Reasons for hospitalisation and cumulative mortality in people, 75 years or older, at high risk of hospital admission: a prospective study.

BACKGROUND: A small proportion of the older population accounts for a high proportion of healthcare use. For effective use of limited healthcare resources, it is important to identify the group with greatest needs. The aim of this study was to explore frequency and reason for hospitalisation and cumulative mortality, in an older population at predicted high risk of hospital admission, and to assess if a prediction model can be used to identify individuals with the greatest healthcare needs. Furthermore, discharge diagnoses were explored to investigate if they can be used as basis for specific interventions in the high-risk group. METHODS: All residents, 75 years or older, living in Östergötland, Sweden, on January 1st, 2017, were included. Healthcare data from 2016 was gathered and used by a validated prediction model to create risk scores for hospital admission. The population was then divided into groups by percentiles of risk. Using healthcare data from 2017-2018, two-year cumulative incidence of hospitalisation was analysed using Gray´s test. Cumulative mortality was analysed with the Kaplan-Meier method and primary discharge diagnoses were analysed with standardised residuals. RESULTS: Forty thousand six hundred eighteen individuals were identified (mean age 82 years, 57.8% women). The cumulative incidence of hospitalisation increased with increasing risk of hospital admission (24% for percentiles < 60 to 66% for percentiles 95-100). The cumulative mortality also increased with increasing risk (7% for percentiles < 60 to 43% for percentiles 95-100). The most frequent primary discharge diagnoses for the population were heart diseases, respiratory infections, and hip injuries. The incidence was significantly higher for heart diseases and respiratory infections and significantly lower for hip injuries, for the population with the highest risk of hospital admission (percentiles 85-100). CONCLUSIONS: Individuals 75 years or older, with high risk of hospital admission, were demonstrated to have considerable higher cumulative mortality as well as incidence of hospitalisation. The results support the use of the prediction model to direct resources towards individuals with highest risk scores, and thus, likely the greatest care needs. There were only small differences in discharge diagnoses between the risk groups, indicating that interventions to reduce hospitalisations should be personalised. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03180606, first posted 08/06/2017.

Improving Magnetic STEM-Differential Phase Contrast Imaging using Precession.

Differential phase contrast in scanning transmission electron microscopy (STEM-DPC) is a technique used to image electromagnetic fields in materials. STEM-DPC is based on tracking the minute changes in the position of the bright-field disk, so any effects which cause inhomogeneities in the intensity or geometry of the disk can lead to the contrast from the electromagnetic fields to be obscured. Structural changes, like grain boundaries, thickness variations, or local crystallographic orientation, are a major cause of these inhomogeneities. In this paper, we present how precession of the STEM probe with the objective lens turned off, providing a near field-free environment for magnetic imaging, can average out nonsystematic inhomogeneities in the electron beam. The methodology was tested on a polycrystalline Fe60Al40 thin film with embedded ferromagnetic structures. The effect of precession was assessed on magnetic induction maps created by three different processing algorithms. Results demonstrate that precessed STEM-DPC with the objective lens turned off shows an improvement in the form of smoothing of the variations found in the DPC signal arising from the underlying polycrystalline background.

Trustful conversations: a qualitative interview study on older patients' experiences of the intervention Proactive healthcare in a Swedish primary care setting.

AIM: To explore older patients' experiences of the intervention Proactive healthcare for frail elderly persons. BACKGROUND: Previous research has indicated that continuity and good access to primary care can improve satisfaction in older people seeking care. However, little is known about the older patients' experiences in taking part of interventions aiming to enhance the care. METHODS: Individual interviews were conducted with 24 older patients who participated in the intervention Proactive healthcare for frail elderly persons, selected from nine Swedish primary care centres. Interviews were analysed using qualitative content analysis. FINDINGS: Older patients' experiences of the intervention involved five manifest categories: Ways of naming the elder care team, covering the older patients' lack of understanding regarding their connection to the team, and the need for clarity on this and on how the specialised care provided differed from conventional care; Availability, indicating how older patients associated easy access and a direct telephone number with a team nurse available at certain times with a sense of security; The importance of relations, covering how patients appreciated continuity in their personal and professional conversations with staff; A feeling of safety and trust, stressing the value of older persons attach to being given enough time, to be listened to and being recognised as people; and Finiteness of life, which refers to the difficulty of having end-of-life conversations and the need for experienced staff with personal knowledge of the patients. The latent theme Trustful conversations was created to give a deeper meaning to the content of the categories.Trustful conversations, created through good personal knowledge of patients and continuity of contact, engender a feeling of safety in older patients. Using elder care teams could result in a better quality of care, with increased satisfaction and feelings of security among patients, and a reduction in healthcare needs.

A Structured Benefit-Risk Assessment Operating Model for Investigational Medicinal Products in the Pharmaceutical Industry.

Robust and transparent formal benefit-risk (BR) analyses for medicinal products represent a means to better understand the appropriate use of medicinal products, and to maximize their value to prescribers and patients. Despite regulatory and social imperatives to conduct structured BR (sBR) assessments, and the availability of a plethora of methodological tools, there exists large variability in the uptake and execution of sBR assessments among pharmaceutical companies. As such, in this paper we present an sBR assessment framework developed and implemented within a large global pharmaceutical company that aims to guide the systematic assessment of BR across the continuum of drug development activities, from first-time-in-human studies through to regulatory submission. We define and emphasize the concepts of Key Clinical Benefits and Key Safety Risks as the foundation for BR analysis. Furthermore, we define and foundationally employ the concepts of sBR and a Core Company BR position as the key elements for our BR framework. We outline 3 simple stages for how to perform the fundamentals of an sBR analysis, along with an emphasis on the weighting of Key Clinical Benefits and Key Safety Risks, and a focus on any surrounding uncertainties. Additionally, we clarify existing definitions to differentiate descriptive, semi-quantitative, and fully quantitative BR methodologies. By presenting our framework, we wish to stimulate productive conversation between industry peers and health authorities regarding best practice in the BR field. This paper may also help facilitate the pragmatic implementation of sBR methodologies for organizations without an established framework for such assessments.

Correcting for probe wandering by precession path segmentation.

Precession electron diffraction has in the past few decades become a powerful technique for structure solving, strain analysis, and orientation mapping, to name a few. One of the benefits of precessing the electron beam, is increased reciprocal space resolution, albeit at a loss of spatial resolution due to an effect referred to as 'probe wandering'. Here, a new methodology of precession path segmentation is presented to counteract this effect and increase the resolution in reconstructed virtual images from scanning precession electron diffraction data. By utilizing fast pixelated electron detector technology, multiple frames are recorded for each azimuthal rotation of the beam, allowing for the probe wandering to be corrected in post-acquisition processing. Not only is there an apparent increase in the resolution of the reconstructed images, but probe wandering due to instrument misalignment is reduced, potentially easing an already difficult alignment procedure.

Background rate estimations for thrombosis with thrombocytopaenia: challenges in evaluating rare safety signals following vaccination in real time during a pandemic.

OBJECTIVES: During COVID-19 vaccination programmes, new safety signals have emerged for vaccines, including extremely rare cases of thrombosis with thrombocytopaenia syndrome (TTS). Background event rates before and during the pandemic are essential for contextualisation of such infrequent events. In the literature, most studies do not report an overall TTS event rate. Rather, background rates are mainly reported for subtypes of thrombotic/thromboembolic diagnoses included in the TTS clinical definition mostly by anatomical location, with reported rates for TTS subtypes varying widely. The objective of this study was to report prepandemic TTS background event rates in the general population. METHODS: Prepandemic background TTS rates were generated via secondary data analysis using a cohort design in the IBM Truven MarketScan (now Merative MarketScan) US health insurance claims database, from 1 January 2019 to 31 December 2019. Two algorithms were applied: thrombocytopaenia occurring±7 days (algorithm 1) or occurring 1 day prior to ≤14 days after the thrombotic/thromboembolic event (algorithm 2). RESULTS: The study population derived from the MarketScan database analysis included approximately 9.8 million adults (aged ≥18 years; mean age 45 years, 52% females). Using this study population, prepandemic background TTS incidence was estimated as 9.8-11.1 per 100 000 person-years. Event rates were higher in males and increased with age. Similar patterns were observed with both algorithms. CONCLUSIONS: This study presents an estimate of aggregate prepandemic background TTS event rates including by type of thrombosis/thromboembolism and age group. The background event rates are dependent on the precision of capturing underlying TTS events in variable data sources, and the ability of electronic health records or insurance claims databases to reflect the TTS clinical definition. Differences between reported event rates demonstrate that estimating background event rates for rare, unprecedented safety events is methodologically challenging.

'Do you have a future when you are 93?' Frail older person's perceptions about the future and end of life - a qualitative interview study in primary care.

OBJECTIVE: To explore frail older persons' perceptions of the future and the end of life. DESIGN: Qualitative content analysis of individual semi-structured interviews. SETTING: Nine primary health care centres in both small and middle-sized municipalities in Sweden that participated in the intervention project Proactive healthcare for frail elderly persons. SUBJECTS/PATIENTS: The study includes 20 older persons (eight women and 12 men, aged 76-93 years). MAIN OUTCOME MEASURES: Frail older persons' perceptions of the future and end of life. RESULTS: The analysis uncovered two main categories: Dealing with the future and Approaching the end of life. Dealing with the future includes two subcategories: Plans and reflections and Distrust and delay. Approaching the end of life includes three subcategories: Practical issues, Worries and realism, and Keeping it away. CONCLUSION: This study highlights the diverse ways older people perceive future and the end of life. The results make it possible to further understand the complex phenomenon of frail older persons' perceptions on the future and the end of life.KEY POINTSThe study found that older persons described their future as contradictory- with a broad spectrum of approaches, where some wanted to deal with these subjects and others wanted to ignore them.•Older persons that consciously planned for the future had tactics that often were related to goals that functioned as motivators to live longer.•Those who adopted a more passive approach did not think about what the future might hold in terms of losing autonomy and deteriorating health.•Older persons that approached end of life in a more proactive way wanted to plan practical arrangements around death but often found it hard to address this issue with relatives.•Those older persons that had a more passive approach to end of life preferred not to think about those issues, and some explicitly stated that they did not want to address the final period of life.

Thrombosis with thrombocytopenia after AZD1222 (ChAdOx1 nCov-19) vaccination: Case characteristics and associations.

BACKGROUND: Post-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management. METHODS: We searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated. FINDINGS: We identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets. CONCLUSIONS: The reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome.

A Structured Methodology to Assess Safety Signal Strength and Inform Causality Assessment.

Causality assessment of safety signals observed with medicinal products is a foundational element of pharmacovigilance and regulatory practice, typically performed by a global introspection process. We have developed a novel, structured methodological framework to support the global introspection process for safety signal causality assessment. This Signal Assessment Guide (SAGe) tool was developed by AstraZeneca and is used internally, both to assess safety signal strength and to inform causality decisions related to safety signals. The term 'safety signal' refers to information arising from one or multiple sources, which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an adverse event. The key concept underlying the SAGe tool is that safety signal data can be reliably sorted into one of three categories: aggregate safety data, plausibility data, and case-level data. When applying the tool, an evidence grade score (Levels A, B, C, and D) is transparently assigned to the available data in each category. This information can then be summarised and presented for formal decision making regarding causality for safety signals. By using a transparent method to categorise the grade of evidence for causal association, with an option to additionally derive a quantitative strength of safety signal score, the SAGe tool can support the global introspection process for causality decisions, contributing to the quality of safety information for medicinal products provided to healthcare professionals and patients. Our anecdotal experience of using the SAGe tool at AstraZeneca is that it has resulted in more efficient and robust conversations regarding the strength of safety signals and the causality question. Wider use of the SAGe tool may bring increased levels of transparency and consistency to the evaluation of safety signals.

Cost-Effectiveness of Comprehensive Geriatric Assessment Adapted to Primary Care.

OBJECTIVES: To estimate the cost-effectiveness of a pragmatic trial of comprehensive geriatric assessment adapted to primary care, compared with care as usual. DESIGN: Within-trial cost-effectiveness study of a prospective controlled multicenter trial. SETTING AND PARTICIPANTS: Nineteen primary care practices in Sweden. The original trial included 1304 individuals aged ≥75 years at high risk of hospitalization selected using a prediction model. From the original trial, 369 individuals participated in the cost-effectiveness analysis, 185 in the intervention group and 184 in the control group. Mean age was 83.9 years and 57% of the participants were men. METHODS: We obtained health care costs from administrative registries. Community costs and health-related quality of life data were obtained from a questionnaire sent to participants. Health-related quality of life was measured using EQ-5D-3L and quality-adjusted life years were calculated. We analyzed all outcomes according to intention to treat, and adjusted them to age, gender, and risk score (risk of hospitalization in the next 12 months). The primary outcome was the incremental cost-effectiveness ratio associated with the intervention at follow-up after 24 months. RESULTS: The difference in total cost (incremental cost) between intervention and control groups was USD -11,275 (95% CI -407 to -22,142). The incremental effect in quality-adjusted life years was -0.05 (95% CI -0.17 to 0.08). In the cost-effectiveness plane that illustrates the uncertainty of the analysis, 77.9 of the observations were within the south-east quadrant, implying lower cost and greater effect in the intervention group. CONCLUSIONS AND IMPLICATIONS: The results suggests that a primary care comprehensive geriatric assessment intervention delivered to older adults at high risk of hospitalization is cost-effective at follow-up after 24 months. The use of a prediction model to select participants and an intervention with a low cost is promising but requires further study.

Atomic resolution HOLZ-STEM imaging of atom position modulation in oxide heterostructures.

It is shown that higher order Laue zone (HOLZ) rings in high energy electron diffraction are specific to individual columns of atoms, and show different strengths, structure and radii for different atom columns along the same projection in a structure. An atomic resolution 4-dimensional STEM dataset is recorded from a <110> direction in a perovskite trilayer, where only the central LaFeO3 layer should show a period doubling that gives rise to an extra HOLZ ring. Careful comparison between experiment and multislice simulations is used to understand the origins of all features in the patterns. A strong HOLZ ring is seen for the La-O columns, indicating strong La position modulation along this direction, whereas a weaker ring is seen along the O columns, and a very weak ring is seen along the Fe columns. This demonstrates that atomic resolution HOLZ-STEM is a feasible method for investigating the 3D periodicity of crystalline materials with atomic resolution.

Costs and effects of comprehensive geriatric assessment in primary care for older adults with high risk for hospitalisation.

BACKGROUND: The healthcare system needs effective strategies to identify the most vulnerable group of older patients, assess their needs and plan their care proactively. To evaluate the effectiveness of comprehensive geriatric assessment (CGA) of older adults with a high risk of hospitalisation we conducted a prospective, pragmatic, matched-control multicentre trial at 19 primary care practices in Sweden. METHODS: We identified 1604 individuals aged 75 years and older using a new, validated algorithm that calculates a risk score for hospitalisation from electronic medical records. After a nine-month run-in period for CGA in the intervention group, 74% of the available 646 participants had accepted and received CGA, and 662 participants remained in the control group. Participants at intervention practices were invited to CGA performed by a nurse together with a physician. The CGA was adapted to the primary care context. The participants thereafter received actions according to individual needs during a two-year follow-up period. Participants at control practices received care as usual. The primary outcome was hospital care days. Secondary outcomes were number of hospital care episodes, number of outpatient visits, health care costs and mortality. Outcomes were analysed according to intention to treat and adjusted for age, gender and risk score. We used generalised linear mixed models to compare the intervention group and control group regarding all outcomes. RESULTS: Mean age was 83.2 years, 51% of the 1308 participants were female. Relative risk reduction for hospital care days was - 22% (- 35% to - 4%, p = 0.02) during the two-year follow-up. Relative risk reduction for hospital care episodes was - 17% (- 30% to - 2%, p = 0.03). There were no significant differences in outpatient visits or mortality. Health care costs were significantly lower in the intervention group, adjusted mean difference was € - 4324 (€ - 7962 to - 686, p = 0.02). CONCLUSIONS AND RELEVANCE: Our findings indicate that CGA in primary care can reduce the need for hospital care days in a high-risk population of older adults. This could be of great importance in order to manage increasing prevalence of frailty and multimorbidity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03180606 , first posted 08/06/2017.