Tuning the contact conductance of anchoring groups in single molecule junctions by molecular design

A tetraphenylmethane tripod functionalized with three thiol moieties in the para position can serve as a supporting platform for functional molecular electronic elements. A combined experimental scanning tunneling microscopy break junction technique with theoretical approaches based on density functional theory and non-equilibrium Green`s function formalism was used for detailed charge transport analysis to find configurations, geometries and charge transport pathways in the molecular junctions of single molecule oligo-

Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Letter to the Editor: Statins and COVID‐19: Efficacy Still to Be Proven

International audienceWe read with interest the article by Bloom et al reporting liver biochemistry–associated trends, etiologies, and outcomes in 60 patients with coronavirus disease 2019 (COVID‐19). The authors reported that 69% of the patients had abnormal liver function tests (LFTs) on admission and 93% during their hospital stay, with an aspartate aminotransferase (AST) predominance. These results are similar to our own experience of 234 patients admitted with COVID‐19 according to World Health Organization (WHO) diagnostic guidelines

Potential role of ketamine in burn-associated cholestasis

International audienceWe read with interest the paper by de Tymowski et al.1 describing the factors and outcomes of burn-associated cholestasis. This retrospective study described 111 patients (52%) with burn-associated cholestasis among 214 patients who had suffered severe burn injuries.The authors suggested that increased levels of total bilirubin ≥2x the upper limit of normal (ULN) with or without an increase in serum alkaline phosphatase (ALP) ≥1.5x the ULN or gamma-glutamyltransferase (GGT) ≥3x the ULN was associated with poorer survival at 90 days. Of the 74 patients alive at the time of discharge from the intensive care unit (ICU), 38 had cholestasis. As the authors describe, biliary lesions in severe burn injuries may be related to hypoxic hepatitis or hypovolemic shock.We report the case of a 29-year-old man admitted to our ICU for burns following a road traffic accident. On Day 17 after admission, he developed icteric cholestasis: aspartate aminotransferase: 79 UI/L, alanine aminotransferase: 69 UI/L, GGT: 551 UI/L, ALP: 332 UI/L, prothrombin time: 62%, total bilirubin: 27 μmol/L. Bilirubin increased to more than 25x the ULN over a 3-month period. Viral hepatitis, autoimmune hepatitis, obstructive jaundice, and alcoholic hepatitis were ruled out. A liver biopsy showed cholangitis without fibrosis or steatosis, and magnetic resonance cholangiography was normal. The only potentially incriminating drug was ketamine administered for analgesia (between 200 mg and 400 mg daily for more than 3 months). When ketamine was stopped, icteric cholestasis gradually improved over several months.Ketamine is a commonly used dissociative anesthetic that antagonizes the N-methyl-d-aspartate (NMDA) receptor. At subanesthetic doses it has strong analgesic properties that can be beneficial for neuropathic pain resistant to conventional therapies

Sofosbuvir, Glecaprevir, Pibrentasvir, and Ribavirin as a Rescue Therapy in Difficult‐to‐Treat HCV Patients

International audiencePangenotypic direct-acting antiviral (DAA) drugs have an HCV cure rate of >95% in almost all treated patients.(1, 2) When DAA treatment fails, retreatment must be guided by virus resistance profiles, and phase 3 trials have reported sustained virological responses (SVR) of 96%-98% after a 12-week course of sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX).(3) However, the management is more uncertain after SOF/VEL/VOX failure, and there is still insufficient evidence to support a particular retreatment. For instance, Dietz et al.(4) reported 77% SVR at 12 weeks (SVR12) in patients with different HCV profiles retreated with glecaprevir (GLE)/pibrentasvir (PIB), SOF, and ribavirin (RBV) for 12-24 weeks after SOF/VEL/VOX failure

Public Health Impact and Cost-Effectiveness Analysis of Routine Infant 4CMenBVaccination in Germany to Prevent SerogroupB Invasive Meningococcal Disease

Scholz S, Schwarz M, Beck E, et al. Public Health Impact and Cost-Effectiveness Analysis of Routine Infant 4CMenBVaccination in Germany to Prevent SerogroupB Invasive Meningococcal Disease. Infectious Diseases and Therapy . 2021.INTRODUCTION: Invasive meningococcal disease (IMD) is an uncommon, severe, life-threatening disease primarily affecting infants, with potential lifelong sequelae. Neisseria meningitidis (Nm) serogroupB (MenB) causes most IMD cases in Germany, many of which can be prevented with four-component MenB (4CMenB) vaccination. The potential public health and economic impact of introducing routine 4CMenB infant vaccination in Germany was assessed.; METHODS: A dynamic transmission-based cost-effectiveness model adapted for Germany assessed the impact of infant 4CMenB universal mass vaccination (UMV) versus no vaccination. The model included the latest real-world evidence on vaccine effectiveness, the comprehensive burden of disease on patients (sequelae) and their family (quality of life impact), comprehensive German IMD costs, and vaccination uptake assumptions.; RESULTS: The largest public health impact was predicted in children: a rapid decline, 5years after UMV implementation, of 39.9% (34.7%) for MenB (all IMD) cases aged 0-4years and 42.4% (36.8%) in infants. Over lifetime (100-year time horizon), 4CMenB could prevent 3154 MenB (3303 all IMD) cases, 291 MenB (304 all IMD) deaths and 1370 MenB (1435 all IMD) long-term sequelae. 4CMenB saved 25,878 quality-adjusted life-years (QALYs), at a cost of 188,762 per QALY gained in the base case (societal perspective including lost productivity). Scenarios including potential Nm carriage protection (enabling herd protection) or societal preferences for the prevention of severe diseases led to more cost-effective results, while a scenario excluding IMD impact beyond the patient with increased discounting of vaccination health benefits produced less cost-effective results.; CONCLUSIONS: MenB IMD is a vaccine-preventable disease. This analysis for Germany can inform decision-makers on the potential impact of introducing infant 4CMenB UMV. The program is predicted to rapidly produce health benefits (reduction in child cases, deaths and sequelae) at a cost per QALY to society of around 190,000 (base case), decreasing to around 78,000 when considering societal preferences and IMD underreporting. © 2021. The Author(s)