. In particular, this study examined the impact of uncertainty on the representations of self and the part played by the patient's health care professionals and the systems in which they are embedded, in limiting or reinforcing its effects. METHODS: Complementary methods of ethnographic observation and serial narrative interviews were adopted to explore both the lo"cal social and health care context and the changing presentation of self by patients with advanced multimorbidity, chronic illness, and cancer. In total, 36 interviews were undertaken with 16 patients. Analysis was guided by concepts of time and place, combining contextual data with the unfolding patient narrative. RESULTS: Good pain and symptom control was a necessary, but not sufficient, condition for the maintenance of a personal identity. Essential agentic elements included knowledge of appropriate and immediate sources of help. Also important were a sense of control achieved through a shared understanding with health care professionals of the condition and active management of uncertainty. In addition, the maintenance of self depended on keeping a connection with aspects of life associated with a pre-illness identity. Critically, this self was contingent on external recognition, acknowledgement, and validation. CONCLUSION: Professional relationships that focus solely on the 'person as patient' may be insufficient for patients' needs. Health care professionals should seek to recognize and acknowledge the personal identity that may be critical to their sense of self-worth. Through an ongoing relationship guiding the patient through the uncertainties they face, health care professionals may play an essential role in sustaining the 'patient as person'. STATEMENT OF CONTRIBUTION: What is already known on this subject? Loss of self or personal identity occurs in a range of serious conditions. The sick self is incorporated in a process of identity reconstruction. Uncertainty is an inherent aspect of serious and advanced illness. Unmanaged uncertainty results in a range of negative psychological consequences that contribute to the loss of personal identity. Information and communication with health care professionals help patients manage uncertainty. What does this study add? Sufferers may retain a personal identity continuous with a pre-illness self using internal and external resources. The pre-illness self may be subsumed by the patient self especially at times of transition and maximum uncertainty. Acknowledgement and facilitation by health care professionals can enable the preservation of the pre-illness self.