Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition.

ConspectusConjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut-Currier (RC) and Morita-Baylis-Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the ß-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position.Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloisomerizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted ß-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.

Enantioselective Synthesis of Cyclopentenes by (3+2) Annulation via a 2-Carbon Phosphonium.

Herein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2-carbon component. The reaction involves an α-umpolung ß-umpolung coupling sequence, enabled by ß-haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that ß-haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α- and ß-positions.

Artificial intelligence and clinical decision support: clinicians' perspectives on trust, trustworthiness, and liability.

Artificial intelligence (AI) could revolutionise health care, potentially improving clinician decision making and patient safety, and reducing the impact of workforce shortages. However, policymakers and regulators have concerns over whether AI and clinical decision support systems (CDSSs) are trusted by stakeholders, and indeed whether they are worthy of trust. Yet, what is meant by trust and trustworthiness is often implicit, and it may not be clear who or what is being trusted. We address these lacunae, focusing largely on the perspective(s) of clinicians on trust and trustworthiness in AI and CDSSs. Empirical studies suggest that clinicians' concerns about their use include the accuracy of advice given and potential legal liability if harm to a patient occurs. Onora O'Neill's conceptualisation of trust and trustworthiness provides the framework for our analysis, generating a productive understanding of clinicians' reported trust issues. Through unpacking these concepts, we gain greater clarity over the meaning ascribed to them by stakeholders; delimit the extent to which stakeholders are talking at cross purposes; and promote the continued utility of trust and trustworthiness as useful concepts in current debates around the use of AI and CDSSs.

Insights from developing and evaluating the NHS blood choices transfusion app to support junior and middle-grade doctor decision making against guidelines.

OBJECTIVES: To: 1. Develop a CE-marked smartphone App to support doctors' concordance with transfusion guidelines in non-bleeding adult patients, emphasising informed consent and anaemia management. 2. Test App accuracy and potential to improve user decisions. BACKGROUND: Studies have shown inappropriate use of blood components and that most junior doctors own smartphones with medical apps. METHODS: A multidisciplinary team developed App screens and logic through an iterative process based on national guidelines. Thirty medical or surgical transfusion scenarios were developed based on national guidelines and each sent to Consultant Haematologist experts in Transfusion Medicine. To obtain a clinical consensus and exclude ambiguous scenarios, their independent decisions and associated certainty were compared. The consensus clinical decision was then compared with guidance from the App. To explore potential App impact on simulated user decisions, 26 junior doctors responded to five transfusion scenarios before and after access to the App. RESULTS: The Blood Choices App agreed with 91% (95% CI: 72%-99%) of expert decisions with a sensitivity of 100% (69% to 100%) and specificity of 85% (55%-98%). Excluding one malfunction scenario, the App had the potential to increase correct decisions by junior doctors from 83% (73%-90%) pre-App use to 96% (88%-99%) post (p-value 0.013), with 90% (67%-99%) saying they would use it in practice. CONCLUSIONS: Transfusion guidelines can be converted into an App with potential to improve guideline concordance. However, evaluating such Apps is essential to understand their limitations, detect malfunctions and prevent harm.

Redox Isomerization/(3+2) Allenoate Annulation by Auto-Tandem Phosphine Catalysis.

A phosphine-catalyzed approach to pyrrolines has been developed that involves two mechanistically unlinked catalytic processes. The first involves the redox isomerization of amino crotonates to provide access to aliphatic tosyl imines, which then engage in a (3+2) annulation with various allenoates. The reaction shows generality, with 24 examples established, along with a low yielding and moderately enantioselective variant. Mechanistic studies indicate that the viability of the process is linked to the selection of catalysts with similar propensity to add to the two coupling partners.

Online Guide for Electronic Health Evaluation Approaches: Systematic Scoping Review and Concept Mapping Study.

BACKGROUND: Despite the increase in use and high expectations of digital health solutions, scientific evidence about the effectiveness of electronic health (eHealth) and other aspects such as usability and accuracy is lagging behind. eHealth solutions are complex interventions, which require a wide array of evaluation approaches that are capable of answering the many different questions that arise during the consecutive study phases of eHealth development and implementation. However, evaluators seem to struggle in choosing suitable evaluation approaches in relation to a specific study phase. OBJECTIVE: The objective of this project was to provide a structured overview of the existing eHealth evaluation approaches, with the aim of assisting eHealth evaluators in selecting a suitable approach for evaluating their eHealth solution at a specific evaluation study phase. METHODS: Three consecutive steps were followed. Step 1 was a systematic scoping review, summarizing existing eHealth evaluation approaches. Step 2 was a concept mapping study asking eHealth researchers about approaches for evaluating eHealth. In step 3, the results of step 1 and 2 were used to develop an "eHealth evaluation cycle" and subsequently compose the online "eHealth methodology guide." RESULTS: The scoping review yielded 57 articles describing 50 unique evaluation approaches. The concept mapping study questioned 43 eHealth researchers, resulting in 48 unique approaches. After removing duplicates, 75 unique evaluation approaches remained. Thereafter, an "eHealth evaluation cycle" was developed, consisting of six evaluation study phases: conceptual and planning, design, development and usability, pilot (feasibility), effectiveness (impact), uptake (implementation), and all phases. Finally, the "eHealth methodology guide" was composed by assigning the 75 evaluation approaches to the specific study phases of the "eHealth evaluation cycle." CONCLUSIONS: Seventy-five unique evaluation approaches were found in the literature and suggested by eHealth researchers, which served as content for the online "eHealth methodology guide." By assisting evaluators in selecting a suitable evaluation approach in relation to a specific study phase of the "eHealth evaluation cycle," the guide aims to enhance the quality, safety, and successful long-term implementation of novel eHealth solutions.

Correction: Online Guide for Electronic Health Evaluation Approaches: Systematic Scoping Review and Concept Mapping Study.

[This corrects the article DOI: .].

Chemotherapy effectiveness in trial-underrepresented groups with early breast cancer: A retrospective cohort study.

BACKGROUND: Adjuvant chemotherapy in early stage breast cancer has been shown to reduce mortality in a large meta-analysis of over 100 randomised trials. However, these trials largely excluded patients aged 70 years and over or with higher levels of comorbidity. There is therefore uncertainty about whether the effectiveness of adjuvant chemotherapy generalises to these groups, hindering patient and clinician decision-making. This study utilises administrative healthcare data-real world data (RWD)-and econometric methods for causal analysis to estimate treatment effectiveness in these trial-underrepresented groups. METHODS AND FINDINGS: Women with early breast cancer aged 70 years and over and those under 70 years with a high level of comorbidity were identified and their records extracted from Scottish Cancer Registry (2001-2015) data linked to other routine health records. A high level of comorbidity was defined as scoring 1 or more on the Charlson comorbidity index, being in the top decile of inpatient stays, and/or having 5 or more visits to specific outpatient clinics, all within the 5 years preceding breast cancer diagnosis. Propensity score matching (PSM) and instrumental variable (IV) analysis, previously identified as feasible and valid in this setting, were used in conjunction with Cox regression to estimate hazard ratios for death from breast cancer and death from all causes. The analysis adjusts for age, clinical prognostic factors, and socioeconomic deprivation; the IV method may also adjust for unmeasured confounding factors. Cohorts of 9,653 and 7,965 were identified for women aged 70 years and over and those with high comorbidity, respectively. In the ≥70/high comorbidity cohorts, median follow-up was 5.17/6.53 years and there were 1,935/740 deaths from breast cancer. For women aged 70 years and over, the PSM-estimated HR was 0.73 (95% CI 0.64-0.95), while for women with high comorbidity it was 0.67 (95% CI 0.51-0.86). This translates to a mean predicted benefit in terms of overall survival at 10 years of approximately3% (percentage points) and 4%, respectively. A limitation of this analysis is that use of observational data means uncertainty remains both from sampling uncertainty and from potential bias from residual confounding. CONCLUSIONS: The results of this study, as RWD, should be interpreted with caution and in the context of existing and emerging randomised data. The relative effectiveness of adjuvant chemotherapy in reducing mortality in patients with early stage breast cancer appears to be generalisable to the selected trial-underrepresented groups.

Correction to: How can clinicians, specialty societies and others evaluate and improve the quality of apps for patient use?

Since the publication of this article [1] it has come to my attention that it contains an error in which the y-axis in Fig. 1 was inverted, thus incorrectly displaying a weak negative correlation rather than a weak positive one. This error was introduced as the order of the data on which Fig. 2 was based [2] was misread. The corrected version of Fig. 2 can be seen below, in which a weak positive correlation is now displayed. This does not change the general point, that app users and app stores appear to take little notice of the source of information on which apps are based. I apologise to readers for this error.

Preserving the Open Access Benefits Pioneered by the Journal of Medical Internet Research and Discouraging Fraudulent Journals.

The Journal of Medical Internet Research (JMIR) was an early pioneer of open access online publishing, and two decades later, some readers and authors may have forgotten the challenges of previous scientific publishing models. This commentary summarizes the many advantages of open access publishing for each of the main stakeholders in scientific publishing and reminds us that, like every innovation, there are disadvantages that we need to guard against, such as the problem of fraudulent journals. This paper then reviews the potential impact of some current initiatives, such as Plan S and JMIRx, concluding with some suggestions to help new open-access publishers ensure that the advantages of open access publishing outweigh the challenges.

Correction to: Boosting robot-assisted rehabilitation of stroke hemiparesis by individualized selection of upper limb movements - a pilot study.

The original article [1] contained a minor error in the following sentence in the Discussion.

Boosting robot-assisted rehabilitation of stroke hemiparesis by individualized selection of upper limb movements - a pilot study.

BACKGROUND: Intensive robot-assisted training of the upper limb after stroke can reduce motor impairment, even at the chronic stage. However, the effectiveness of practice for recovery depends on the selection of the practised movements. We hypothesized that rehabilitation can be optimized by selecting the movements to be practiced based on the trainee's performance profile. METHODS: We present a novel principle ('steepest gradients') for performance-based selection of movements. The principle is based on mapping motor performance across a workspace and then selecting movements located at regions of the steepest transition between better and worse performance. To assess the benefit of this principle we compared the effect of 15 sessions of robot-assisted reaching training on upper-limb motor impairment, between two groups of people who have moderate-to-severe chronic upper-limb hemiparesis due to stroke. The test group (N = 7) received steepest gradients-based training, iteratively selected according to the steepest gradients principle with weekly remapping, whereas the control group (N = 9) received a standard "centre-out" reaching training. Training intensity was identical. RESULTS: Both groups showed improvement in Fugl-Meyer upper-extremity scores (the primary outcome measure). Moreover, the test group showed significantly greater improvement (twofold) compared to control. The score remained elevated, on average, for at least 4 weeks although the additional benefit of the steepest-gradients -based training diminished relative to control. CONCLUSIONS: This study provides a proof of concept for the superior benefit of performance-based selection of practiced movements in reducing upper-limb motor impairment due to stroke. This added benefit was most evident in the short term, suggesting that performance-based steepest-gradients training may be effective in increasing the rate of initial phase of practice-based recovery; we discuss how long-term retention may also be improved. TRIAL REGISTRATION: ISRCTN, ISRCTN65226825 , registered 12 June 2018 - Retrospectively registered.

Independent validation of the PREDICT breast cancer prognosis prediction tool in 45,789 patients using Scottish Cancer Registry data.

BACKGROUND: PREDICT is a widely used online prognostication and treatment benefit tool for patients with early stage breast cancer. The aim of this study was to conduct an independent validation exercise of the most up-to-date version of the PREDICT algorithm (version 2) using real-world outcomes from the Scottish population of women with breast cancer. METHODS: Patient data were obtained for all Scottish Cancer Registry (SCR) records with a diagnosis of primary invasive breast cancer diagnosed in the period between January 2001 and December 2015. Prognostic scores were calculated using the PREDICT version 2 algorithm. External validity was assessed by statistical analysis of discrimination and calibration. Discrimination was assessed by area under the receiver-operator curve (AUC). Calibration was assessed by comparing the predicted number of deaths to the observed number of deaths across relevant sub-groups. RESULTS: A total of 45,789 eligible cases were selected from 61,437 individual records. AUC statistics ranged from 0.74 to 0.77. Calibration results showed relatively close agreement between predicted and observed deaths. The 5-year complete follow-up sample reported some overestimation (11.5%), while the 10-year complete follow-up sample displayed more limited overestimation (1.7%). CONCLUSIONS: Validation results suggest that the PREDICT tool remains essentially relevant for contemporary patients with early stage breast cancer.

How can clinicians, specialty societies and others evaluate and improve the quality of apps for patient use?

BACKGROUND: Health-related apps have great potential to enhance health and prevent disease globally, but their quality currently varies too much for clinicians to feel confident about recommending them to patients. The major quality concerns are dubious app content, loss of privacy associated with widespread sharing of the patient data they capture, inaccurate advice or risk estimates and the paucity of impact studies. This may explain why current evidence about app use by people with health-related conditions is scanty and inconsistent. MAIN TEXT: There are many concerns about health-related apps designed for use by patients, such as poor regulation and implicit trust in technology. However, there are several actions that various stakeholders, including users, developers, health professionals and app distributors, can take to tackle these concerns and thus improve app quality. This article focuses on the use of checklists that can be applied to apps, novel evaluation methods and suggestions for how clinical specialty organisations can develop a low-cost curated app repository with explicit risk and quality criteria. CONCLUSIONS: Clinicians and professional societies must act now to ensure they are using good quality apps, support patients in choosing between available apps and improve the quality of apps under development. Funders must also invest in research to answer important questions about apps, such as how clinicians and patients decide which apps to use and which app factors are associated with effectiveness.

Mapping upper-limb motor performance after stroke - a novel method with utility for individualized motor training.

BACKGROUND: Chronic upper limb motor impairment is a common outcome of stroke. Therapeutic training can reduce motor impairment. Recently, a growing interest in evaluating motor training provided by robotic assistive devices has emerged. Robot-assisted therapy is attractive because it provides a means of increasing practice intensity without increasing the workload of physical therapists. However, movements practised through robotic assistive devices are commonly pre-defined and fixed across individuals. More optimal training may result from individualizing the selection of the trained movements based on the individual's impairment profile. This requires quantitative assessment of the degree of the motor impairment prior to training, in relevant movement tasks. However, standard clinical measures for profiling motor impairment after stroke are often subjective and lack precision. We have developed a novel robot-mediated method for systematic and fine-grained mapping (or profiling) of individual performance across a wide range of planar arm reaching movements. Here we describe and demonstrate this mapping method and its utilization for individualized training. We also present a novel principle for the individualized selection of training movements based on the performance maps. METHODS AND RESULTS: To demonstrate the utility of our method we present examples of 2D performance maps produced from the kinetic and kinematics data of two individuals with stroke-related upper limb hemiparesis. The maps outline distinct regions of high motor impairment. The procedure of map-based selection of training movements and the change in motor performance following training is demonstrated for one participant. CONCLUSIONS: The performance mapping method is feasible to produce (online or offline). The 2D maps are easy to interpret and to be utilized for selecting individual performance-based training. Different performance maps can be easily compared within and between individuals, which potentially has diagnostic utility.

Breast cancer survivors' recollection of their illness and therapy seven years after enrolment into a randomised controlled clinical trial.

BACKGROUND: Little is known about the subjective experience of breast cancer survivors after primary treatment. However, these experiences are important because they shape their communication about their illness in everyday life, usage and acceptance of healthcare, and expectations of new generations of patients. The present study investigated this topic by combining qualitative and quantitative methods. METHODS: Breast cancer survivors in Bavaria, Germany were mailed a questionnaire up to seven years after enrolment into a randomised controlled clinical trial and start of their therapy. This enquired about their worst experiences during the breast cancer episode, positive aspects of the illness and any advice they would give to newly diagnosed patients. A category system for themes was systematically created and answers were categorised by two independent raters. Frequencies of key categories were then quantitatively analysed using descriptive statistics. In addition, local treating physicians gave their opinion on the response categories chosen by their patients. RESULTS: 133 (80%) of 166 eligible patients who survived up to seven years returned the questionnaire. The most prominent worst experience reported by survivors was psychological distress (i.e. anxiety, uncertainty; prevalence 38%) followed by chemotherapy (25%), and cancer diagnosis (18%). Positive aspects of the illness were reported by 48% with the most frequent including change in life priorities (50%) and social support (22%). The most frequent advice survivors gave was fighting spirit (i.e. think positive, never give up; prevalence 42%). Overall, physicians' estimates of the frequency of these responses corresponded well with survivors' answers. CONCLUSIONS: Although physicians' understanding of breast cancer patients was good, psychological distress and chemotherapy-related side effects were remembered as particularly burdensome by a substantial part of survivors. On the one hand, patients' quality of life needs to be assessed repeatedly during medical follow-up to identify such specific complaints also including specific recommendations to the physician for targeted psychosocial and medical support. On the other hand the advices and positive aspects of the disease, reported by the survivors, can be used to promote positive ways of coping with the illness.

App Usage Factor: A Simple Metric to Compare the Population Impact of Mobile Medical Apps.

BACKGROUND: One factor when assessing the quality of mobile apps is quantifying the impact of a given app on a population. There is currently no metric which can be used to compare the population impact of a mobile app across different health care disciplines. OBJECTIVE: The objective of this study is to create a novel metric to characterize the impact of a mobile app on a population. METHODS: We developed the simple novel metric, app usage factor (AUF), defined as the logarithm of the product of the number of active users of a mobile app with the median number of daily uses of the app. The behavior of this metric was modeled using simulated modeling in Python, a general-purpose programming language. Three simulations were conducted to explore the temporal and numerical stability of our metric and a simulated app ecosystem model using a simulated dataset of 20,000 apps. RESULTS: Simulations confirmed the metric was stable between predicted usage limits and remained stable at extremes of these limits. Analysis of a simulated dataset of 20,000 apps calculated an average value for the app usage factor of 4.90 (SD 0.78). A temporal simulation showed that the metric remained stable over time and suitable limits for its use were identified. CONCLUSIONS: A key component when assessing app risk and potential harm is understanding the potential population impact of each mobile app. Our metric has many potential uses for a wide range of stakeholders in the app ecosystem, including users, regulators, developers, and health care professionals. Furthermore, this metric forms part of the overall estimate of risk and potential for harm or benefit posed by a mobile medical app. We identify the merits and limitations of this metric, as well as potential avenues for future validation and research.

mHealth and mobile medical Apps: a framework to assess risk and promote safer use.

The use of mobile medical apps by clinicians and others has grown considerably since the introduction of mobile phones. Medical apps offer clinicians the ability to access medical knowledge and patient data at the point of care, but several studies have highlighted apps that could compromise patient safety and are potentially dangerous. This article identifies a range of different kinds of risks that medical apps can contribute to and important contextual variables that can modify these risks. We have also developed a simple generic risk framework that app users, developers, and other stakeholders can use to assess the likely risks posed by a specific app in a specific context. This should help app commissioners, developers, and users to manage risks and improve patient safety.

Enantioselective Synthesis of Cyclopentanes by Phosphine-Catalyzed ß,γ-Annulation of Allenoates.

Herein, we report the enantioselective phosphine-catalyzed ß,γ-annulation of electron-poor allenes with bifunctional malonates. The reaction exploits a 2C phosphonium synthon that when accessed using (R)-SITCP gives 23 cyclopentanes with high stereoselectivity (most >95:5 er and >9:1 dr) and yield. In addition to the (3+2) annulation, a one-pot three-component variant to give the same cyclopentanes and a (3+2) annulation/Dieckmann cyclization cascade, along with mechanistic studies, are reported.

Which computable biomedical knowledge objects will be regulated? Results of a UK workshop discussing the regulation of knowledge libraries and software as a medical device.

Introduction: To understand when knowledge objects in a computable biomedical knowledge library are likely to be subject to regulation as a medical device in the United Kingdom. Methods: A briefing paper was circulated to a multi-disciplinary group of 25 including regulators, lawyers and others with insights into device regulation. A 1-day workshop was convened to discuss questions relating to our aim. A discussion paper was drafted by lead authors and circulated to other authors for their comments and contributions. Results: This article reports on those deliberations and describes how UK device regulators are likely to treat the different kinds of knowledge objects that may be stored in computable biomedical knowledge libraries. While our focus is the likely approach of UK regulators, our analogies and analysis will also be relevant to the approaches taken by regulators elsewhere. We include a table examining the implications for each of the four knowledge levels described by Boxwala in 2011 and propose an additional level. Conclusions: If a knowledge object is described as directly executable for a medical purpose to provide decision support, it will generally be in scope of UK regulation as "software as a medical device." However, if the knowledge object consists of an algorithm, a ruleset, pseudocode or some other representation that is not directly executable and whose developers make no claim that it can be used for a medical purpose, it is not likely to be subject to regulation. We expect similar reasoning to be applied by regulators in other countries.