Background/Objectives: The recommendations included in medical guidelines (GLs) provide important help to medical professionals for making clinical decisions regarding the diagnosis and treatment of various diseases. However, there are no systematic methods to measure the helpfulness of GLs. Thus, we developed an objective assessment of GLs which indicates their helpfulness and quality. We hypothesized that a simple mathematical analysis of \'Recommendations\' and \'Evidence\' would suffice. Methods: As a proof of concept, a mathematical analysis was conducted on the \'2020 European Society of Cardiology Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease Guideline\' (SCE-guideline). First, the frequencies of Classes of Recommendations (CLASS) and the Levels of Evidence (LEVEL) (n = 159) were analysed. Then, LEVEL areas under CLASS were calculated to form a certainty index (CI: -1 to +1). Results: The frequency of CLASS I (\'to do\') and CLASS III (\'not to do\') was relatively high in the SCE-guideline (52.2%). Yet, the most frequent LEVEL was C (41.2-83.8%), indicating only a relatively low quality of scientific evidence in the SCE-guideline. The SCE-guideline showed a relatively high CI (+0.57): 78.4% certainty and 21.6% uncertainty. Conclusions: The SCE-guideline provides substantial help in decision making through the recommendations (CLASS), while the supporting evidence (LEVEL) in most cases is of lower quality. This is what the newly introduced certainty index showed: a tool for \'quality control\' which can identify specific areas within GLs, and can promote the future improvement of GLs. The newly developed mathematical analysis can be used as a Guideline for the Guidelines, facilitating the assessment and comparison of the helpfulness and quality of GLs.

BACKGROUND: A new quality assurance and control method for electrometers using a new current source, different from the method published in the guidelines for electrometers, has been reported. This current source uses dry batteries and exhibits excellent performance in terms of voltage, temperature, and time characteristics. The electrometer sensitivity coefficient can be calculated by comparing the sensitivity of one electrometer with that of another on the electrometer calibration coefficient that has been calibrated by a calibration laboratory in advance in both methods. The guideline method requires two or more sets of ionization chambers and electrometers in the facility. In contrast, our method does not use ionization chambers; therefore, the sensitivity ratio of the electrometer can be measured in any facility. This study compared the uncertainty of the electrometer sensitivity factor calculated using the new current source method (current method) with that calculated using a linear accelerator (LINAC) and ionization chambers (LINAC method) described in the electrometer guidelines.
METHODS: In this study, we used a current source that we invented previously by Kawaguchi Electric Works in Japan. The sensitivity ratios of the electrometers were measured with three manufacture\'s electrometers. The electrometer sensitivity factor was calculated by multiplying the electrometer calibration coefficient. The ionization chamber was 30013 (PTW), and the current source was the current obtained from 10 MV TrueBeam X-rays under calibration conditions. The mean value, standard deviation, and coefficient of variation were calculated. The time required to set up the ionization chamber for calculating the sensitivity ratio of the electrometer was also measured. The accuracy was confirmed by calculating the expanded uncertainty of the electrometer sensitivity coefficients.
RESULTS: The LINAC method had a maximum coefficient of variation of 0.072%. The gross time of the LINAC method was approximately 110 min. The current method had a maximum coefficient of variation of 0.0055% and took less than half the time taken by the LINAC method (35 min) because there was no waiting time for the ionization chamber to be set up and the applied voltage to stabilize under calibration conditions. The expanded uncertainties of the electrometer calibration coefficients were 0.36% and 0.36%, respectively.
CONCLUSIONS: The new cross-comparison method for electrometer sensitivity factors using a current source is more efficient and useful than the linear accelerator method described in the guidelines; furthermore, this method ensured accuracy for quality assurance and control of electrometers.

The goal of metrological traceability is to have equivalent results for a measurand in clinical samples (CSs) irrespective of the in-vitro diagnostic medical device (IVD-MD) used for measurements. The International Standards Organization standard 17511 defines requirements for establishing metrological traceability of values assigned to calibrators, trueness control materials and human samples used with IVD-MDs. Each step in metrological traceability has an uncertainty associated with the value assigned to a material. The uncertainty at each step adds to the uncertainty from preceding steps such that the combined uncertainty gets larger at each step. The combined uncertainty for a CS result must fulfil an analytical performance specification (APS) for the maximum allowable uncertainty (umax CS). The umax CS can be partitioned among the steps in a metrological traceability calibration hierarachy to derive the APS for maximum allowable uncertainty at each step. Similarly, the criterion for maximum acceptable noncommutability bias can be derived from the umax CS. One of the challenges in determining if umax CS is fulfilled is determining the repeatability uncertainty (u Rw) from operating an IVD-MD within a clinical laboratory. Most of the current recommendations for estimating u Rw from internal quality control data do not use a sufficiently representative time interval to capture all relevant sources of variability in measurement results. Consequently, underestimation of u Rw is common and may compromise assessment of how well current IVD-MDs and their supporting calibration hierarchies meet the needs of clinical care providers.

BACKGROUND: Serious illness is characterised by uncertainty, particularly in older age groups. Uncertainty may be experienced by patients, family carers, and health professionals about a broad variety of issues. There are many evidence gaps regarding the experience and management of uncertainty.
OBJECTIVE: We aimed to identify priority research areas concerning uncertainty in serious illness, to ensure that future research better meets the needs of those affected by uncertainty and reduce research inefficiencies.
METHODS: Rapid prioritisation workshop comprising five focus groups to identify research areas, followed by a ranking exercise to prioritise them. Participants were healthcare professionals caring for those with serious illnesses including geriatrics, palliative care, intensive care; researchers; patient/carer representatives, and policymakers. Descriptive analysis of ranking data and qualitative framework analysis of focus group transcripts was undertaken.
RESULTS: Thirty-four participants took part; 67% female, mean age 47 (range 33-67). The highest priority was communication of uncertainty, ranked first by 15 participants (overall ranking score 1.59/3). Subsequent priorities were: 2) How to cope with uncertainty; 3) healthcare professional education/training; 4) Optimising clinical approaches to uncertainty; and 5) exploring in-depth experiences of uncertainty. Research questions regarding optimal management of uncertainty were given higher priority than questions about experiences of uncertainty and its impact.
CONCLUSIONS: These co-produced, clinically-focused research priorities map out key evidence gaps concerning uncertainty in serious illness. Managing uncertainty is the most pressing issue, and researchers should prioritise how to optimally manage uncertainty in order to reduce distress, unlock decision paralysis and improve illness and care experience.

Evidence-based clinical guidelines are essential to maximize patient benefit and to reduce clinical uncertainty and inconsistency in clinical practice. Gaps in the evidence base can be addressed by data acquired in routine practice. At present, there is no international consensus on management of women diagnosed with atypical lesions in breast screening programmes. Here, we describe how routine NHS breast screening data collected by the Sloane atypia project was used to inform a management pathway that maximizes early detection of cancer and minimizes over-investigation of lesions with uncertain malignant potential. A half-day consensus meeting with 11 clinical experts, 1 representative from Independent Cancer Patients\' Voice, 6 representatives from NHS England (NHSE) including from Commissioning, and 2 researchers was held to facilitate discussions of findings from an analysis of the Sloane atypia project. Key considerations of the expert group in terms of the management of women with screen detected atypia were: (1) frequency and purpose of follow-up; (2) communication to patients; (3) generalizability of study results; and (4) workforce challenges. The group concurred that the new evidence does not support annual surveillance mammography for women with atypia, irrespective of type of lesion, or woman\'s age. Continued data collection is paramount to monitor and audit the change in recommendations.

Develop a consensus on the content and form of safety netting advice (SNA) for parents of acutely ill children.
Four-round modified e-Delphi using online questionnaires and feedback among clinical and research experts.
Ambulatory care in high-income countries.
Forty-one experts from 13 countries: 3 emergency physicians, 15 general practitioners, 4 nurses and 19 paediatricians.
The experts defined the content of SNA as advice on the normal, expected disease course of the provisional diagnosis, diagnostic uncertainty, alarm signs that indicate the need for medical help and information on where and how to find such help. Regarding the form of the SNA, the experts agree that a reliable source should give SNA verbally with paper or digital written or video/image resources at every appropriate healthcare encounter in a short and simple empowering fashion, specific to the child\'s situation and seek confirmatory feedback from parents.
SNA needs to contain advice on the expected disease course, alarm signs and where and how to find help. It should be given verbally with written resources by a reliable healthcare professional or digital platform. Short, simple and specific, SNA needs to empower the parent whose understanding of the advice should be checked. The effectiveness of SNA resources coproduced by parents and experts should be assessed in different settings and those providing SNA require up-to-date and reliable training.

Due to uncertainty in tumor phylogeny inference from sequencing data, many methods infer multiple, equally plausible phylogenies for the same cancer. To summarize the solution space T of tumor phylogenies, consensus tree methods seek a single best representative tree S under a specified pairwise tree distance function. One such distance function is the ancestor-descendant (AD) distance [Formula: see text] , which equals the size of the symmetric difference of the transitive closures of the edge sets [Formula: see text] and [Formula: see text] . Here, we show that finding a consensus tree S for tumor phylogenies T that minimizes the total AD distance [Formula: see text] is NP-hard.

Further improvements of outcome after solid organ transplantation will depend on our ability to integrate personalized medicine in clinical routine. Not only better risk stratification or improved diagnostics, also targeted therapies and predictive markers of treatment success are needed, as there is a virtual standstill in the development and implementation of novel therapies for prevention and treatment of allograft rejection. The integration of clinical decision support algorithms and novel biomarkers in clinical practice will require a different reasoning, embracing concepts of uncertainty and probabilistic thinking as the ground truth is often unknown and the tools imperfect. This is important for communication between healthcare professionals, but patients and their caregivers also need to be informed and educated about the levels of uncertainty inherent to personalized medicine. In the translation of research findings and personalized medicine to routine clinical care, it remains crucial to maintain global consensus on major aspects of clinical routine, to avoid further divergence between centres and countries in the standard of care. Such consensus can only be reached when experts with divergent opinions are willing to transcend their own convictions, understand that there is not one single truth, and thus are able to embrace a level of uncertainty.

Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children\'s situations.
In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents\' and child\'s DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child\'s future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child\'s future developmental of autonomous capacities.
When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD.

AbstractProfessional statements guide neonatal resuscitation thresholds at the border of viability. A 2015 systematic review of international guidelines by Guillen et al. found considerable variability between statements\' clinical recommendations for infants at 23-24 weeks gestational age (GA). The authors concluded that differences in the type of data included were one potential source for differing resuscitation thresholds within this \"ethical gray zone.\" How statements present ethical considerations that support their recommendations, and how this may account for variability, has not been as rigorously explored. We performed a mixed-methods exploratory analysis of 25 current international guidelines for neonatal resuscitation at 22+0-25+0 weeks GA. Qualitative analysis using a modified grounded theory yielded 34 distinct codes, eight categories, and four overarching themes. Three themes, consequentialism, principlism, and rights-based, consisted of concepts central to these ethical frameworks. The fourth theme, clinical reasoning, described counseling practices, medical management, outcomes data, and prognostic uncertainty, without any ethical context. The theme of clinical reasoning appeared in 22 of 25 guidelines. Ten guidelines lacked any ethical theme. Guidelines with an identified ethical theme were more likely to recommend comfort care than guidelines without an identified ethical theme, and recommended it at a higher average GA (22.7 weeks vs. 22.0 weeks, p = 0.03). Thus, how ethical concepts are incorporated into guidelines potentially impacts resuscitation thresholds. We argue that inclusion of explicit discussion of ethical considerations surrounding resuscitation in the \"gray zone\" would clarify values that inform recommendations and facilitate discussions about how neonatology ought to approach periviability as outcomes continue to evolve.