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Cristina Bermejo Boixareu,1,&ast; Cristina Ojeda-Thies,2,&ast; Ainhoa Guijarro Valtueña,3 Bernardo Abel Cedeño Veloz,4 María Gonzalo Lázaro,4 Laura Navarro Castellanos,5 Rocío Queipo Matas,5,6 Paloma Gómez Campelo,5 Ana Royuela Vicente,7 Juan Ignacio González-Montalvo,5,8 Pilar Sáez-López5,9,10 1Geriatrics Department, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain; 2Orthopaedic Surgery and Traumatology Department, 12 de Octubre University Hospital, Madrid, Spain; 3Orthopaedic Surgery and Traumatology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain; 4Geriatrics Department, University Hospital of Navarra, Pamplona, Spain; 5La Paz Institute for Health Research - IdiPAZ, Hospital Universitario La Paz - Universidad Autónoma de Madrid, Madrid, Spain; 6European University of Madrid, Madrid, Spain; 7Biostatistics Unit, Puerta de Hierro Majadahonda University Hospital, IDIPHISA, CIBERESP, Madrid, Spain; 8Geriatrics Department, La Paz University Hospital, Madrid, Spain; 9Geriatrics Department, Fundación Alcorcón University Hospital, Madrid, Spain; 10Spanish National Hip Fracture Registry, Madrid, Spain&ast;These authors contributed equally to this workCorrespondence: Cristina Bermejo Boixareu, Geriatrics Department, Puerta de Hierro University Hospital, Madrid, Spain, Email cristina_bermejo@hotmail.comObjective: The primary objective was to describe the clinical characteristics, management, and outcomes of centenarians with fragility hip fracture and compare them to other age groups. The secondary objective was to determine the variables associated with length of stay, in-hospital mortality and 30-day mortality.Materials and Methods: This is a secondary analysis of the Spanish National Hip Fracture Registry. We included patients ≥ 75 years admitted for fragility hip fractures in 86 Spanish hospitals between 2017 and 2019, dividing the sample into four age groups. The variables studied were baseline characteristics, type of fracture, management, length of stay, in-hospital mortality and 30-day mortality.Results: We included 25,938 patients (2888 were 75– 79 years old; 14,762 octogenarians; 8,035 nonagenarians and 253 centenarians). Of the centenarians, 83% were women, 33% had severe dementia, 9% had severe dependency and 36% lived in residential care homes. Six out of ten had intertrochanteric fracture. Length of hospital stay was 8.6 days; in-hospital mortality was 10.3% and 30-day mortality 20.9%. Older age groups had more women, severe functional dependency, severe dementia, intertrochanteric fracture, living in care facilities and being discharged to nursing care. They had less frequent early mobilization, osteoporosis treatment and discharge to rehabilitation units. In-hospital and 30-day mortality were higher with increasing age. In centenarians, time to surgery > 48 hours was independently associated with length of stay (correlation coefficient 3.99 [95% CI: 2.35– 5.64; p< 0.001]) and anaesthetic risk, based on an ASA score of V, was related to 30-day mortality (ASA score II [OR 0.25, 95% CI: 0.09– 0.70; p=0.009] and ASA score III [OR 0.43, 95% CI: 0.19– 0.96; p=0.039]).Conclusion: Centenarians had different clinical characteristics, management and outcomes. Although centenarians had worse outcomes, nearly 4 out of 5 centenarians were alive one month after surgery.Keywords: centenarians, fracture, registry, mortality, ASA grade

One of the peculiarities of the Spanish labour market has been the existence of a high share of temporary employment, a result of the 1984 labour reform which made the use of temporary contracts more flexible. Since 1994, various reforms have sought to increase the use of open-ended contracts and discourage the use of fixed-term contracts. Although these reforms, in particular the 2012 and 2021 reforms, have led to a reduction in the share of temporary workers they have also created other unintended problems, such as a reduction in the duration of fixed-term contracts, the proliferation of part-time contracts and atypical open-ended contracts, and a high share of temporary employment in public sector.

Reseña de: Parra Bañón, J. J. (2022). Noé en imágenes. Arquitecturas de la catástrofe. Girona: Atalanta, 392 pp.

Calculations of total, complete and incomplete fusion cross sections are presented as function of the incident energy of the weakly bound projectile 8B in reactions with light 27Al, 28Si and heavy 208Pb and 209Bi mass targets. In particular, the relative effect of the breakup fragments; proton and 7Be of 8B on incomplete fusion is determined. Also, the effect of an additional proton to the nuclear potential of the targets 28Si, 209Bi respect to 27Al and 208Pb is determined as a function of the incident energy. It is found that the proton absorption becomes more important than for 7Be for light targets for energies around and above the barrier, however, the inverse occurs for heavy targets. The calculations are performed with two different methods. The CDCC to determine the relative projectile-target radial wave functions which subsequently are used in the angular momentum-dependent model of fusion probabilities to calculate complete, incomplete and total fusion.

This paper analyses the role played by the flexibilization of labour markets on functional income distribution. Specifically, we analyse whether employment protection legislation affects the evolution of labour income share, measured by the size of compensation of employees as a percentage of GDP, the sum of wages and salaries as a percentage of GDP and the size of the adjusted wage share, in twenty European economies. Our study’s results show that the evolution of labour income share is explained by the economic growth, the growth of employment and unemployment rates, and the growth of real wages. Regarding the role played by the flexibility of the labour market, and specifically of the employment protection legislation, only employment protection for temporary workers has a significant impact on the evolution of labour shares. Our results show that stricter provisions on the use of fixed-term and temporary agency contracts have a positive impact on the growth of labour shares.

The paper analyses the determinant elements of the evolution of labour income share, measured by the size of compensation of employees as a percentage of GDP in twenty European economies. In doing so, special attention is paid to the impact of employment protection legislation. Our study’s results show that the evolution of labour income share is explained by the economic growth, the growth of employment and unemployment rates, and the growth of real wages. Regarding employment protection, only employment protection for temporary workers matters. Our results shows that stricter provisions on the use of fixed-term and temporary agency contracts have a positive impact on the growth of the labour shares.

Although a key condition for the creation of a monetary union is the existence of similar structural characteristics that reduce the existence and incidence of asymmetric shocks, in the case of the Eurozone, most, if not all, studies have emphasized the existence of sizeable divergences both in the macroeconomic performances and in the structural elements of the Eurozone countries. The objective of the paper is to analyse whether the economic and financial crisis that is affecting the Eurozone since the year 2008 has had any impact of the coherence of the Eurozone, that is, whether after 2008 the differences in the macroeconomic performance of the euro counties are declining (convergence) or increasing (divergence).

Presentamos el caso de una aspergilosis pulmonar crónica cavitada en un varón de 82 años con enfermedad pulmonar obstructiva crónica (EPOC), que finalmente se resolvió con un antifúngico de segunda elección y la instilación de Anfo- tericina B liposomal intracavitaria.

El período periconcepcional, embrionario/fetal y lactancia/crianza constituyen una de las ventanas de vulnerabilidad a exposiciones medioambientales más importante de la vida de un individuo. Enfermeras y matronas por su forma de entender el binomio salud/enfermedad ocupan un lugar estratégico para el desarrollo de tareas relacionadas con la salud medioambiental en general y durante estos periodos en particular. Diferentes asociaciones enfermeras, así como instituciones sanitarias internacionales instan a los profesionales de enfermería a ejercer tareas que permitan reconocer y manejar factores de riesgo medioambiental (riesgos físicos, químicos, biológicos, sociales y psicosociales) y a promover factores de protección en sus comunidades, en la pareja embarazada y en su descendencia. Existen experiencias enfermeras como la consulta de enfermería de salud medioambiental reproductiva y la hoja verde como herramienta clínica de cribado medioambiental que permiten, de manera sistemática y organizada, identificar, modificar y promover estilos de vida más sanos y más saludables. La capacitación de los profesionales de enfermería y el aumento de la conciencia medioambiental en los cuidados, tiene un impacto positivo en la calidad de los embarazos, su descendencia, sus familias y la comunidad que los rodea.

The outbreak of the economic and financial crisis in 2008, the socalled Great Recession, has made that many European Union countries have made massive interventions in their banking and financial systems. These interventions have had a considerable impact in the public finances of these countries. The aim of the paper is to analyze the impact on the national public budgets of the measures of public support to problem financial institutions carried out between the years 2008 and 2013, and to study how this budgetary impact has affected to the fiscal imbalances and to the strategies of fiscal impulse and consolidation implemented along these years.

Purpose of Review: This article aims to provide an intuitive framework for diagnosing and managing healthcare-associated diarrhea (HCAD) in the immunocompromised (IC) host., Recent Findings: Our understanding of diarrhea in hospitalized IC patients has significantly evolved. However, the challenge lies in distinguishing between these patients' numerous causes of diarrhea. The incorporation of gastrointestinal (GI) multiplex polymerase chain reaction (PCR) panels has led to a paradigm shift in our approach to diarrhea. However, using these panels judiciously is of utmost importance, as their misuse can lead to over-testing, overtreatment, and increased hospital costs. We propose a stepwise diagnostic algorithm that ensures diagnostic stewardship, optimal patient care, and resource utilization., Summary: Diarrhea is a common complication in hospitalized IC patients and is associated with significant morbidity and rare mortality. The advent of new diagnostics, such as GI multiplex PCR panels, holds promise in facilitating the detection of recognized pathogens and may allow for improved outcomes using pathogen-targeted therapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Nocardiosis typically requires a prolonged treatment duration of ≥6 months and initial combination therapy with 2-3 antibiotics. First-line regimens for nocardiosis are associated with considerable toxicity; therefore, alternative therapies are needed. Omadacycline is an aminomethylcycline with broad antimicrobial activity whose in vitro activity against Nocardia species has not been formally assessed. The in vitro potency of omadacycline was evaluated against 300 Nocardia clinical isolates by broth microdilution. The most common Nocardia species tested were N. cyriacigeorgica (21%), N. nova (20%), and N. farcinica (12%). The most common specimens were respiratory (178 isolates, 59%) and wound (57 isolates, 19%). Omadacycline minimum inhibitory concentrations (MICs) across all Nocardia species ranged from 0.06 µg/mL to 8 µg/mL, with an MIC 50 of 2 µg/mL and MIC 90 of 4 µg/mL. The lowest MICs were found among N. paucivorans (MIC 50 = 0.25 µg/mL, MIC 90 = 0.25 µg/mL), N. asiatica (MIC 50 = 0.25 µg/mL, MIC 90 = 1 µg/mL), N. abscessus complex (MIC 50 = 0.5 µg/mL, MIC 90 = 1 µg/mL), N. beijingensis (MIC 50 = 0.5 µg/mL, MIC 90 = 2 µg/mL), and N. otitidiscaviarum (MIC 50 = 1 µg/mL, MIC 90 = 2 µg/mL). The highest MICs were found among N. farcinica (MIC 50 = 4 µg/mL, MIC 90 = 8 µg/mL). In vitro potency differed by species among Nocardia clinical isolates. Further studies are warranted to evaluate the potential clinical utility of omadacycline for nocardiosis., Competing Interests: R.J.B. reports receiving prior research support from Rempex Pharmaceuticals. The other authors have no relevant conflicts of interest to disclose.

Objective: To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy., Methods: Participants with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry., Results: Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05)., Conclusion: Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AYC reports consulting for Valneva. RLA reports stock ownership of Abbvie, Pfizer, Johnson & Johnson, & Briston Myers Squibb. GSF reports consulting for Eli Lilly. Other authors report no commercial interest or conflicts of interest in relation to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose: Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat multiple hematologic malignancies and graft-versus-host disease. Though less myelosuppressive than cytotoxic chemotherapy, increased infections, including invasive fungal infections (IFIs), have been reported with ibrutinib use. This study aimed to determine the characteristics and risk factors for infection associated with ibrutinib at our institution., Methods: Patients who received ibrutinib between June 2014 and August 2019 were included. Primary endpoints were the incidence of any infection and the incidence of serious infection (defined as hospitalization, parenteral antimicrobial therapy, or pneumonia regardless of hospitalization). Infection risk factors were assessed using logistic regression., Results: One hundred thirty-two patients were identified (78% male; median age, 71 years). The most common indications for ibrutinib were chronic lymphocytic leukemia (67%) and mantle cell lymphoma (12%). Infection and serious infection occurred in 94 (71%) and 47 (36%) patients, respectively; when pneumonia was excluded as a criterion for serious infection, the serious infection rate was 27%. The median time from ibrutinib initiation to first infection was 125 days. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) (odds ratio [OR], 4.60; 95% CI, 1.22-17.4) and corticosteroid use (OR, 5.55; 95% CI, 1.52-20.3) were significant risk factors for serious infection. IFIs were diagnosed in 7 patients (5%): 5 had Pneumocystis jirovecii pneumonia and 2 were infected with invasive molds., Conclusion: Serious infection and IFI rates are high but similar to those previously described. Risk factors for serious infection included allo-HSCT and corticosteroid use. Targeted antimicrobial prophylaxis should be evaluated in prospective studies in patients on ibrutinib to reduce serious infections and IFI., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Syndromic molecular panels for the diagnosis of gastroenteritis, meningitis/encephalitis, and pneumonia are becoming routinely used for patient care throughout the world., Content: These rapid, sample-to-answer assays have great potential to improve patient care, infection control, and antimicrobial stewardship. However, diagnostic stewardship is essential for their optimal use and accuracy, and interventions can be applied at all phases of the diagnostic process., Summary: The aim of this review article is to describe effective approaches to diagnostic stewardship for syndromic molecular panels to ensure appropriate test utilization and quality assured results., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diarrhea in hematopoietic stem-cell transplantation (HSCT) remains a multifactorial challenge that demands a nuanced diagnostic approach. The causes of infectious diarrhea in HSCT recipients are diverse and influenced by patient-specific risk factors, the post-transplant timeline, and local epidemiology. During the past decade, our understanding of diarrhea in HSCT has witnessed a transformative shift through the incorporation of gastrointestinal (GI) multiplex polymerase chain reaction (PCR) panels. However, the judicious application of these panels is imperative to avoid overtesting and prevent adverse outcomes. The challenge lies in distinguishing between the diverse causes of diarrhea, ascertaining the clinical significance of detected pathogens, and navigating the diagnostic uncertainty presented by several non-infectious conditions such as mucositis, intestinal dysbiosis, and acute graft-versus-host disease (aGvHD), all of which mimic infection. This review examines the landscape of infectious diarrhea in the HSCT population, encompassing both established (e.g., Cytomegalovirus, Clostridioides difficile, and norovirus) and emerging pathogens (e.g., sapoviruses, astroviruses). We propose a multifaceted diagnostic algorithm that combines clinical assessment, risk stratification, and tailored utilization of molecular platforms. While multiplex GI panels present invaluable opportunities for rapid and comprehensive pathogen detection, their judicious use is pivotal in preserving diagnostic stewardship. Customization of diagnostic algorithms tailored to local epidemiology ensures optimal patient care and resource utilization., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Pentaerythritol tetranitrate (PETN) is a nitrate ester explosive that may be persistent with scarce reports on its environmental fate and impacts. Our main objective was to isolate and characterize bacteria that transform PETN under aerobic and anaerobic conditions. Biotransformation of PETN (100 mg L-1) was evaluated using mineral medium with (M + C) and without (M - C) additional carbon sources under aerobic conditions and with additional carbon sources under anaerobic conditions. Here, we report on the isolation of 12 PETN-transforming cultures (4 pure and 8 co-cultures) from environmental samples collected at an explosive manufacturing plant. The highest transformation of PETN was observed for cultures in M + C under aerobic conditions, reaching up to 91% ± 2% in 2 d. Under this condition, PETN biotransformation was observed in conjunction with the release of nitrites and bacterial growth. No substantial transformation of PETN (<45%) was observed during 21 d in M - C under aerobic conditions. Under anaerobic conditions, five cultures could transform PETN (up to 52% ± 13%) as the sole nitrogen source, concurrent with the formation of two unidentified metabolites. PETN-transforming cultures belonged to Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, and Actinobacteria. In conclusion, we isolated 12 PETN-transforming cultures belonging to diverse taxa, suggesting that PETN transformation is phylogenetically widespread., (© The Author(s) 2023. Published by Oxford University Press on behalf of Applied Microbiology International.)

Nucleic acid-based receptors, known as aptamers, are relatively fast to discover and manufacture but lack the diverse functional groups of protein receptors (e.g., antibodies). The binding properties of DNA aptamers can be enhanced by attaching abiotic functional groups; for example, aromatic groups such as naphthalene slow dissociation from proteins. Although the terminal alkyne is a π-electron-rich functional group that has been used in small molecule drugs to enhance binding to proteins through noncovalent interactions, it remains unexplored for enhancing DNA aptamer binding affinity. Here, we demonstrate the utility of the terminal alkyne for improving the binding of DNA to proteins. We prepared a library of 256 terminal-alkyne-bearing variants of HD22, a DNA aptamer that binds the protein thrombin with nanomolar affinity. After a one-step thrombin-binding selection, a high-affinity aptamer containing two alkynes was discovered, exhibiting 3.2-fold tighter thrombin binding than the corresponding unmodified sequence. The tighter binding was attributable to a slower rate of dissociation from thrombin (5.2-fold slower than HD22). Molecular dynamics simulations with enhanced sampling by Replica Exchange with Solute Tempering (REST2) suggest that the π-electron-rich alkyne interacts with an asparagine side chain N-H group on thrombin, forming a noncovalent interaction that stabilizes the aptamer-protein interface. Overall, this work represents the first case of terminal alkynes enhancing the binding properties of an aptamer and underscores the utility of the terminal alkyne as an atom economical π-electron-rich functional group to enhance binding affinity with minimal steric perturbation.

The ability to site-selectively modify equivalent functional groups in a molecule has the potential to streamline syntheses and increase product yields by lowering step counts. Enzymes catalyze site-selective transformations throughout primary and secondary metabolism, but leveraging this capability for non-native substrates and reactions requires a detailed understanding of the potential and limitations of enzyme catalysis and how these bounds can be extended by protein engineering. In this review, we discuss representative examples of site-selective enzyme catalysis involving functional group manipulation and C-H bond functionalization. We include illustrative examples of native catalysis, but our focus is on cases involving non-native substrates and reactions often using engineered enzymes. We then discuss the use of these enzymes for chemoenzymatic transformations and target-oriented synthesis and conclude with a survey of tools and techniques that could expand the scope of non-native site-selective enzyme catalysis.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL). Several risk factors including CAR-T cell-related toxicities and their treatments often lead to infectious complications (ICs); however, the pattern and timeline is not well established. We evaluated ICs in 48 patients with R/R B-cell NHL following CAR-T cell therapy at our institution. Overall, 15 patients experienced 22 infection events. Eight infections (4 bacterial, 3 viral and 1 fungal) occurred within the first 30 days and 14 infections (7 bacterial, 6 viral, 1 fungal) between days 31 to 180 following CAR-T infusion. Most infections were mild-to-moderate and fifteen infections involved the respiratory tract. Two patients developed mild-to-moderate COVID-19 infection and one patient a cytomegalovirus reactivation after CAR-T infusion. Two patients developed IFIs: one case each of fatal disseminated candidiasis and invasive pulmonary aspergillosis at day 16 and 77, respectively. Patients with more than 4 prior antitumor regimens and patient's ≥ 65 years had a higher infection rate. Infections in patients with relapsed/refractory B-cell NHL are common after CAR-T despite the use of infection prophylaxis. Age ≥ 65 years and having > 4 prior antitumor treatments were identified as risk factors for infection. Fungal infections carried significant impact in morbidity and mortality, suggesting a role for increase fungal surveillance and/or anti-mold prophylaxis following high-dose steroids and tocilizumab. Four of ten patients developed an antibody response following two doses of SARS-CoV-2 mRNA vaccine., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined., Methods: We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots., Results: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets., Conclusions: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease., Competing Interests: Potential conflicts of interest. N. J. reports salary support to his institution by Sagent Pharmaceuticals. D. I. has received clinical trial funding paid to her institution from Gilead Sciences. M. K. J. has received grant funding paid to her institution from Gilead Sciences. R. A. M. has received grants and research funding to his institution from Gilead Sciences, Pfizer, Sanofi, and GlaxoSmithKline (GSK). A. R. B. has received grant funding to her institution from Pfizer, Merck, and Cynavac, and has consulted for Janssen and GSK. A. L. has received research grant support to her institution from Gilead. R. G. has received research funding from Gilead Sciences and GSK. W. R. S. has received clinical trial funding paid to his institution from Gilead Sciences. C. A. B. has received contracts and grants to her institution from Gilead Sciences. All other authors report no potential conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Fe II - and α-ketoglutarate-dependent halogenases and oxygenases can catalyze site-selective functionalization of C-H bonds via a variety of C-X bond forming reactions, but achieving high chemoselectivity for functionalization using non-native functional groups remains rare. The current study shows that directed evolution can be used to engineer variants of the dioxygenase SadX that address this challenge. Site-selective azidation of succinylated amino acids and a succinylated amine was achieved as a result of mutations throughout the SadX structure. The installed azide group was reduced to a primary amine, and the succinyl group required for azidation was enzymatically cleaved to provide the corresponding amine. These results provide a promising starting point for evolving additional SadX variants with activity on structurally distinct substrates and for enabling enzymatic C-H functionalization with other non-native functional groups., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear., Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial)., Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4])., Setting: 94 hospitals in 10 countries (86% U.S. participants)., Participants: Adults hospitalized with COVID-19., Intervention: SOC., Measurements: 28-day mortality and recovery., Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages., Limitation: Unmeasured confounding., Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Mononuclear non-heme Fe(II)- and α-ketoglutarate-dependent oxygenases (FeDOs) catalyze a site-selective C-H hydroxylation. Variants of these enzymes in which a conserved Asp/Glu residue in the Fe(II)-binding facial triad is replaced by Ala/Gly can, in some cases, bind various anionic ligands and catalyze non-native chlorination and bromination reactions. In this study, we explore the binding of different anions to an FeDO facial triad variant, SadX, and the effects of that binding on HO • vs X • rebound. We establish not only that chloride and bromide enable non-native halogenation reactions but also that all anions investigated, including azide, cyanate, formate, and fluoride, significantly accelerate and influence the site selectivity of SadX hydroxylation catalysis. Azide and cyanate also lead to the formation of products resulting from N 3 • , NCO • , and OCN • rebound. While fluoride rebound is not observed, the rate acceleration provided by this ligand leads us to calculate barriers for HO • and F • rebound from a putative Fe(III)(OH)(F) intermediate. These calculations suggest that the lack of fluorination is due to the relative barriers of the HO • and F • rebound transition states rather than an inaccessible barrier for F • rebound. Together, these results improve our understanding of the FeDO facial triad variant tolerance of different anionic ligands, their ability to promote rebound involving these ligands, and inherent rebound preferences relative to HO • that will aid efforts to develop non-native catalysis using these enzymes.

Background: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19., Methods: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168., Findings: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012)., Interpretation: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered., Funding: National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To report on pathogenic germline variants detected among individuals undergoing genetic testing for hereditary breast and/or ovarian cancer (HBOC) from Latin America and compare them with self-reported Hispanic individuals from the United States., Methods: In this cross-sectional study, unrelated individuals with a personal/family history suggestive of HBOC who received clinician-ordered germline multigene sequencing were grouped according to the location of the ordering physician: group A, Mexico, Central America, and the Caribbean; group B, South America; and group C, United States with individuals who self-reported Hispanic ethnicity. Relatives who underwent cascade testing were analyzed separately., Results: Among 24,075 unrelated probands across all regions, most were female (94.9%) and reported a personal history suggestive of HBOC (range, 65.0%-80.6%); the mean age at testing was 49.1 ± 13.1 years. The average number of genes analyzed per patient was highest in group A (A 63 ± 28, B 56 ± 29, and C 40 ± 28). Between 9.1% and 18.7% of patients had pathogenic germline variants in HBOC genes (highest yield in group A), with the majority associated with high HBOC risk. Compared with US Hispanics individuals the overall yield was significantly higher in both Latin American regions (A v C P = 1.64×10 -9 , B v C P < 2.2×10 -16 ). Rates of variants of uncertain significance were similar across all three regions (33.7%-42.6%). Cascade testing uptake was low in all regions (A 6.6%, B 4.5%, and C 1.9%)., Conclusion: This study highlights the importance of multigene panel testing in Latin American individuals with newly diagnosed or history of HBOC, who can benefit from medical management changes including targeted therapies, eligibility to clinical trials, risk-reducing surgeries, surveillance and prevention of secondary malignancy, and genetic counseling and subsequent cascade testing of at-risk relatives.

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant., Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation., Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall., Conclusions: In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management., Methods: This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results., Results: Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases., Clinical Trials Registration: NCT02912117., Conclusion: KT shows promise in the diagnosis and treatment optimization of FN., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

The objective of the study was to determine enteric methane emissions using the sulfur hexafluoride (SF 6 ) technique and comparing with The Intergovernmental Panel on Climate Change (IPCC) methodology in lactating cows (LC) and dry cows (DC) in the Peruvian highlands. Enteric methane (CH 4 ) emissions were measured on 5 LC and 6 DC Brown Swiss in a grazing system without concentrate. Forages samples were collected and analyzed for dry matter, crude protein, and neutral detergent fiber. Milk samples were collected and analyzed for fat, crude protein, and lactose to estimate energy-corrected milk. Animal intakes were measured using the external marker titanium dioxide (production of feces) and crude protein in feces (organic digestibility of the feed) and estimated by using performance data. The enteric methane emissions of LC were higher than methane emissions of DC (325 and 266 g CH 4 /cow/day for LC and DC, respectively (P < 0.001)). Methane emissions were 358.5 g CH 4 /day by SF 6 technique and 291.6 g CH 4 /day by IPCC methodology for LC and 337.4 g CH 4 /day by SF 6 technique and 195.8 g CH 4 /day by IPCC methodology for DC. Methane yields measured by SF 6 were higher than methane yields estimated by IPCC methodology (29 g CH 4 /kg DM and 22 g CH 4 /kg DM using SF 6 technique and IPCC methodology, respectively (P < 0.001)). Methane yields were differently for all expressions by physiological stage and method. The methane conversion factor (Ym) was 9.7% for LC and 9.6% for DC. Methane intensities were similar by method (P > 0.05). It was concluded that IPCC's methodology underestimate the CH 4 emissions of dairy systems in the Peruvian Andes; therefore, in order to obtain precise Ym, direct measurements of enteric CH 4 in the different regions of Peruvian highlands are required., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19., Methods: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475., Findings: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group., Interpretation: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo., Funding: The National Institute of Allergy and Infectious Diseases (USA)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Frequency-domain diffuse optical spectroscopic imaging (FD-DOS) is a non-invasive method for measuring absolute concentrations of tissue chromophores such as oxy- and deoxy-hemoglobin in vivo. The utility of FD-DOS for clinical applications such as monitoring chemotherapy response in breast cancer has previously been demonstrated, but challenges for further clinical translation, such as slow acquisition speed and lack of user feedback, remain. Here, we propose a new high speed FD-DOS instrument that allows users to freely acquire measurements over the tissue surface, and is capable of rapidly imaging large volumes of tissue., Methods: We utilize 3D monocular probe tracking combined with custom digital FD-DOS hardware and a high-speed data processing pipeline for the instrument. Results are displayed during scanning over the surface of the sample using a probabilistic Monte Carlo light propagation model., Results: We show this instrument can measure absorption and scattering coefficients with an error of 7% and 1% respectively, with 0.7 mm positional accuracy. We demonstrate the equivalence of our visualization methodology with a standard interpolation approach, and demonstrate two proof-of-concept in vivo results showing superficial vasculature in the human forearm and surface contrast in a healthy human breast., Conclusion: Our new FD-DOS system is able to compute chromophore concentrations in real-time (1.5 Hz) in vivo., Significance: This method has the potential to improve the quality of FD-DOS image scans while reducing measurement times for a variety of clinical applications.

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0-4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8-52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

Background: During 2017, in response to a physician's report, the Wisconsin Department of Health Services, Division of Public Health, began investigating an outbreak of febrile illness among attendees of a retreat where never frozen, intentionally undercooked, locally harvested venison was served. Preliminary testing tentatively identified the illness as toxoplasmosis., Methods: Confirmatory human serology panels and testing of the venison to confirm and categorize the presence and type of Toxoplasma gondii were completed by French and American national reference laboratories. All 12 retreat attendees were interviewed; medical records were reviewed., Results: All attendees were male; median age was 51 years (range: 22-75). After a median incubation period of 7 days, 9 (82%) of 11 exposed persons experienced illness lasting a median of 12 days. All 9 sought outpatient healthcare for symptoms including fever, chills, sweats, and headache (100%) and ocular disturbances (33%). Testing confirmed the illness as toxoplasmosis and venison as the infection source. Multiple laboratory results were atypical for toxoplasmosis, including transaminitis (86%), lymphocytopenia (88%), thrombocytopenia (38%), and leukopenia (63%). One exposed but asymptomatic person was seronegative; the other had immunity from prior infection. The T. gondii strain was identified as closely related to an atypical genotype (haplogroup 12, polymerase chain reaction restriction fragment length polymorphism genotype 5) common in North American wildlife but with previously uncharacterized human clinical manifestations., Conclusions: The T. gondii strain contaminating the venison might explain the unusual clinical presentations. In North America, clinicians and venison consumers should be aware of risk for severe or unusual presentations of acute toxoplasmosis after consuming undercooked game meat., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)