Impacto de prótesis valvular pulmonar en la función ventricular derecha y eventos cardiacos en pacientes con tetralogía de Fallot: análisis retrospectivo / Impact of pulmonary valve replacement on ventricular function and cardiac events in patients with tetralogy of Fallot. A retrospective cohort study

Introducción y objetivos: Evaluar el impacto del recambio valvular pulmonar (RVP) en pacientes con tetralogía de Fallot reparada (TFr) en la evolución de los volúmenes y función b-ventricular, y en los eventos adversos.MétodosSe identificó adultos con TFr del registro SACHER. Se evaluó los datos seriados de cardiorresonancia magnética, ecocardiografía, capacidad de ejercicio y fracción aminoterminal del propéptido natriurético cerebral (tipo B) (NT-proBNP). El objetivo primario fue la fracción de eyección del ventrículo derecho (FEVD) medida por cardiorresonancia. Los objetivos secundarios fueron volúmenes biventriculares, capacidad de ejercicio, valores de NT-proBNP y tiempo hasta eventos adversos (arritmia auricular o ventricular, endocarditis). Se analizó las asociaciones entre el RVP previo y las trayectorias longitudinales de los resultados funcionales, y el tiempo hasta los eventos cardiacos adversos con modelos lineales de efectos mixtos y modelos de riesgos proporcionales de Cox, respectivamente.ResultadosSe analizó a 308 pacientes (153 con y 155 sin RVP) con 887 visitas de estudio. No se asoció el RVP de manera significativa con la trayectoria de la FEVD (CE=-1,33; IC95%, –5,87-3,21; p=0,566). Se asoció el RVP previo con menor volumen telediastólico del ventrículo derecho, pero no tuvo efecto significativo en la fracción de eyección del ventrículo izquierdo, capacidad de ejercicio o valores de NT-proBNP. Se asoció el RVP previo con un riesgo incrementado de arritmias auriculares (HR=2,09; IC95%, 1,17-3,72; p=0,012) y endocarditis infecciosa (HR=12,72; IC95%, 4,69-34,49; p<0,0001), pero no con un riesgo aumentado de arritmias ventriculares sostenidas (HR=0,64; IC95%, 0,18-2,27; p=0,490).ConclusionesNo se asoció el RVP previo de manera significativa con la trayectoria de la FEVD, pero sí con un riesgo aumentado de arritmias auriculares y endocarditis infecciosa. (AU)

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.MethodsAdults 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.ResultsA 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).ConclusionsPrevious PVR was not significantly associated with changes in RVEF but was associated with an increased risk of atrial arrhythmias and infective endocarditis. (AU)

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.

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.

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.

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.

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.

Determinants of Advanced Liver Fibrosis in Adult Patients After Fontan Palliation: Usefulness of Ultrasound Transient Elastography.

BACKGROUND: Fontan-associated liver disease is an increasing concern. Our aim was to assess prevalence and predictors of advanced liver fibrosis with a specific focus on utility of liver stiffness measurement by ultrasound transient elastography. METHODS: A total of 97 adult Fontan patients (55% male, median age: 23.1 years, interquartile range [IQR]: 18.7-30.6); 92 (95%) were evaluated with transient elastography, and 50 (52%) underwent transjugular liver biopsy. Advanced liver fibrosis was defined as congestive hepatic fibrosis score 3 or 4. RESULTS: Only 4 patients (4%) had liver stiffness values < 10 kilopascal (kPa). Liver-stiffness measurements correlated weakly with peak oxygen uptake on exercise testing and Fontan pressure but not with Model for End-Stage Liver Disease excluding INR (MELD-XI) score or spleen size. Serial follow-up liver stiffness measurements in 73 clinically stable patients showed large variability among individual patients. Advanced liver fibrosis was present in 35 of 50 (70%) patients on liver biopsy and was associated to MELD-XI-Score ≥ 11 and splenomegaly but not to liver-stiffness measurements. Advanced liver fibrosis was not associated with patient age or time since Fontan operation but with younger age at completion of Fontan (3.7 years, IQR: 2.3-6.3 vs 6.8 years; IQR: 3.5-12.1; P = 0.037). CONCLUSIONS: In our cohort, advanced liver fibrosis was present in the majority of adult Fontan patients. Liver stiffness as measured by transient elastography was not associated with the degree of liver fibrosis. Because of its high variability on serial measurements, it seems not to be useful for clinical decision making. The unexpected finding that younger age at completion of Fontan was associated with advanced liver fibrosis merits further evaluation.

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.

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.

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.

No Roots, No Fruits: Marcel Tanner's Scholarly Contribution, Achievements in Capacity Building, and Impact in Global Health.

On 1 October 2022, Marcel Tanner celebrated his 70th birthday with his family and friends on the River Rhein in Basel. Trained in epidemiology (Ph.D.) and public health (MPH), Tanner devoted his entire working life to research, teaching, and capacity building. Indeed, he built up productive partnerships, fostered multinational consortia, served on numerous scientific and strategic advisory boards, and contributed measurably to improving people's health and well-being. We systematically searched the Web of Science Core Collection to identify Tanner's scholarly contribution and pursued an in-depth analysis of his scientific oeuvre including the main areas of research, pathogens, diseases, and health systems, and the geographical foci of his scholarly activities. Additionally, we examined Tanner's impact on personal and institutional capacity building in the arena of global health. We also invited a handful of colleagues to describe their experiences while working with Marcel Tanner. What transpires is a considerable breadth and depth of peer-reviewed publications in tropical medicine; epidemiology, environmental, and occupational health; parasitology; and infectious diseases. More than a third of the 622 peer-reviewed articles, the first piece published in 1978, focused on various aspects of the protozoan parasite Plasmodium and the disease it causes: malaria. Tanner trained, taught, and inspired generations of students, scientists, and practitioners all over the world. His unique ability to bring people and institutions together to work in partnership is at the heart of an impactful career in global health.

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.

Marcel Tanner, Global Health Specialist "Extraordinaire" Incl Supplementary Materials with Personal Contributions from Renowned Experts.

Marcel Tanner, President of the Swiss Academy of the Sciences, Director emeritus of the Swiss Tropical and Public Health Institute (Swiss TPH), and Professor of Epidemiology and Medical Parasitology at the University of Basel, Switzerland, is indeed extraordinary, especially when considering the broad set of global health issues covered by his research [...].

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.

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?

More than seven decades of Acta Tropica: Looking back to move into the future.

Acta Tropica is an international, peer-reviewed journal advancing scientific research in the fields of tropical medicine and parasitology. This article elucidates the rich history of the journal and speculates about its future. Acta Tropica was launched in 1944 and formed an integral part of the establishment and running of the Swiss Tropical Institute in Basel. After two distinct periods of relatively small publication activities (1944-1976 and 1977-1988), in 1989, Acta Tropica was transferred to the Dutch publisher Elsevier. Subsequently, the annual number of publications steadily increased and the scope of the journal broadened to the biology of pathogens and their vectors, to genetics, host-parasite relationships, mechanisms of pathogenicity, diagnostics, and treatment of tropical diseases. The body of published articles contributed to an improved understanding of the prevention, surveillance, control, and elimination of diseases that are intimately linked to poverty, such as malaria and neglected tropical diseases. In recent years, the scope of Acta Tropica was widening to target emerging and re-emerging infectious diseases, epidemics and pandemics, interrelations of microbes, viruses, and parasites, co-dependencies of epidemiology, ecology, environment, and climate change. Importantly, non-communicable diseases are gaining interest in low- and middle-income countries due to urbanization, globalization, and rapidly changing life styles, and hence, these issues receive growing prominence. Acta Tropica continues to embrace inter- and, indeed, transdisciplinary research to address pressing global health issues and sustainable development.