"My Biomarkers Are Fine, Thank You": On the Biomarkerization of Modern Medicine.

Biomarkers are becoming crucial in ever more medical tasks and are proposed to change medicine in profound ways. By biomarking ever more attributes of human life, they tend to blur the distinction between health and disease and come to characterize life as such. Not only do biomarkers strongly influence the professional conception of disease by pervading ever more diagnoses, but they also impact patients' experience of illness. To manage how biomarkers influence patients, professionals, and societies, we urgently need to move from identifying potentially relevant biomarkers to determine their meaning and value to individuals, professionals, and public health.

Success factors for interventions to reduce low-value imaging. Six crucial lessons learned from a practical case study in Norway.

BACKGROUND: Substantial overuse of health care services is identified and intensified efforts are incited to reduce low-value services in general and in imaging in particular. OBJECTIVE: To report crucial success factors for developing and implementing interventions to reduce specific low-value imaging examinations based on a case study in Norway. MATERIALS AND METHODS: Mixed methods design including one systematic review, one scoping review, implementation science, qualitative interviews, content analysis of stakeholders' input, and stakeholder deliberations. RESULTS: The description and analysis of an intervention to reduce low-value imaging in Norway identifies six general success factors: 1) Acknowledging complexity: advanced knowledge synthesis, competence of the context, and broad and strong stakeholder involvement is crucial to manage de-implementation complexity. 2) Clear consensus-based criteria for selecting low-value imaging procedures are key. 3) Having a clear target group is critical. 4) Stakeholder engagement is essential to ascertain intervention relevance and compliance. 5) Active and well-motivated intervention collaborators is imperative. 6) Paying close attention to the mechanisms of low-value imaging and the barriers to reduce it is decisive. CONCLUSION: Reducing low-value imaging is crucial to increase the quality, safety, efficiency, and sustainability of the health services. Reducing low-value imaging is a complex task and paying attention to specific practical success factors is key.

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Although incidental findings can be crucial for some patients, incidental testing is a poor diagnostic method.

Reproducibility and across-site transferability of an improved deep learning approach for aneurysm detection and segmentation in time-of-flight MR-angiograms.

This study aimed to (1) replicate a deep-learning-based model for cerebral aneurysm segmentation in TOF-MRAs, (2) improve the approach by testing various fully automatic pre-processing pipelines, and (3) rigorously validate the model's transferability on independent, external test-datasets. A convolutional neural network was trained on 235 TOF-MRAs acquired on local scanners from a single vendor to segment intracranial aneurysms. Different pre-processing pipelines including bias field correction, resampling, cropping and intensity-normalization were compared regarding their effect on model performance. The models were tested on independent, external same-vendor and other-vendor test-datasets, each comprised of 70 TOF-MRAs, including patients with and without aneurysms. The best-performing model achieved excellent results on the external same-vendor test-dataset, surpassing the results of the previous publication with an improved sensitivity (0.97 vs. ~ 0.86), a higher Dice score coefficient (DSC, 0.60 ± 0.25 vs. 0.53 ± 0.31), and an improved false-positive rate (0.87 ± 1.35 vs. ~ 2.7 FPs/case). The model further showed excellent performance in the external other-vendor test-datasets (DSC 0.65 ± 0.26; sensitivity 0.92, 0.96 ± 2.38 FPs/case). Specificity was 0.38 and 0.53, respectively. Raising the voxel-size from 0.5 × 0.5×0.5 mm to 1 × 1×1 mm reduced the false-positive rate seven-fold. This study successfully replicated core principles of a previous approach for detecting and segmenting cerebral aneurysms in TOF-MRAs with a robust, fully automatable pre-processing pipeline. The model demonstrated robust transferability on two independent external datasets using TOF-MRAs from the same scanner vendor as the training dataset and from other vendors. These findings are very encouraging regarding the clinical application of such an approach.

Reducing low-value imaging-A qualitative evaluation of a pilot intervention in Norway.

RATIONAL: Low-value radiological imaging threatens patient safety and efficient use of limited health resources. It is important to evaluate measures for reducing low-value utilisation, to learn and to improve. Accordingly, the objective of this study was to qualitatively evaluate a pilot intervention for reducing low-value imaging in Norway. METHODS: Semi-structured interviews were conducted aimed at describing stakeholders' experience with a multicomponent pilot intervention consisting of a standardised procedure for referral assessment, a standardised return letter, and information about the value and possible risks of magnetic resonance imaging-examinations to the public. Data were analysed in line with qualitative content analysis with a deductive approach. RESULTS: Seven healthcare providers were interviewed, including two radiologists, two radiographers, one manual therapist, one practice consultant and one general practitioner. Data analysis yielded four categories: (1) information and reception, (2) referral- and assessment processes, (3) suggestions for improvement and facilitation and (4) outcomes of the pilot intervention. CONCLUSIONS: The pilot intervention was deemed acceptable, feasible, engaging and relevant. Specific training in the use of the new procedure was suggested to improve the intervention. The simple design, as well as the positive acceptance demonstrated and the few resources needed, make the pilot intervention and methodology highly relevant for other settings or when aiming to reduce the number of other low-value radiology examinations.

Prognostic value of platelet levels in patients with aneurysmal Subarachnoid Hemorrhage.

Pathophysiological processes following aneurysmal subarachnoid hemorrhage (aSAH) include upregulated underlying systemic inflammation, which is reflected by changes in different peripheral blood cells and their sub-populations. As inflammation is a crucial process that contributes to post-aSAH complications and clincal outcome, blood cell numbers and ratios in systemic circulation may predict the outcome and provide rapid and easy to quantify point of care biomarkers for these critically ill patients. To identify blood-derived cellular inflammatory parameters which allow a precise prediction of patient outcome after aSAH. In this single-center retrospective study, 19 whole blood-derived cellular inflammatory markers and clinical and demographic parameters for 101 aSAH patients were recorded within 24 h after aSAH. Clinical outcome was quantified with modified Rankin scale (mRS) on discharge. Proportional odds logistic regression (POLR) was used to model the patient outcome as the function of clinical parameters and inflammatory markers. The results were validated on a separate hold-out dataset (220 patients). The on-admission platelet count, mean platelet volume (MPV) and mean platelet volume to platelet ratio (MPR) were found to be significant and predictive of patient outcome on discharge. Mean platelet volume (MPV) and mean platelet volume to platelet ratio (MPR) predicted clinical outcome and may serve as easy to quantify point of care biomarker. The findings are potentially relevant for the management of aSAH.

Norwegian general practitioners' and radiologists' perspectives on the referral, justification, and unnecessary imaging-a survey.

AIM: This study aimed to survey general practitioners' (GPs) and radiologists' perspectives on referrals, imaging justification, and unnecessary imaging in Norway. MATERIALS AND METHODS: The survey covered access to imaging, responsibilities, attitudes toward justification assessment, referral process, and demographics using multiple choice questions, statements to report agreement with using the Likert scale and one open question. RESULTS: Forty radiologists and 58 GPs attending national conferences completed a web-based survey, with a 20/15% response rate, respectively. Both radiologists (97%) and GPs (100%) considered avoiding unnecessary examinations essential to their role in the healthcare service. Still, 91% of GPs admitted that they referred to imaging they thought was not helpful, while about 60% of the radiologists agreed that unnecessary imaging was conducted in their workplace. GPs reported pressure from patients and patients having private insurance as the most common reasons for doing unnecessary examinations. In contrast, radiologists reported a lack of clinical information and the inability to discuss patient cases with the GPs as the most common reasons. CONCLUSION: This study adds to our understanding of radiologists' and GPs' perspectives on unnecessary imaging and referrals. Better guidelines and, even more importantly, better communication between the referrer and the radiologist are needed. Addressing these issues can reduce unnecessary imaging and improve the quality and safety of care.

Temporal and geographical variations in diagnostic imaging in Norway.

BACKGROUND: Unwarranted temporal and geographical variations are acknowledged as a profound problem for equal access and justice in the provision of health services. Even more, they challenge the quality, safety, and efficiency of such services. This is highly relevant for imaging services. OBJECTIVE: To analyse the temporal and geographical variation in the number of diagnostic images in Norway from 2013 to 2021. METHODS: Data on outpatient imaging provided by the Norwegian Health Economics Administration (HELFO) and inpatient data afforded by fourteen hospital trusts and hospitals in Norway. Data include the total number of imaging examinations according to the Norwegian Classification of Radiological Procedures (NCRP). Analyses were performed with descriptive statistics. RESULTS: More than 37 million examinations were performed in Norway during 2013-2021 giving an average of 4.2 million examinations per year. In 2021 there was performed and average of 0.8 examinations per person and 2.2 examinations per person for the age group > 80. There was a 9% increase in the total number of examinations from 2013 to 2015 and a small and stable decrease of 0.5% per year from 2015 to 2021 (with the exception of 2020 due to the pandemic). On average 71% of all examinations were outpatient examinations and 32% were conducted at private imaging centres. There were substantial variations between the health regions, with Region South-East having 53.1% more examinations per inhabitant than Region West. The geographical variation was even more outspoken when comparing catchment areas, where Oslo University Hospital Trust had twice as many examinations per inhabitant than Finnmark Hospital Trust. CONCLUSION: As the population in Norway is homogeneous it is difficult to attribute the variations to socio-economic or demographic factors. Unwarranted and supply-sensitive variations are challenging for healthcare systems where equal access and justice traditionally are core values.

Cost of Low-Value Imaging Worldwide: A Systematic Review.

BACKGROUND AND OBJECTIVE: Imaging with low or no benefit for the patient undermines the quality of care and amounts to vast opportunity costs. More than 3.6 billion imaging examinations are performed annually, and about 20-50% of these are of low value. This study aimed to synthesize knowledge of the costs of low-value imaging worldwide. METHODS: This systematic review was based on the PRISMA statement. The database search was developed in Medline and further adapted to Embase-Ovid, Cochrane Library, and Scopus. Primary empirical studies assessing the costs of low-value diagnostic imaging were included if published between 2012 and March 2022. Studies designed as randomized controlled trials, non-randomized trials, cohort studies, cross-sectional studies, descriptive studies, cost analysis, cost-effectiveness analysis, and mixed-methods studies were eligible. The analysis was descriptive. RESULTS: Of 5,567 records identified, 106 were included. Most of the studies included were conducted in the USA (n = 76), and a hospital or medical center was the most common setting (n = 82). Thirty-eight of the included studies calculated the costs of multiple imaging modalities; in studies with only one imaging modality included, conventional radiography was the most common (n = 32). Aggregated costs for low-value examinations amounts to billions of dollars per year globally. Initiatives to reduce low-value imaging may reduce costs by up to 95% without harming patients. CONCLUSIONS: This study is the first systematic review of the cost of low-value imaging worldwide, documenting a high potential for cost reduction. Given the universal challenges with resource allocation, the large amount used for low-value imaging represents a vast opportunity cost and offers great potential to improve the quality and efficiency of care.

Moral obligations towards human persons' wellbeing versus their suffering: An analysis of perspectives of moral philosophy.

What do we owe other persons? Are we as much obliged to promote their wellbeing as we are to reduce their suffering? This question is crucial for a range of social institutions and welfare services, and especially for the health services. To address this question the article investigates prominent positions and arguments in moral philosophy. It finds that while classical utilitarianism claims that there is symmetry in the moral obligation with respect to peoples' wellbeing and their suffering, a wide range of other positions and perspectives argue for an asymmetric relationship with stronger moral obligations towards other persons' suffering than towards their wellbeing. This difference in obligations is supported ontologically by basic differences inherent in wellbeing and suffering and axiologically by a relative (gradual) difference in value. The many well-founded arguments for stronger moral obligations towards other persons' suffering than towards their wellbeing has important implications for health policy; especially for priority setting. Avoiding and reducing suffering should have priority to the promotion and enhancement of wellbeing.

Bioethics: No Method-No Discipline?

This article raises the question of whether bioethics qualifies as a discipline. According to a standard definition of discipline as "a field of study following specific and well-established methodological rules" bioethics is not a specific discipline as there are no explicit "well-established methodological rules." The article investigates whether the methodological rules can be implicit, and whether bioethics can follow specific methodological rules within subdisciplines or for specific tasks. As this does not appear to be the case, the article examines whether bioethics' adherence to specific quality criteria (instead of methodological rules) or pursuing of a common goal can make it qualify as a discipline. Unfortunately, the result is negative. Then, the article scrutinizes whether referring to bioethics institutions and professional qualifications can ascertain bioethics as a discipline. However, this makes the definition of bioethics circular. The article ends by admitting that bioethics can qualify as a discipline according to broader definitions of discipline, for example, as an "area of knowledge, research and education." However, this would reduce bioethics' potential for demarcation and identity-building. Thus, to consolidate the discipline of bioethics and increase its impact, we should explicate and elaborate on its methodology.

Low-value MRI of the knee in Norway: a register-based study to identify the proportion of potentially low-value MRIs and estimate the related costs.

OBJECTIVES: The objective of this study is to investigate the proportion of potentially low-value knee MRI in Norway and to provide an estimate of the related costs. DESIGN: Register study based on conditional data extraction and analysis of data from Control and Reimbursement of Healthcare Claims registry in Norway. SETTING: MRI in public specialist healthcare with universal health coverage (Norway). PARTICIPANTS: 48 212 MRIs for 41 456 unique patients and 45 946 reimbursement claims. OUTCOME MEASURES: Proportion of MRIs of the knee that (1) did not have a relevant tentative diagnosis prior to the knee MRI, (2) did not have a relevant alternative image of the knee before the MRI or (3) did not have a relevant code from the specialist care within 6 months after the MRI, and those that had combinations of 1, 2 and 3. Estimated costs for those that had combinations of 1, 2 and 3. RESULTS: Very few patients (6.4%) had a relevant diagnosis code or prior imaging examination when having the MRI and only 14.6% got a knee-related diagnosis code from the specialist care within 6 months after the MRI. 21.8% of the patients had knee X-ray, CT or ultrasound within 6 months before the MRI. Between 58% and 85% of patients having knee MRIs in Norway have no relevant examinations or diagnoses six months prior to or after the MRI examination. These examinations are unlikely to benefit patients and they correspond to between 24 108 and 35 416 MRIs at a cost of €6.7-€9.8 million per year. CONCLUSION: A substantial proportion of MRIs of the knee in Norway have no relevant examinations or diagnoses before or after the MRI and are potentially of low value. Reducing low-value MRIs could free resources for high-value imaging, reduce waiting times, improve the quality of care and increase patient safety and professional integrity.

Kairos in diagnostics.

Kairos has been a key concept in medicine for millennia and is frequently understood as "the right time" in relation to treatment. In this study we scrutinize kairos in the context of diagnostics. This has become highly topical as technological developments have caused diagnostics to be performed ever earlier in the disease development. Detecting risk factors, precursors, and predictors of disease (in biomarkers, pre-disease, and pre-pre-disease) has resulted in too early diagnoses, i.e., overdiagnoses. Nonetheless, despite vast advances in science and technology, diagnoses also come too late. Accordingly, timing diagnostics right is crucial. In this article we start with giving a brief overview of the etymology and general use of the concepts of kairos and diagnosis. Then we delimit kairos in diagnostics by analysing "too early" and "too late" diagnosis and by scrutinizing various phases of diagnostics. This leads us to define kairos of diagnostics as the time when there is potential for sufficient information for making a diagnosis that is most helpful for the person. It allows us to conclude that kairos is as important in diagnostics as in therapeutics.

Evaluation of FRESH scores in predicting outcome and quality of life after aneurysmal subarachnoid haemorrhage in a European patient cohort.

BACKGROUND: Despite aneurysmal subarachnoid haemorrhage (aSAH) patients often experiencing physical and mental disabilities impacting their quality of life (QoL), routine assessment of long-term QoL data and predictive tools are limited. This study evaluates the newly developed "functional recovery expected after subarachnoid haemorrhage" (FRESH) scores with long-term outcomes and QoL in European aSAH patients. METHODS: FRESH, FRESH-cog, and FRESH-quol scores were retrospectively obtained from aSAH patients. Patients were contacted, and the modified Rankin Scale (mRS), extended short form-36 (SF-36), and telephone interview for cognitive status (TICS) were collected and performed. The prognostic and empirical outcomes were compared. RESULTS: Out of 374 patients, 171 patients (54.1%) completed the SF-36, and 154 patients completed the TICS. The SF-36 analysis showed that 32.7% had below-average physical component summary (PCS) scores, and 39.8% had below-average mental component summary (MCS) scores. There was no significant correlation between the FRESH score and PCS (p = 0.09736), MCS (p = 0.1796), TICS (p = 0.7484), or mRS 10-82 months (average 46 months) post bleeding (p = 0.024), respectively. There was also no significant correlation found for "FRESH-cog vs. TICS" (p = 0.0311), "FRESH-quol vs. PCS" (p = 0.0204), "FRESH-quol vs. MCS" (p = 0.1361) and "FRESH-quol vs. TICS" (p = 0.1608). CONCLUSIONS: This study found no correlation between FRESH scores and validated QoL tools in a European population of aSAH patients. The study highlights the complexity of reliable long-term QoL prognostication in aSAH patients and emphasises the need for further prospective research to also focus on QoL as an important outcome parameter.

Revisiting the WFNS Score: Native Computed Tomography Imaging Improves Identification of Patients With "False Poor Grade" Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: In patients suffering from aneurysmal subarachnoid hemorrhage (aSAH), the optimal time to determine the World Federation of Neurosurgical Societies (WFNS) score remains controversial because of possible confounding factors. Goals of this study were (1) to analyze the most sensitive timepoint to determine the WFNS score in patients with aSAH and (2) to evaluate the impact of initial native computed tomography (CT) imaging on reducing the mismatch of "false poor grade" patients. METHODS: We retrospectively analyzed daily WFNS scores from admission until day 7 in 535 aSAH patients and evaluated their predictive value for the modified Rankin Scale at discharge and 6 months postbleeding. Patients with an initial WFNS score of IV-V who showed improvement to a WFNS score of I-II within the first 7 days (even short-term) were defined as "false poor grade" patients. We tried to identify the "false poor grade" patients using parameters of the initial native CT imaging. RESULTS: Later determination of the WFNS score (day 1 vs 7; pseudo-R 2 = 0.13 vs 0.21) increasingly improved its predictive value for neurological outcome at discharge ( P < .001). We identified 39 "false poor grade" patients who had significantly better outcomes than "real poor grade" patients (N = 220) (modified Rankin Scale-discharge: 0-2, 56% vs 1%, P < .001; 3-5: 41% vs 56%, P = .12; 6: 3% vs 43%, P < .001). "False poor grade" patients differed significantly in initial CT parameters. A predictive model called "initial CT WFNS" ( ICT WFNS) was developed, incorporating SEBES, Hijdra score, and LeRoux score (sensitivity = 0.95, specificity = 0.84, accuracy = 0.859, F1 = 0.673). ICT WFNS scores of ≤4.6 classified patients as "false poor grade." CONCLUSION: The initial WFNS score may misclassify a subgroup of patients with aSAH as poor grade, which can be avoided by later determination of the WFNS score, at days 3-4 losing its usefulness. Alternatively, the initial WFNS score can be improved in its predictive value, especially in poor-grade patients, using criteria from the initial native CT imaging, such as the Hijdra, LeRoux, and Subarachnoid Hemorrhage Early Brain Edema score, combined in the ICT WFNS score with even higher predictive power.

Clinical Outcome Prediction of Early Brain Injury in Aneurysmal Subarachnoid Hemorrhage: the SHELTER-Score.

BACKGROUND: Despite intensive research on preventing and treating vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage (aSAH), mortality and morbidity rates remain high. Early brain injury (EBI) has emerged as possibly the major significant factor in aSAH pathophysiology, emphasizing the need to investigate EBI-associated clinical events for improved patient management and decision-making. This study aimed to identify early clinical and radiological events within 72 h after aSAH to develop a conclusive predictive EBI score for clinical practice. METHODS: This retrospective analysis included 561 consecutive patients with aSAH admitted to our neurovascular center between 01/2014 and 09/2022. Fourteen potential predictors occurring within the initial 72 h after hemorrhage were analyzed. The modified Rankin Scale (mRS) score at 6 months, discretized to three levels (0-2, favorable; 3-5, poor; 6, dead), was used as the outcome variable. Univariate ordinal regression ranked predictors by significance, and forward selection with McFadden's pseudo-R2 determined the optimal set of predictors for multivariate proportional odds logistic regression. Collinear parameters were excluded, and fivefold cross-validation was used to avoid overfitting. RESULTS: The analysis resulted in the Subarachnoid Hemorrhage Associated Early Brain Injury Outcome Prediction score (SHELTER-score), comprising seven clinical and radiological events: age (0-4 points), World Federation of Neurosurgical Societies (0-2.5 points), cardiopulmonary resuscitation (CPR) (2 points), mydriasis (1-2 points), midline shift (0.5-1 points), early deterioration (1 point), and early ischemic lesion (2 points). McFadden's pseudo-R2 = 0.339, area under the curve for death or disability 0.899 and 0.877 for death. A SHELTER-score below 5 indicated a favorable outcome (mRS 0-2), 5-6.5 predicted a poor outcome (mRS 3-5), and ≥ 7 correlated with death (mRS 6) at 6 months. CONCLUSIONS: The novel SHELTER-score, incorporating seven clinical and radiological features of EBI, demonstrated strong predictive performance in determining clinical outcomes. This scoring system serves as a valuable tool for neurointensivists to identify patients with poor outcomes and guide treatment decisions, reflecting the great impact of EBI on the overall outcome of patients with aSAH.

Undermining autonomy and consent: the transformative experience of disease.

Disease radically changes the life of many people and satisfies formal criteria for being a transformative experience. According to the influential philosophy of Paul, transformative experiences undermine traditional criteria for rational decision-making. Thus, the transformative experience of disease can challenge basic principles and rules in medical ethics, such as patient autonomy and informed consent. This article applies Paul's theory of transformative experience and its expansion by Carel and Kidd to investigate the implications for medical ethics. It leads to the very uncomfortable conclusion that disease involves transformative experiences in ways that can reduce people's rational decision-making ability and undermine the basic principle of respect for autonomy and the moral rule of informed consent. While such cases are limited, they are crucial for medical ethics and health policy and deserve more attention and further scrutiny.

Variations in wait times for imaging services: a register-based study of self-reported wait times for specific examinations in Norway.

BACKGROUND: While the number of medical images has increased substantially, the demand has outpaced access, resulting in long wait times in many countries. Long wait times are a key problem for patient safety and quality of care as they can result in prolonged suffering, delayed diagnosis and treatment, as well as poorer prognosis and loss of lives. Surprisingly, little is known about wait times for imaging services. OBJECTIVE: Investigate wait times for specific imaging services in Norway and to compare wait times with the total number of examinations and their development over time. METHODS: Data from the wait time registry at the Norwegian Directorate of Health from 2018 to 2021 as well as data on outpatient imaging provided by the Norwegian Health Economics Administration (HELFO) and in-patient data afforded by fourteen hospital trusts and hospitals in Norway were analysed. Data include the total number of imaging examinations according to the Norwegian Classification of Radiological Procedures (NCRP). Analyses were performed with descriptive statistics. RESULTS: Wait times vary through the months of the year. Conventional X-ray (XR) had the shortest wait times (3.0-4.4 weeks), and Magnetic Resonance Imaging (MRI) and ultrasound (US) had the lengthiest (8.7-12.0 and 7.9-11.4 weeks respectively). The wait times were lengthiest during the summer and winter holidays. Variations in wait times were also found for specific examination types between Norway's four public health regions. In addition, there was variation over time within the health regions. The wait times with the private health providers were substantially lower than with the public health providers. From 2018 to 2021, the wait time for MRIs increased by 6.6%, while the number of examinations (per 10,000) increased by 8.6%. Those regions with the highest number of examinations per 1,000 inhabitants per year had the lowest wait times. CONCLUSION: Wait times for diagnostic imaging procedures varied with time, region, and modality in Norway from 2018 to 2021. Long wait times may entail many negative consequences for patients, professionals, and the healthcare system. Reducing long wait times is an obvious way to improve the quality, safety, and efficiency of care.