Translating theories of justice into a practice model for triage of scarce intensive care resources during a pandemic.

During the COVID-19 pandemic, national triage guidelines were developed to address the anticipated shortage of life-saving resources, should ICU capacities be overloaded. Rationing and triage imply that in addition to individual patient interests, interests of population health have to be integrated. The transfer of theoretical and empirical knowledge into feasible and useful practice models and their implementation in clinical settings need to be improved. This paper analyzes how triage protocols could translate abstract theories of distributive justice into concrete material and procedural criteria for rationing intensive care resources during a pandemic. We reconstruct the development and implementation of a rationing protocol at a German university hospital: describing the ethical challenge of triage, clarifying the aspirational norms, and summarizing specific norms of fair triage and allocation for developing an institutional policy and practice model and implementing it. We reflect on how critical topics are seen by clinicians and what helped manage the perceived burdens of the triage dilemma. We analyze what can be learned from this debate regarding the difficult issues around triage protocols and their potential implementation into clinical settings. Analyzing the ought-to-is gap of triage, integrating abstract ethical principles into practical concepts, and evaluating those should clarify the benefits and risks of different allocation options. We seek to inform debates on triage concepts and policies to ensure the best possible treatment and fair allocation of resources as well as to help protect patients and professionals in worst-case scenarios.

Basel: A Hotspot for Drug Discovery and Development Against Poverty-Related Diseases.

In discussion with Lukas Meier from the Swiss Tropical and Public Health Institute (Swiss TPH), Lutz Hegemann, Head of Novartis Global Health and Sustainability and Marcel Tanner, President of the Swiss Academies of Arts and Sciences, give their opinions on the changes that occurred in drug discovery and development for poverty-related diseases over the past 30 years. They emphasise the power of public-private partnerships and provide their points of views on what needs to be done in the future to ensure that the poorest of the poor also have access to important therapies.

Repurposing Know-how for Drug Development: Case Studies from the Swiss Tropical and Public Health Institute.

In pursuing novel therapeutic solutions, drug discovery and development rely on efficiently utilising existing knowledge and resources. Repurposing know-how, a strategy that capitalises on previously acquired information and expertise, has emerged as a powerful approach to accelerate drug discovery and development processes, often at a fraction of the costs of de novo developments. For 80 years, collaborating within a network of partnerships, the Swiss Tropical and Public Health Institute (Swiss TPH) has been working along a value chain from innovation to validation and application to combat poverty-related diseases. This article presents an overview of selected know-how repurposing initiatives conducted at Swiss TPH with a particular emphasis on the exploration of drug development pathways in the context of neglected tropical diseases and other infectious diseases of poverty, such as schistosomiasis, malaria and human African trypanosomiasis.

Memories without Survival: Personal Identity and the Ascending Reticular Activating System.

Lockean views of personal identity maintain that we are essentially persons who persist diachronically by virtue of being psychologically continuous with our former selves. In this article, I present a novel objection to this variant of psychological accounts, which is based on neurophysiological characteristics of the brain. While the mental states that constitute said psychological continuity reside in the cerebral hemispheres, so that for the former to persist only the upper brain must remain intact, being conscious additionally requires that a structure originating in the brainstem-the ascending reticular activating system-be functional. Hence, there can be situations in which even small brainstem lesions render individuals irreversibly comatose and thus forever preclude access to their mental states, while the neural correlates of the states themselves are retained. In these situations, Lockeans are forced to regard as fulfilled their criterion of diachronic persistence since psychological continuity, as they construe it, is not disrupted. Deeming an entity that is never again going to have any mental experiences to be a person, however, is an untenable position for a psychological account to adopt. In their current form, Lockean views of personal identity are therefore incompatible with human neurophysiology.

Highly Strained Arene-Fused 1,2-Diborete Biradicaloid.

The stepwise reduction of a doubly cyclic alkyl(amino)carbene (CAAC)-stabilized 2,3-bis(dibromoboryl)naphthalene enables the isolation of the corresponding mono- and bis(boryl) radicals (one- and two-electron reduction), a 2π-aromatic 1,2-diborete (four-electron reduction), which shows biradical character in the solid-state EPR spectrum, and its cyclic bis(alkylidene)diboron dianion (six-electron reduction). The X-ray crystallographic analysis of the diborete shows a highly strained and twisted four-membered ring with a formal cis-diborene motif featuring a very elongated B-B double bond. Calculations based on DFT and multireference approaches reveal that the diborete possesses an open-shell singlet biradicaloid ground state, which is slightly energetically preferred to its EPR-active triplet-state congener. The addition of CO to the diborete resulted in B-B bond splitting and the formation of the corresponding closed-shell singlet, doubly Lewis base-stabilized bis(borylene), whereas a twofold γ insertion of phenyl azide generates a 1,3-bis(diazenyl)-1,3,2,4-diazadiboretidine.

Preparing for the Worst-Case Scenario in a Pandemic: Intensivists Simulate Prioritization and Triage of Scarce ICU Resources.

OBJECTIVES: Simulation and evaluation of a prioritization protocol at a German university hospital using a convergent parallel mixed methods design. DESIGN: Prospective single-center cohort study with a quantitative analysis of ICU patients and qualitative content analysis of two focus groups with intensivists. SETTING: Five ICUs of internal medicine and anesthesiology at a German university hospital. PATIENTS: Adult critically ill ICU patients ( n = 53). INTERVENTIONS: After training the attending senior ICU physicians ( n = 13) in rationing, an impending ICU congestion was simulated. All ICU patients were rated according to their likelihood to survive their acute illness (good-moderate-unfavorable). From each ICU, the two patients with the most unfavorable prognosis ( n = 10) were evaluated by five prioritization teams for triage. MEASUREMENTS AND MAIN RESULTS: Patients nominated for prioritization visit ( n = 10) had higher Sequential Organ Failure Assessment scores and already a longer stay at the hospital and on the ICU compared with the other patients. The order within this worst prognosis group was not congruent between the five teams. However, an in-hospital mortality of 80% confirmed the reasonable match with the lowest predicted probability of survival. Qualitative data highlighted the tremendous burden of triage and the need for a team-based consensus-oriented decision-making approach to ensure best possible care and to support professionals. Transparent communication within the teams, the hospital, and to the public was seen as essential for prioritization implementation. CONCLUSIONS: To mitigate potential bias and to reduce the emotional burden of triage, a consensus-oriented, interdisciplinary, and collaborative approach should be implemented. Prognostic comparative assessment by intensivists is feasible. The combination of long-term ICU stay and consistently high Sequential Organ Failure Assessment scores resulted in a greater risk for triage in patients. It remains challenging to reliably differentiate between patients with very low chances to survive and requires further conceptual and empirical research.

Algorithms for Ethical Decision-Making in the Clinic: A Proof of Concept.

Machine intelligence already helps medical staff with a number of tasks. Ethical decision-making, however, has not been handed over to computers. In this proof-of-concept study, we show how an algorithm based on Beauchamp and Childress' prima-facie principles could be employed to advise on a range of moral dilemma situations that occur in medical institutions. We explain why we chose fuzzy cognitive maps to set up the advisory system and how we utilized machine learning to train it. We report on the difficult task of operationalizing the principles of beneficence, non-maleficence and patient autonomy, and describe how we selected suitable input parameters that we extracted from a training dataset of clinical cases. The first performance results are promising, but an algorithmic approach to ethics also comes with several weaknesses and limitations. Should one really entrust the sensitive domain of clinical ethics to machine intelligence?

Systemising triage: COVID-19 guidelines and their underlying theories of distributive justice.

The COVID-19 pandemic has been overwhelming public health-care systems around the world. With demand exceeding the availability of medical resources in several regions, hospitals have been forced to invoke triage. To ensure that this difficult task proceeds in a fair and organised manner, governments scrambled experts to draft triage guidelines under enormous time pressure. Although there are similarities between the documents, they vary considerably in how much weight their respective authors place on the different criteria that they propose. Since most of the recommendations do not come with ethical justifications, analysing them requires that one traces back these criteria to their underlying theories of distributive justice. In the literature, COVID-19 triage has been portrayed as a value conflict solely between utilitarian and egalitarian elements. While these two accounts are indeed the main antipodes, I shall show that in fact all four classic theories of distributive justice are involved: utilitarianism, egalitarianism, libertarianism, and communitarianism. Detecting these in the documents and classifying the suggested criteria accordingly enables one to understand the balancing between the different approaches to distributive justice-which is crucial for both managing the current pandemic and in preparation for the next global health crisis.

Long-term outcomes of percutaneous closure of coronary artery fistulae in the adult: A single-center experience.

Coronary artery fistulae (CAF) are rare congenital cardiac abnormalities. With increasing age, patients with moderate to large fistulae are likely to become symptomatic and encounter complications. Percutaneous closure has been accepted as a safe and effective alternative to surgery; however, information regarding long-term outcomes in adult patients after transcatheter closure is limited. METHODS: We describe our 20-year experience with percutaneous closure of CAF in adult patients, focusing on long-term outcomes. RESULTS: From 1995 to 2015, 25 adult patients underwent 33 transcatheter interventions to close 26 CAF at our institution. Mean age was 51.4 ± 16.8 years, and 14 (56%) were female. All the patients were symptomatic with dyspnea (21/25, 84%) being the most common complaint followed by chest pain (17/25, 68%), palpitations (9/25, 36%), and heart failure (2/25, 8%). Two patients presented with acute coronary syndrome, whereas 10/25 (40%) also had inducible ischemia on stress test. These CAFs were classified as medium (12, 46.2%), large (5, 19.2%), and giant (9, 34.6%). Immediately postprocedure complete occlusion was achieved in 21 (21/26, 81%), and residual trace leak was observed in three fistulae, whereas we could not deliver coils/device in two cases. Periprocedural complications occurred in the form of coronary dissection (n = 1), myocardial infarction (n = 2), coil embolization (n = 1), transient ST elevation (n = 1); the majority of complications were observed in the early years of our experience. Patients reported marked improvement in symptoms after the intervention. During a mean follow-up of 76 ± 69 (5-214 months) (n = 22), 15 patients were investigated by either conventional (n = 6) or CT angiography (n = 8) or both (n = 1) that demonstrated thrombotic occlusion of a proximal coronary artery where a distal fistula was treated. Another patient was noted to have thrombus proximal to a vascular plug in a distal giant fistula. Three patients were lost to follow-up. None of the investigated patients had recanalization of their fistula. We did not observe remodeling of the native coronary artery that was feeding the fistula, even after successful complete closure. CONCLUSION: Percutaneous device closure of CAF is a feasible and effective therapeutic intervention in adult patients; however, patients with distal fistulas represent a significant challenge and the outcomes of these procedures are in question. All patients should have long-term angiographic follow-up.

Are the irreversibly comatose still here? The destruction of brains and the persistence of persons.

When an individual is comatose while parts of her brain remain functional, the question arises as to whether any mental characteristics are still associated with this brain, that is, whether the person still exists. Settling this uncertainty requires that one becomes clear about two issues: the type of functional loss that is associated with the respective profile of brain damage and the persistence conditions of persons. Medical case studies can answer the former question, but they are not concerned with the latter. Conversely, in the philosophical literature, various accounts of personal identity are discussed, but usually detached from any empirical basis. Only uniting the two debates and interpreting the real-life configurations of brain damage through the lens of the philosophical concepts enables one to make an informed judgment regarding the persistence of comatose persons. Especially challenging are cases in which three mental characteristics that normally occur together-wakefulness, awareness and memory storage-come apart. These shall be the focus of this paper.

Validation of Quantitative 3-Dimensional Transesophageal Echocardiography Mitral Valve Analysis Using Stereoscopic Display.

OBJECTIVE: The use of 3-dimensional (3D) transesophageal echocardiography (TEE) in perioperative evaluation of the mitral valve (MV) is increasing progressively, including the use of 3D MV models for quantitative analysis. However, the use of 3D MV models in clinical practice still is limited by the need for specific training and the long time required for analysis. A new stereoscopic visualization tool (EchoPixel True 3D) allows virtual examination of anatomic structures in the clinical setting, but its accuracy and feasibility for intraoperative use is unknown. The aim of this study was to assess the feasibility of 3D holographic display and evaluate 3D quantitative measurements on a volumetric MV image using the EchoPixel system compared with the 3D MV model generated by QLAB Mitral Valve Navigation (MVN) software. DESIGN: This was a retrospective comparative study. SETTING: The study took place in a tertiary care center. PARTICIPANTS: A total of 40 patients, 20 with severe mitral regurgitation who underwent mitral valve repair and 20 controls with normal MV, were enrolled retrospectively. INTERVENTIONS: The 3D-TEE datasets of the MV were analyzed using a 3D MV model and stereoscopic display. The agreement of measurements, intraobserver and interobserver variability, and time for analysis were assessed. MEASUREMENTS AND MAIN RESULTS: Fair agreement between the 2 software systems was found for annular circumference and area in pathologic valves, but good agreement was reported for prolapse height and linear annular diameters. A higher agreement for all annular parameters and prolapse height was seen in normal valves. Excellent intraobserver and interobserver reliability was proved for the same parameters; time for analysis between the 2 methods in pathologic valves was substantially equivalent, although longer in pathologic valves when compared with normal MV using both tools. CONCLUSION: EchoPixel proved to be reliable to display 3D TEE datasets and accurate for direct linear measurement of both MV annular sizes and prolapse height compared to QLAB MVN software; it also carries a low interobserver and intraobserver variability for most measurements.

Management of acute heart failure in adult patients with congenital heart disease.

Heart failure is an increasing reason for hospitalization and the leading cause of death in patients with adult congenital heart disease (ACHD). Recently, the European Society of Cardiology and the American Heart Association published consensus documents on the management of chronic heart failure in ACHD patients. However, little data and/or guidelines are available for the management of (sub)acute heart failure. The ACHD population is heterogeneous by definition and often has complex underlying anatomy, which could pose a challenge to the physician confronted with the ACHD patient in (sub)acute heart failure. Recognizing the underlying anatomy and awareness of the possible complications related would result in better treatment, avoid unnecessary delays, and improve outcomes of the ACHD patient with (sub)acute heart failure. This review focuses on the management of (sub)acute heart failure in ACHD with specific attention to lesion-specific issues.

Breath analysis in real time by mass spectrometry in chronic obstructive pulmonary disease.

BACKGROUND: It has been suggested that exhaled breath contains relevant information on health status. OBJECTIVES: We hypothesized that a novel mass spectrometry (MS) technique to analyze breath in real time could be useful to differentiate breathprints from chronic obstructive pulmonary disease (COPD) patients and controls (smokers and nonsmokers). METHODS: We studied 61 participants including 25 COPD patients [Global Initiative for Obstructive Lung Disease (GOLD) stages I-IV], 25 nonsmoking controls and 11 smoking controls. We analyzed their breath by MS in real time. Raw mass spectra were then processed and statistically analyzed. RESULTS: A panel of discriminating mass-spectral features was identified for COPD (all stages; n = 25) versus healthy nonsmokers (n = 25), COPD (all stages; n = 25) versus healthy smokers (n = 11) and mild COPD (GOLD stages I/II; n = 13) versus severe COPD (GOLD stages III/IV; n = 12). A blind classification (i.e. leave-one-out cross validation) resulted in 96% sensitivity and 72.7% specificity (COPD vs. smoking controls), 88% sensitivity and 92% specificity (COPD vs. nonsmoking controls) and 92.3% sensitivity and 83.3% specificity (GOLD I/II vs. GOLD III/IV). Acetone and indole were identified as two of the discriminating exhaled molecules. CONCLUSIONS: We conclude that real-time MS may be a useful technique to analyze and characterize the metabolome of exhaled breath. The acquisition of breathprints in a rapid manner may be valuable to support COPD diagnosis and to gain insight into the disease.

Transcriptional Regulation of Liver-Type OATP1B3 (Lt-OATP1B3) and Cancer-Type OATP1B3 (Ct-OATP1B3) Studied in Hepatocyte-Derived and Colon Cancer-Derived Cell Lines.

Due to alternative splicing, the SLCO1B3 gene encodes two protein variants; the hepatic uptake transporter liver-type OATP1B3 (Lt-OATP1B3) and the cancer-type OATP1B3 (Ct-OATP1B3) expressed in several cancerous tissues. There is limited information about the cell type-specific transcriptional regulation of both variants and about transcription factors regulating this differential expression. Therefore, we cloned DNA fragments from the promoter regions of the Lt-SLCO1B3 and the Ct-SLCO1B3 gene and investigated their luciferase activity in hepatocellular and colorectal cancer cell lines. Both promoters showed differences in their luciferase activity depending on the used cell lines. We identified the first 100 bp upstream of the transcriptional start site as the core promoter region of the Ct-SLCO1B3 gene. In silico predicted binding sites for the transcription factors ZKSCAN3, SOX9 and HNF1α localized within these fragments were further analyzed. The mutagenesis of the ZKSCAN3 binding site reduced the luciferase activity of the Ct-SLCO1B3 reporter gene construct in the colorectal cancer cell lines DLD1 and T84 to 29.9% and 14.3%, respectively. In contrast, using the liver-derived Hep3B cells, 71.6% residual activity could be measured. This indicates that the transcription factors ZKSCAN3 and SOX9 are important for the cell type-specific transcriptional regulation of the Ct-SLCO1B3 gene.

Cyclic alkyl(amino)iminates (CAAIs) as strong 2σ,4π-electron donor ligands for the stabilisation of boranes and diboranes(4): a synthetic and computational study.

Singly and doubly cyclic alkyl(amino)iminate (CAAI)-substituted boranes and diboranes(4) were synthesised by halosilane elimination between a silylimine and halo(di)borane precursors. 11B NMR-spectroscopic studies show that the CAAI ligand is a much stronger electron donor than amino ligands. X-ray crystallographic analyses reveal that the degree of B-NCAAI double bonding increases with the electron-withdrawing capacity of the other substituents at boron. The C-N-B bond angle displays a great flexibility, ranging from 131° to near-linear 176°, the narrowest angles being observed for NMe2-substituted derivatives and the widest angles for highly sterically demanding substituents. Density functional theory (DFT) calculations on the electronic structures of the anionic CAAI ligand compared to unsaturated and saturated N-heterocyclic iminate (NHI) ligands show that the former is the best σ donor of the three but less π-donating than the unsaturated NHI. Nevertheless, the linear (CAAI)BH2 complex displays somewhat stronger C-N and N-B π bonding than the corresponding ((S)NHI)BH2 complexes.

Anomalous Origin of Left Circumflex Coronary Artery From Right Pulmonary Artery: An Unusual Cause of Sudden Cardiac Arrest.

Anomalous origin of the left circumflex coronary artery from the right pulmonary artery is an extremely rare coronary anomaly out of the group of anomalous coronary arteries arising from the pulmonary artery. We present the case of a 27-year-old male, in whom the diagnosis of an anomalous left circumflex coronary artery from the pulmonary artery was made after sudden cardiac arrest. The diagnosis was confirmed by multimodal imaging and the patient underwent successful surgical correction. Abnormal origins of a coronary artery may become symptomatic later in life and may occur as an isolated cardiac malformation. Due to a potentially unfavorable clinical course, surgical correction should be considered as soon as a diagnosis is made.

Impact of pulmonary valve replacement on ventricular function and cardiac events in patients with tetralogy of Fallot. A retrospective cohort study.

INTRODUCTION AND OBJECTIVES: Our aim was to assess the impact of prosthetic pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF) on changes in biventricular volumes and function and on adverse cardiac events. METHODS: Adults with rTOF were identified from the SACHER-registry. Data from serial cardiac magnetic resonance imaging, echocardiography, exercise capacity and n-terminal pro b-type natriuretic peptide (NT-proBNP) were collected. The primary endpoint was right ventricular ejection fraction (RVEF) as measured by cardiac magnetic resonance. Secondary endpoints were biventricular volumes, left ventricular ejection fraction, exercise capacity and NT-proBNP levels, and time to adverse cardiac outcomes (atrial and ventricular arrhythmia, endocarditis). Associations between previous PVR and longitudinal changes in functional outcomes and time to adverse cardiac outcomes were analyzed using linear mixed-effects models and Cox proportional hazards models, respectively. RESULTS: A total of 308 patients (153 with and 155 without PVR) with 887 study visits were analyzed. Previous PVR was not significantly associated with changes in RVEF (CE, -1.33; 95%CI, -5.87 to 3.21; P=.566). Previous PVR was associated with lower right ventricular end-diastolic volume but had no significant effect on left ventricular ejection fraction, exercise capacity, or NT-proBNP-levels. Previous PVR was associated with an increased hazard of atrial arrhythmias (HR, 2.09; 95%CI, 1.17-3.72; P=.012) and infective endocarditis (HR, 12.72; 95%CI, 4.69-34.49; P<.0001) but not with an increased hazard of sustained ventricular arrhythmias (HR, 0.64; 95%CI, 0.18-2.27; P=.490). CONCLUSIONS: Previous PVR was not significantly associated with changes in RVEF but was associated with an increased risk of atrial arrhythmias and infective endocarditis.