The normativist-naturalist puzzle: Functions and assumptions of health assessment tools.

While there is no shortage in discussions of health assessment tools, little is known about health professionals' experience of their practical uses. However, these tools rely on assumptions that have significant impacts on the practice of health assessment. In this study, we explore health professionals' experiences with health assessment tools, that is, how they define, use, and understand these tools, and whether they take them to measure health and wellbeing. We combine a qualitative, interview-based study of the uses and understandings of health assessment tools among Danish health professionals with a philosophical analysis of these applications and perceptions. Our study shows that contrary assumptions are involved in the use of the tools, to the extent that one can speak of a normativist-naturalist puzzle: health professionals generally apply a normativist conception of health, find health assessment useful and valuable for their clinical practice, but believe that what the tools measure is basically not health proper but some proximal entity of a more naturalist kind. This result demonstrates the complexity of health assessment tools and suggests that they are used with care to ensure both that particular tools are used for the kinds of tasks they are most apt for, and that they are put to use in awareness of their limitations.

Cerebral fat emboli in a patient with paraplegia caused by bilateral femur fractures.

Cerebral fat embolism is a rare cause of stroke and therefore an overlooked diagnosis. Often it is seen as a consequence of major bone fractures or after arthroplasty, and can lead to respiratory or circulatory collapse. We present a case of a patient with a history of paraplegia after a thoracic spinal cord injury that developed cerebral fat embolism following a bilateral femur fracture. Since the patient was paraplegic and with an altered mental state upon admission, femoral bone fractures were not initially suspected. The case shows the difficulties in diagnosing this condition.

Enhanced specificity of Bacillus metataxonomics using a tuf-targeted amplicon sequencing approach.

Bacillus species are ubiquitous in nature and have tremendous application potential in agriculture, medicine, and industry. However, the individual species of this genus vary widely in both ecological niches and functional phenotypes, which, hence, requires accurate classification of these bacteria when selecting them for specific purposes. Although analysis of the 16S rRNA gene has been widely used to disseminate the taxonomy of most bacterial species, this gene fails proper classification of Bacillus species. To circumvent this restriction, we designed novel primers and optimized them to allow exact species resolution of Bacillus species in both synthetic and natural communities using high-throughput amplicon sequencing. The primers designed for the tuf gene were not only specific for the Bacillus genus but also sufficiently discriminated species both in silico and in vitro in a mixture of 11 distinct Bacillus species. Investigating the primers using a natural soil sample, 13 dominant species were detected including Bacillus badius, Bacillus velezensis, and Bacillus mycoides as primary members, neither of which could be distinguished with 16S rRNA sequencing. In conclusion, a set of high-throughput primers were developed which allows unprecedented species-level identification of Bacillus species and aids the description of the ecological distribution of Bacilli in various natural environment.

Dose and route of administration determine the efficacy of prophylactic immunotherapy for peanut allergy in a Brown Norway rat model.

Introduction: Allergen-specific immunotherapy (IT) is emerging as a viable option for treatment of peanut allergy. Yet, prophylactic IT remains unexplored despite early introduction of peanut in infancy was shown to prevent allergy. There is a need to understand how allergens interact with the immune system depending on the route of administration, and how different dosages of allergen may protect from sensitisation and a clinical active allergy. Here we compared peanut allergen delivery via the oral, sublingual (SL), intragastric (IG) and subcutaneous (SC) routes for the prevention of peanut allergy in Brown Norway (BN) rats. Methods: BN rats were administered PBS or three different doses of peanut protein extract (PPE) via either oral IT (OIT), SLIT, IGIT or SCIT followed by intraperitoneal (IP) injections of PPE to assess the protection from peanut sensitisation. The development of IgE and IgG1 responses to PPE and the major peanut allergens were evaluated by ELISAs. The clinical response to PPE was assessed by an ear swelling test (EST) and proliferation was assessed by stimulating splenocytes with PPE. Results: Low and medium dose OIT (1 and 10 mg) and all doses of SCIT (1, 10, 100 µg) induced sensitisation to PPE, whereas high dose OIT (100 mg), SLIT (10, 100 or 1000 µg) or IGIT (1, 10 and 100 mg) did not. High dose OIT and SLIT as well as high and medium dose IGIT prevented sensitisation from the following IP injections of PPE and suppressed PPE-specific IgE levels in a dose-dependent manner. Hence, administration of peanut protein via different routes confers different risks for sensitisation and protection from peanut allergy development. Overall, the IgE levels toward the individual major peanut allergens followed the PPE-specific IgE levels. Discussion: Collectively, this study showed that the preventive effect of allergen-specific IT is determined by the interplay between the specific site of PPE delivery for presentation to the immune system, and the allergen quantity, and that targeting and modulating tolerance mechanisms at specific mucosal sites may be a prophylactic strategy for prevention of peanut allergy.

Perineural and Systemic Dexamethasone and Ulnar Nerve Block Duration: A Randomized, Blinded, Placebo-controlled Trial in Healthy Volunteers.

BACKGROUND: The authors hypothesized that both perineural and systemic dexamethasone as adjuncts to bupivacaine increase the duration of an ulnar nerve block compared with bupivacaine alone, and that systemic dexamethasone is noninferior to perineural dexamethasone. METHODS: The authors performed bilateral ulnar nerve blocks with 3 ml bupivacaine 5 mg/ml in 16 healthy volunteers on two trial days. According to randomization, subjects received adjunct treatment with 1 ml dexamethasone 4 mg/ml + 1 ml of saline (perineural condition) in one arm and 2 ml saline in the other arm (systemic condition, through absorption and redistribution of the contralaterally administered perineural dexamethasone) on one trial day; and 2 ml saline in one arm (placebo condition) and 2 ml of lidocaine in the other arm (lidocaine condition) on the other trial day. The primary outcome was the duration of the sensory nerve block assessed by temperature discrimination. RESULTS: Mean sensory block duration was 706 ± 94 min for the perineural condition, 677 ± 112 min for the systemic condition, and 640 ± 121 min for the placebo condition. The duration of the sensory nerve block was greater with perineural dexamethasone versus placebo (mean difference 66 min (95% CI, 23 to 108). Block duration was similar between systemic dexamethasone and placebo (mean difference 36 min; 95% CI, -30 to 103). CONCLUSIONS: Perineural dexamethasone as an adjunct to bupivacaine in healthy volunteers resulted in a greater duration of an ulnar nerve block when compared with placebo. Systemic dexamethasone resulted in a similar duration as placebo.

Pandemic justice: fairness, social inequality and COVID-19 healthcare priority-setting.

A comprehensive understanding of the ethics of the COVID-19 pandemic priorities must be sensitive to the influence of social inequality. We distinguish between ex-ante and ex-post relevance of social inequality for COVID-19 disadvantage. Ex-ante relevance refers to the distribution of risks of exposure. Ex-post relevance refers to the effect of inequality on how patients respond to infection. In the case of COVID-19, both ex-ante and ex-post effects suggest a distribution which is sensitive to the prevalence social inequality. On this basis, we provide a generic fairness argument for the claim that welfare states ought to favour a healthcare priority scheme that gives particular weight to protecting the socially disadvantaged.

Disability Discrimination and Patient-Sensitive Health-Related Quality of Life.

It is generally accepted that morally justified healthcare rationing must be non-discriminatory and cost-effective. However, given conventional concepts of cost-effectiveness, resources spent on disabled people are spent less cost-effectively, ceteris paribus, than resources spent on non-disabled people. Thus, it is reasonable to assume that standard cost-effectiveness discriminates against the disabled. Call this the disability discrimination problem. Part of the disability discrimination involved in cost-effectiveness stems from the way in which health-related quality of life is accounted for and measured. This paper offers and defends a patient-sensitive account of health-related quality of life, which can effectively make cost-effectiveness less discriminatory against the disabled and thus more morally justified.

Effectiveness and Safety of Ibrutinib for Chronic Lymphocytic Leukemia in Routine Clinical Practice: 3-Year Follow-up of the Belgian Ibrutinib Real-World Data (BiRD) Study.

The multicenter observational BiRD study investigated the real-world effectiveness and safety of ibrutinib in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) in Belgium. This interim analysis reports results for patients with CLL, with a median follow-up of 34 months. Overall, patients had predominantly relapsed/refractory disease (73%) and were elderly (median age 72 years) with high-risk features such as del17p and/or TP53 mutations (59%). Patients were included either prospectively or retrospectively, and the total patient population effectiveness results were adjusted with left truncation. In the effectiveness population (N = 221: prospective, n = 71; retrospective, n = 150), the overall response rate was 90.0%. Median progression-free survival was 38.3 months (prospective, not estimable; retrospective, 51.5 months) and median overall survival was not yet estimable in the total, prospective and retrospective groups. Treatment-emergent adverse events (TEAEs) for the prospective and retrospective groups are reported separately. Any-grade TEAEs of interest in the prospective/retrospective groups included infections (67.1%/60.1%), diarrhea (20.5%/10.5%), hypertension (16.4%/9.8%) and atrial fibrillation (12.3%/7.2%). Major bleeding was reported in 5.5%/3.3% of prospective/retrospective patients, with little difference observed between those receiving versus not receiving antithrombotic treatment. Discontinuations due to toxicity were reported in 10.5% of patients. Results from this interim analysis show treatment with ibrutinib to be effective and tolerable, with no new safety signals observed. Future analyses will report on longer-term follow-up.

Effect of once-weekly semaglutide versus thrice-daily insulin aspart, both as add-on to metformin and optimized insulin glargine treatment in participants with type 2 diabetes (SUSTAIN 11): A randomized, open-label, multinational, phase 3b trial.

AIM: To compare the efficacy and safety of once-weekly (OW) semaglutide versus thrice-daily (TID) insulin aspart (IAsp) in participants with inadequately controlled type 2 diabetes (T2D) treated with insulin glargine (IGlar) and metformin. MATERIALS AND METHODS: SUSTAIN 11 (NCT03689374) was a randomized (1:1), parallel, open-label, multinational, phase 3b trial. After a 12-week run-in to optimize once-daily IGlar U100, 1748 adults with T2D (HbA1c >7.5% to ≤10.0%) were randomized to OW semaglutide or TID IAsp as add-on to optimized IGlar and metformin for 52 weeks. The primary outcome was change in HbA1c from randomization to week 52. Confirmatory secondary endpoints included the occurrence of severe hypoglycaemic episodes and change in body weight (BW). Safety was assessed. RESULTS: HbA1c (randomization: 8.6% [70.0 mmol/mol]) decreased by 1.5% points (16.6 mmol/mol) and 1.2% points (13.4 mmol/mol) with semaglutide (n = 874) and IAsp (n = 874), respectively (estimated treatment difference [ETD] -0.29% points [95% confidence interval {CI} -0.38; -0.20]; P < .0001 for non-inferiority). Few severe hypoglycaemic episodes were recorded in either group, with no statistically significant difference between the groups. Change in BW from randomization (87.9 kg) to week 52 was in favour of semaglutide (-4.1 kg) versus IAsp (+2.8 kg) (ETD -6.99 kg [95% CI -7.41; -6.57]). A higher proportion of participants experienced adverse events with semaglutide (58.5%) versus IAsp (52.1%); most were mild to moderate. CONCLUSIONS: In this basal insulin-treated population, OW semaglutide improved glycaemic control to a greater extent than TID IAsp and provided numerically greater weight loss.

Pandemic prioritarianism.

Prioritarianism pertains to the generic idea that it matters more to benefit people, the worse off they are, and while prioritarianism is not uncontroversial, it is considered a generally plausible and widely shared distributive principle often applied to healthcare prioritisation. In this paper, I identify social justice prioritarianism, severity prioritarianism and age-weighted prioritarianism as three different interpretations of the general prioritarian idea and discuss them in light of the effect of pandemic consequences on healthcare priority setting. On this analysis, the paper arrives at the following three conclusions: (1) that we have strong prioritarian reasons for special concern about the vulnerable and socially disadvantaged in reference to pandemic effects, (2) that severity of illness is an important factor in identifying the worse off in priority setting but that this must not over-ride the special priority to the socially disadvantaged and (3) that the maximisation rationale of the age-weighted view runs against the core prioritarian idea, and the age-weighted prioritarianism is thus unfitting as a prioritarian response to the COVID-19 case.

Don't Downplay "Play": Reasons Why Health Systems Should Protect Childhood Play.

Much research has studied the importance of play for children's development. However, questions of its political importance and our public institutions' duties to protect it have been largely neglected. This article argues that childhood play is politically important due to having both intrinsic and instrumental value, and it suggests that the duty to protect the capability for play in childhood falls especially on the public health system. If this argument succeeds, it follows that we have stronger duties toward our children than we currently believe.

The effect of external flow on the feeding currents of sessile microorganisms.

Microscopic sessile suspension feeders live attached to surfaces and, by consuming bacteria-sized prey and by being consumed, they form an important part of aquatic ecosystems. Their environmental impact is mediated by their feeding rate, which depends on a self-generated feeding current. The feeding rate has been hypothesized to be limited by recirculating eddies that cause the organisms to feed from water that is depleted of food particles. However, those results considered organisms in still water, while ambient flow is often present in their natural habitats. We show, using a point-force model, that even very slow ambient flow, with speed several orders of magnitude less than that of the self-generated feeding current, is sufficient to disrupt the eddies around perpendicular suspension feeders, providing a constant supply of food-rich water. However, the feeding rate decreases in external flow at a range of non-perpendicular orientations due to the formation of recirculation structures not seen in still water. We quantify the feeding flow and observe such recirculation experimentally for the suspension feeder Vorticella convallaria in external flows typical of streams and rivers.

Foraging trade-offs, flagellar arrangements, and flow architecture of planktonic protists.

Unicellular flagellated protists are a key element in aquatic microbial food webs. They all use flagella to swim and to generate feeding currents to encounter prey and enhance nutrient uptake. At the same time, the beating flagella create flow disturbances that attract flow-sensing predators. Protists have highly diverse flagellar arrangements in terms of number of flagella and their position, beat pattern, and kinematics, but it is unclear how the various arrangements optimize the fundamental trade-off between resource acquisition and predation risk. Here we describe the near-cell flow fields produced by 15 species and demonstrate consistent relationships between flagellar arrangement and swimming speed and between flagellar arrangement and flow architecture, and a trade-off between resource acquisition and predation risk. The flow fields fall in categories that are qualitatively described by simple point force models that include the drag force of the moving cell body and the propulsive forces of the flagella. The trade-off between resource acquisition and predation risk varies characteristically between flow architectures: Flagellates with multiple flagella have higher predation risk relative to their clearance rate compared to species with only one active flagellum, with the exception of the highly successful dinoflagellates that have simultaneously achieved high clearance rates and stealth behavior due to a unique flagellar arrangement. Microbial communities are shaped by trade-offs and environmental constraints, and a mechanistic explanation of foraging trade-offs is a vital part of understanding the eukaryotic communities that form the basis of pelagic food webs.

Pharmacokinetics, Safety and Tolerability of Once-Weekly Subcutaneous Semaglutide in Healthy Chinese Subjects: A Double-Blind, Phase 1, Randomized Controlled Trial.

INTRODUCTION: Once-weekly (OW) subcutaneous (s.c.) semaglutide is an injectable glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. This trial was designed to assess the pharmacokinetics, safety and tolerability of OW s.c. semaglutide in healthy Chinese subjects. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, 36 healthy subjects were randomised to OW s.c. semaglutide 0.5 mg (n = 12), 1.0 mg (n = 12), or placebo (n = 12). Treatment (semaglutide or placebo) was blinded for the subjects, investigators and sponsor. The primary endpoint was steady-state semaglutide exposure, defined as the area under the curve over a dosing interval at steady state (AUC0-168 h,SS). RESULTS: In total, 34 subjects completed the trial. The steady-state exposure of semaglutide was higher for subjects treated with 1.0 mg semaglutide (AUC0-168 h,ss: 7961 nmol h/l and Cmax,ss: 55.9 nmol/l) compared to 0.5 mg semaglutide (AUC0-168 h,ss: 4000 nmol h/l and Cmax,ss: 28.8 nmol/l). The total exposure of semaglutide increased in a dose-proportional manner in healthy Chinese subjects; the treatment ratio (1.0 mg/0.5 mg) [95% confidence interval] for AUC0-168 h,SS was 1.99 [1.78; 2.23]. Treatment with OW s.c. semaglutide was well tolerated in healthy Chinese subjects. As expected for the GLP-1 receptor agonist class, the most common adverse events were gastrointestinal, and no new safety signals were identified. CONCLUSION: The pharmacokinetics, safety and tolerability of OW s.c. semaglutide in healthy Chinese subjects were consistent with previous clinical pharmacology trials of OW s.c. semaglutide in other populations. The results suggest that no dose adjustment is necessary for semaglutide in Chinese patients with T2D. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03288740.

Contractualist age rationing under outbreak circumstances.

Age rationing is a central issue in the health care priority-setting literature, but it has become ever more salient in the light of the Covid-19 outbreak, where health authorities in several countries have given higher priority to younger over older patients. But how is age rationing different under outbreak circumstances than under normal circumstances, and what does this difference imply for ethical theories? This is the topic of this paper. The paper argues that outbreaks such as that of Covid-19 involve special circumstances that change how age should influence our prioritization decisions, and that while this shift in circumstances poses a problem for consequentialist views such as utilitarianism and age-weighted consequentialism, contractualism is better equipped to cope with it. The paper then offers a contractualist prudential account of age rationing under outbreak circumstances.

Irresponsible parties, responsible voters? Legislative gridlock and collective accountability.

Legislative gridlock is a failure of one of the key functions of government: to pass legislation. Can voters counter such political dysfunction? This paper examines whether and how voters hold politicians accountable for gridlock. We focus on the passage of the government budget, the central task of any legislature, and define a legislature to experience budgetary gridlock if it fails to pass the budget on time. We argue, based on evidence from twenty years of budget enactment data, that voters hold state legislators accountable for budget gridlock in US state governments, with gridlocked incumbents losing their seat more often than incumbents passing budgets on time. Based on established theories of party organization in American politics, we develop three competing theoretical hypotheses to guide our understanding of the observed patterns of retrospective voting. We find strong support for collective electoral accountability with voters punishing incumbent members of state legislature majority parties.

Convex Decomposition for a Coverage Path Planning for Autonomous Vehicles: Interior Extension of Edges.

To cover an area of interest by an autonomous vehicle, such as an Unmanned Aerial Vehicle (UAV), planning a coverage path which guides the unit to cover the area is an essential process. However, coverage path planning is often problematic, especially when the boundary of the area is complicated and the area contains several obstacles. A common solution for this situation is to decompose the area into disjoint convex sub-polygons and to obtain coverage paths for each sub-polygon using a simple back-and-forth pattern. Aligned with the solution approach, we propose a new convex decomposition method which is simple and applicable to any shape of target area. The proposed method is designed based on the idea that, given an area of interest represented as a polygon, a convex decomposition of the polygon mainly occurs at the points where an interior angle between two edges of the polygon is greater than 180 degrees. The performance of the proposed method is demonstrated by comparison with existing convex decomposition methods using illustrative examples.

Hydrodynamic functionality of the lorica in choanoflagellates.

Choanoflagellates are unicellular eukaryotes that are ubiquitous in aquatic habitats. They have a single flagellum that creates a flow toward a collar filter composed of filter strands that extend from the cell. In one common group, the loricate choanoflagellates, the cell is suspended in an elaborate basket-like structure, the lorica, the function of which remains unknown. Here, we use Computational Fluid Dynamics to explore the possible hydrodynamic function of the lorica. We use the choanoflagellate Diaphaoneca grandis as a model organism. It has been hypothesized that the function of the lorica is to prevent refiltration (flow recirculation) and to increase the drag and, hence, increase the feeding rate and reduce the swimming speed. We find no support for these hypotheses. On the contrary, motile prey are encountered at a much lower rate by the loricate organism. The presence of the lorica does not affect the average swimming speed, but it suppresses the lateral motion and rotation of the cell. Without the lorica, the cell jiggles from side to side while swimming. The unsteady flow generated by the beating flagellum causes reversed flow through the collar filter that may wash away captured prey while it is being transported to the cell body for engulfment. The lorica substantially decreases such flow, hence it potentially increases the capture efficiency. This may be the main adaptive value of the lorica.

Hydrodynamics of microbial filter feeding.

Microbial filter feeders are an important group of grazers, significant to the microbial loop, aquatic food webs, and biogeochemical cycling. Our understanding of microbial filter feeding is poor, and, importantly, it is unknown what force microbial filter feeders must generate to process adequate amounts of water. Also, the trade-off in the filter spacing remains unexplored, despite its simple formulation: A filter too coarse will allow suitably sized prey to pass unintercepted, whereas a filter too fine will cause strong flow resistance. We quantify the feeding flow of the filter-feeding choanoflagellate Diaphanoeca grandis using particle tracking, and demonstrate that the current understanding of microbial filter feeding is inconsistent with computational fluid dynamics (CFD) and analytical estimates. Both approaches underestimate observed filtration rates by more than an order of magnitude; the beating flagellum is simply unable to draw enough water through the fine filter. We find similar discrepancies for other choanoflagellate species, highlighting an apparent paradox. Our observations motivate us to suggest a radically different filtration mechanism that requires a flagellar vane (sheet), something notoriously difficult to visualize but sporadically observed in the related choanocytes (sponges). A CFD model with a flagellar vane correctly predicts the filtration rate of D. grandis, and using a simple model we can account for the filtration rates of other microbial filter feeders. We finally predict how optimum filter mesh size increases with cell size in microbial filter feeders, a prediction that accords very well with observations. We expect our results to be of significance for small-scale biophysics and trait-based ecological modeling.

Trophic Strategies of Unicellular Plankton.

Unicellular plankton employ trophic strategies ranging from pure photoautotrophs over mixotrophy to obligate heterotrophs (phagotrophs), with cell sizes from 10-8 to 1 µg C. A full understanding of how trophic strategy and cell size depend on resource environment and predation is lacking. To this end, we develop and calibrate a trait-based model for unicellular planktonic organisms characterized by four traits: cell size and investments in phototrophy, nutrient uptake, and phagotrophy. We use the model to predict how optimal trophic strategies depend on cell size under various environmental conditions, including seasonal succession. We identify two mixotrophic strategies: generalist mixotrophs investing in all three investment traits and obligate mixotrophs investing only in phototrophy and phagotrophy. We formulate two conjectures: (1) most cells are limited by organic carbon; however, small unicellulars are colimited by organic carbon and nutrients, and only large photoautotrophs and smaller mixotrophs are nutrient limited; (2) trophic strategy is bottom-up selected by the environment, while optimal size is top-down selected by predation. The focus on cell size and trophic strategies facilitates general insights into the strategies of a broad class of organisms in the size range from micrometers to millimeters that dominate the primary and secondary production of the world's oceans.