The NHS England 100,000 Genomes Project: feasibility and utility of centralised genome sequencing for children with cancer

Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally.Methods Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value.Results Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36).Conclusion Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.Subject terms: Cancer genomics, Cancer genomics     

Experimental evidence of physician social preferences

Physicians’ professional ethics require that they put patients’ interests ahead of their own and that they should allocate limited medical resources efficiently. Understanding physicians’ extent of adherence to these principles requires understanding the social preferences that lie behind them. These social preferences may be divided into two qualitatively different trade-offs: the trade-off between self and other (altruism) and the trade-off between reducing differences in payoffs (equality) and increasing total payoffs (efficiency). We experimentally measure social preferences among a nationwide sample of practicing physicians in the United States. Our design allows us to distinguish empirically between altruism and equality–efficiency orientation and to accurately measure both trade-offs at the level of the individual subject. We further compare the experimentally measured social preferences of physicians with those of a representative sample of Americans, an “elite” subsample of Americans, and a nationwide sample of medical students. We find that physicians’ altruism stands out. Although most physicians place a greater weight on self than on other, the share of physicians who place a greater weight on other than on self is twice as large as for all other samples—32% as compared with 15 to 17%. Subjects in the general population are the closest to physicians in terms of altruism. The higher altruism among physicians compared with the other samples cannot be explained by income or age differences. By contrast, physicians’ preferences regarding equality–efficiency orientation are not meaningfully different from those of the general sample and elite subsample and are less efficiency oriented than medical students.

In a classic article, Kenneth Arrow (1) argued that asymmetric information pervades the health-care market. Patients rely on physicians’ expert knowledge in planning their medical care. Health insurers and government agencies (Medicare and Medicaid) largely rely on physicians to decide which treatments are appropriate for their patients. This deference to physicians’ authority may be justified given their superior expertise and informational advantages (2). However, the dual role of recommending and providing treatments creates opportunities for physicians to place their interests ahead of their patients’ interests, for example by recommending profitable tests and treatments that offer little or no health benefits. A second risk is more subtle. Physicians must trade off their individual patients’ interests in getting care, even if the benefit is likely to be small, against society’s interest in allocating limited medical resources efficiently, in order to generate the greatest benefits for the overall health of a population.The norms of physician professionalism—including, in particular, the patient-centered norms that constitute physicians’ traditional professional ethic—are intended to address the risk of selfishness. Arrow argues that due to information asymmetry, the principle of“buyer beware” that governs ordinary consumer markets should be replaced, in health care, by the physicians’ professional responsibility to put patients’ interests ahead of their own (1). Physician leaders publicly promote the importance of professionalism, while exhorting physicians to act altruistically. For example, the editors of the New England Journal of Medicine have asserted that “medicine is one of the few spheres of human activity in which the purposes are unambiguously altruistic” (3), while the American Board of Internal Medicine similarly asserts that “altruism is the essence of professionalism … the best interest of patients, not self-interest, is the rule” (4). On the other hand, empirical studies have suggested that, at least in some situations, some physicians create “supplier-induced demand,” which influences a patient’s demand for care “against the physician’s interpretation of the best interest of the patient” (5), contributing to skepticism about whether physicians do in fact behave altruistically. [Such skepticism is not limited to medicine. Legal ethics, for example, has long sought to control lawyers’ abuse of discretion through professional norms of client loyalty and care (6). But skeptics have cast these norms as self-serving, and the law governing lawyers increasingly subjects them to elaborate institutionalized mechanisms of bureaucratic control.]While the effects of professional norms on physician behavior are difficult to measure directly, a clearer understanding of physicians’ social preferences can help to illuminate whether professional norms and physicians’ individual preferences are oppositional or aligned. Our study therefore helps to evaluate the likely effectiveness of both professional norms and the turn to bureaucracy. While altruism and related professional norms are important in many other professions (7), the distinct characteristics of the market for medical care, namely information asymmetry and uncertainty in the relationship between medical treatments and patient outcomes (1), render it especially critical to study these issues among physicians.Health care systems in the US and elsewhere address the second risk—concerning efficiency—in more complex ways. Although professional ethics give physicians a responsibility to conserve scarce medical resources (8), the norm that directs individual physicians to put their patients first may render a norm-based approach inadequate to the problem of efficiency (9). Health insurers therefore use bureaucratic mechanisms and financial incentives to manage the information asymmetry between a physician who knows the specific patient’s situation and the insurer which does not (9).^*We deploy an incentivized economic experiment to investigate both altruism (the trade-off between self and other) and equality–efficiency orientation (the trade-off between reducing self–other differences in payouts and increasing payout totals) in practicing US physicians, and we compare our results with analogous experiments that measure parallel behaviors in other populations. A vast literature considers social preferences, and laboratory experiments have been very fruitful in both establishing the empirical reliability of such preferences and directing theoretical attention to them. [We will not attempt to review the enormous body of work in behavioral and experimental economics on social preferences. Camerer (10) provides a comprehensive discussion, if now somewhat dated, of the vast body of experimental and theoretical research in economics focusing on dictator, ultimatum, and trust games. Engel (11) provides the most comprehensive meta-study of dictator games.] After presenting our results, we relate them to the results from prior work that are particularly relevant to our study (Discussion). We note that the social preferences of physicians and professionals more generally remain relatively understudied, and our discussion of the relationship between our study and prior work explains the specific contributions that we make.Our sample consists of 284 physicians from 36 medical groups around the United States, including physicians in primary care (internal medicine and family medicine) and cardiology, and physicians in private practices and employed by hospitals. Our experiment gives subjects broad discretion to implement their preferences, free from bureaucratic control or even surveillance. Our results therefore inform the question whether norms are likely to affect physician choices along both dimensions of behavior. Our study measures altruism in a large multisite sample of practicing physicians and measures both dimensions of social preferences.Our experiment asked subjects to make trade-offs between their own self-interest and the interest of an anonymous other and, at the same time, between equality and efficiency. These two aspects of social preferences often operate together, but they remain conceptually distinct. [Social preferences can be weighted toward equality (reducing differences in payoffs) or weighted toward efficiency (increasing total payoffs) and range from pure utilitarian to maxmin or Rawlsianism. As the dispute between Harsanyi (12, 13) and Rawls (14) shows, fair-minded people (who are all perfectly impartial between self and other) can disagree about how to trade off equality and efficiency. The work of Harsanyi and Rawls, and of the many others who have followed them, has had broad-reaching influence across many disciplines, including philosophy, economics, and law.] To capture both of these features in our experiment, we employ a modified dictator game (15–17) in which we ask physicians to allocate real money between themselves and an anonymous other drawn from a broadly representative sample of the US population. Our experiment presents subjects with allocation decisions in which the “price of giving” varies across decision problems—sometimes the subject may need to sacrifice more than a token (the experimental currency)—to give a single token to other (the recipient); in other decisions, it may cost only a fraction of a token. These decisions are made through an intuitive “point-and-click” graphical interface in which the choices are represented as a budget line where each point represents a possible allocation. The slope of the line captures the price of giving tokens to other.^†Intuitively, this method allowed us to collect a rich dataset capable of measuring both altruism and equality–efficiency orientation at the level of the individual subject. [The importance of studying individual heterogeneity in social preferences is emphasized by Andreoni and Miller (17). Because of this heterogeneity, it is necessary to investigate behavior at an individual level. Our experimental design allows subjects to make numerous choices over a wide range of budget lines, and this yields a rich dataset that is well-suited to analysis at the individual level. It is clearly advantageous to estimate individual-level parameters and then generate individual-level distributions of the estimations rather than to pool data and then estimate population-level parameters.] The degree of altruism is reflected in the amount subjects give on average, whereas equality–efficiency orientation is captured by how subjects respond to the price of giving. Increasing the fraction of the budget spent on other as the price of giving increases indicates social preferences weighted toward equality (reducing the difference in payoffs between self and other), whereas decreasing it when the price of giving increases indicates social preferences weighted toward efficiency (increasing the total payoffs to self and other). We rely on techniques developed in our prior work (15, 16, 18) to evaluate the consistency of physicians’ choices (i.e., whether they reflect a complete and transitive preference ordering) and to explore the structure of the social utility functions that rationalize the observed data.We further compare physicians’ preferences with preferences previously measured in three other populations using equivalent experiments: 1) a broadly representative sample of US adults (18), 2) an “elite” subsample of those who hold a graduate degree and have an annual household income over $100,000 (15, 18), and 3) a sample of medical students from nine schools around the United States (19, 20). The social preferences of these populations provide important benchmarks against which physicians’ social preferences can be assessed; furthermore, the comparison with medical students may shed light on whether physicians’ distinctive social preferences reflect a “selection effect” based on who enters medicine or a “treatment effect” of practicing medicine.^‡We begin our analysis of the experimental data by using classical revealed preference theory (21–23) to test whether subjects’ choices are consistent with the essence of all traditional models of economic decision-making—utility maximization.^§ Our physician subjects exhibit a remarkably high degree of consistency when compared with other populations, including medical students and also students from Yale Law School (YLS), the population that had exhibited the highest degree of consistency in prior experiments (15). [In our subsequent analysis, we do not draw detailed comparisons between our physician sample and the sample YLS students (15). The experimental design in Fisman et al. (15) differs from the current one in that the YLS student subjects were asked to allocate money between themselves and another student, rather than an individual drawn from a sample broadly representative of the US adults.] This result reveals that our physician subjects are highly adept at implementing a consistent, well-behaved social preference ordering. This makes it natural to estimate—at the level of the individual subject—the substantive social preferences that physicians display.We then estimate social preferences at the level of the individual physician using a constant elasticity of substitution (CES) utility function commonly employed by economists in demand analysis. The CES functional form is appealing because the degree of altruism and equality–efficiency orientation are each independently represented in a precise and transparent manner through its two parameters, which we estimate separately for each subject (further details on the CES specification and estimation are provided in Empirical Framework).We find that physicians are more altruistic than any other population, while physicians’ preferences concerning the trade-off between equality and efficiency are almost indistinguishable graphically from the preferences of the American Life Panel (ALP) elites and also the broader ALP sample. These findings on physicians’ distinctive social preferences have direct and concrete implications for professionalism, incentives, and bureaucratic rules directed at physicians. Insofar as physicians are altruistic, they may be more likely to live up to the professional ideal of putting patients’ interests ahead of their own. At the same time, altruism as captured in our experiment is far from ubiquitous, even among physicians and, furthermore, physicians’ efficiency orientation is indistinguishable from than that of the general population. Taken together, our findings suggest that the ideal of physician professionalism—putting the patient first—is not merely a self-serving myth but that other mechanisms may be required to support the quality of medical care and to promote efficient allocation of medical resources.     

Lung Transplant Recipients Immunogenicity after Heterologous ChAdOx1 nCoV-19—BNT162b2 mRNA Vaccination

(1) Background: High immunosuppressive regimen in lung transplant recipients (LTRs) hampers the immune response to vaccination. We prospectively investigated the immunogenicity of heterologous ChAdOx1 nCoV-19-BNT162b2 mRNA vaccination in an LTR cohort. (2) Methods: Forty-nine COVID-19 naïve LTRs received a two-dose regimen ChAdOx1 nCoV-19 vaccine. A subset of 32 patients received a booster dose of BNT162b2 mRNA vaccine 18 weeks after the second dose. (3) Results: Two-doses of ChAdOx1 nCoV-19 induced poor immunogenicity with 7.2% seropositivity at day 180 and low neutralizing capacities. The BNT162b2 mRNA vaccine induced significant increases in IgG titers with means of 197.8 binding antibody units per milliliter (BAU/mL) (95% CI 0–491.4) and neutralizing antibodies, with means of 76.6 AU/mL (95% CI 0–159.6). At day 238, 32.2% of LTRs seroconverted after the booster dose. Seroneutralization capacities against Delta and Omicron variants were found in only 13 and 9 LTRs, respectively. Mycophenolate mofetil and high-dose corticosteroids were associated with a weak serological response. (4) Conclusions: The immunogenicity of a two-dose ChAdOx1 nCoV-19 vaccine regimen was very poor in LTRs, but was significantly enhanced after the booster dose in one-third of LTRs. In immunocompromised individuals, the administration of a fourth dose may be considered to increase the immune response against SARS-CoV-2.     

Adolescent Knowledge,Attitudes and Practices of Healthy Eating: Findings of Qualitative Interviews among Hong Kong Families

To tackle unhealthy eating among adolescents, it is crucial to understand the dietary knowledge, attitudes, and practices (KAP) on which adolescent eating habits are based. This qualitative study identifies the gaps in KAP by exploring what Chinese adolescents know, perceive, and practice regarding healthy eating to better inform targeted interventions for this important health problem. Parent–adolescent dyads were purposively sampled based on, for example, the dietary intake, age, and gender of the adolescent and household income, and each completed a 30 to 60 min interview. Twelve themes were synthesized: knowledge: (1) dietary recommendations, (2) health outcomes of healthy eating, (3) nutrition content in food, and (4) access to healthy meals; attitudes: (5) outcome expectation for healthy eating, (6) food preferences, and (7) self-efficacy regarding adopting healthy eating; and practices: (8) going grocery shopping for healthy food, (9) eating home-prepared meals. (10) eating out in restaurants or consuming takeaway food, (11) fruit and vegetable consumption, and (12) snacking, perceived unhealthy eating to be low risk, made unhealthy choices regarding snacking and eating out, and had insufficient fruit and vegetable intake. Programs should emphasize the positive short-term health outcomes of healthy eating and empower adolescents to acquire food preparation skills to sustain healthy eating habits.     

Physiology and pathobiology of the microcirculation

The delivery of nutrients to the tissues and the removal of waste products from the tissues is made possible by forcing a stream of blood through an arborizing network of microscopic blood vessels that comprise the microcirculation. The rapidity of the flow stream and, therefore, the rate of nutrient delivery to the tissue, is regulated by the automatic adjustment of the caliber of the precapillary arterioles that serve as the primary loci of vascular resistance. Exchange between the blood stream and the parenchymal cells occurs in capillaries and pericytic venules. Pathologic processes such as inflammation, diabetes, ischemia, and hypertension are characterized by abnormalities in microvascular structure and function.     

A 12-year, prospective study of extraocular muscle imaging in complex strabismus

INTRODUCTION: Diagnostic imaging by magnetic resonance imaging (MRI) or computed x-ray tomography (CT) has become the standard of care in many medical fields. Clinical imaging of the extraocular muscles (EOMs) can now provide insight into some causes of strabismus, in some cases challenging traditional concepts of etiology and suggesting alternative treatments. METHODS: Between 1990 and 2001, 62 orthotropic volunteers and 261 strabismic patients underwent orbital imaging under a prospective protocol. Surface coil MRI was performed with fixation control with slice thickness of 1.5 to 3 mm; CT was performed with 1-mm slice thickness. Images were correlated with ophthalmological examinations. RESULTS: MRI was performed in 267 and CT in 56 subjects. Comparison with normal orbits commonly demonstrated abnormalities of EOM size or location in strabismic patients. These included absence (5 patients) or atrophy (33 patients) of the superior oblique (SO) muscle in SO palsy; abnormalities of the trochlea or SO tendon in Brown's syndrome (8 patients); heterotopy of the rectus pulleys associated with incomitant strabismus (46 patients), including instability of pulleys (9 patients); trauma to rectus EOMs (16 patients); atrophy of the lateral rectus (10 patients), inferior rectus (4 patients), medial rectus (4 patients), superior rectus (4 patients), and inferior oblique (1 patient) muscles; and EOMs disinserted by scleral buckles (3 patients). EOM abnormalities correlated closely with clinically abnormal patterns of ocular motility. CONCLUSIONS: With the appropriate technique, EOM imaging is a valuable adjunct in clinical evaluation of complex strabismus. Because imaging can provide unique information unavailable from the clinical examination alone, it should be performed when indicated to evaluate patients with strabismus more complex than concomitant esotropia and exotropia.