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The influence of kidney function on the prognostic value of cardiac troponin
No full textBackgroundKidney function influences the concentration of cardiac troponin T (cTnT) and I (cTnI). We investigate how this impacts their prognostic ability.MethodsThis Danish nationwide study included patients from 2013 to 2023 with at least two measurements of Roche hs-cTnT, Abbott hs-cTnI, or Siemens hs-cTnI Vista or Atellica during the index admission. Patients were stratified by estimated glomerular filtration rate (eGFR). We assessed prognostic ability by Cox models and area under the receiver operating characteristics curve (AUC). The primary endpoint was 30-day all-cause mortality.ResultsWe included 277,723 patients (median age 69 years, 38.4 % female) of whom 19,565 (7.0 %) died within 30 days. Almost all patients with eGFR <30 ml/min/1.73 m2 had myocardial injury using hs-cTnT (99.4 %) compared to hs-cTnI (85.4 %). Hazard ratios (HRs) for overall myocardial injury were higher than for acute myocardial injury and declined with worsening eGFR, particularly for hs-cTnT: HR 15.58 (95 % CI 12.77–19.00) for eGFR ≥90 ml/min/1.73 m2, while estimation was impossible at eGFR 15–30 ml/min/1.73 m2 due to few normal values. The highest HR for acute myocardial injury at eGFR ≥90 ml/min/1.73 m2 was for hs-cTnI Abbott, HR 3.50 (95 % CI 2.79–4.38). AUC decreased with worsening eGFR across assays, 0.68–0.76 for eGFR ≥90 ml/min/1.73 m2 to 0.59–0.63 for eGFR <15 ml/min/1.73 m2. At eGFR ≥90 ml/min/1.73 m2 the optimal cutoff was 16.5 ng/l for hs-cTnT and below the sex-specific 99th percentile for all hs-cTnI assays, increasing 5–20-fold with lower eGFR for all assays.ConclusionKidney function affects cTn prognostic performance, with reduced predictive ability and higher optimal cutoff concentrations for lower eGFR.Background: Kidney function influences the concentration of cardiac troponin T (cTnT) and I (cTnI). We investigate how this impacts their prognostic ability. Methods: This Danish nationwide study included patients from 2013 to 2023 with at least two measurements of Roche hs-cTnT, Abbott hs-cTnI, or Siemens hs-cTnI Vista or Atellica during the index admission. Patients were stratified by estimated glomerular filtration rate (eGFR). We assessed prognostic ability by Cox models and area under the receiver operating characteristics curve (AUC). The primary endpoint was 30-day all-cause mortality. Results: We included 277,723 patients (median age 69 years, 38.4 % female) of whom 19,565 (7.0 %) died within 30 days. Almost all patients with eGFR <30 ml/min/1.73 m2 had myocardial injury using hs-cTnT (99.4 %) compared to hs-cTnI (85.4 %). Hazard ratios (HRs) for overall myocardial injury were higher than for acute myocardial injury and declined with worsening eGFR, particularly for hs-cTnT: HR 15.58 (95 % CI 12.77–19.00) for eGFR ≥90 ml/min/1.73 m2, while estimation was impossible at eGFR 15–30 ml/min/1.73 m2 due to few normal values. The highest HR for acute myocardial injury at eGFR ≥90 ml/min/1.73 m2 was for hs-cTnI Abbott, HR 3.50 (95 % CI 2.79–4.38). AUC decreased with worsening eGFR across assays, 0.68–0.76 for eGFR ≥90 ml/min/1.73 m2 to 0.59–0.63 for eGFR <15 ml/min/1.73 m2. At eGFR ≥90 ml/min/1.73 m2 the optimal cutoff was 16.5 ng/l for hs-cTnT and below the sex-specific 99th percentile for all hs-cTnI assays, increasing 5–20-fold with lower eGFR for all assays. Conclusion: Kidney function affects cTn prognostic performance, with reduced predictive ability and higher optimal cutoff concentrations for lower eGFR.</p
Importance of relativistic pericenter precession in identifying the presence of a third body near eccentric binaries
No full textMany astrophysical processes can produce gravitational wave (GW) sources with significant orbital eccentricity. These binaries emit bursts of gravitational radiation during each pericenter passage. In isolated systems, the intrinsic timing of these bursts is solely determined by the properties of the binary. The presence of a nearby third body perturbs the system and alters the burst timing. Accurately modeling such perturbations therefore offers a novel approach to detecting the presence of a nearby companion. Existing timing models account for Newtonian dynamics and leading order radiation reaction effects but neglect the higher order post-Newtonian (PN) contributions to the inner binary. In this paper, we present an improved timing model that incorporates conservative PN corrections that lead to the precession of the binary's pericenter. We find that these PN corrections significantly impact the binary's orbital evolution and the timing of the GW burst. In particular, 1PN precession gives rise to distinctive modulation features in the binary's semilatus rectum and eccentricity. These modulations encode valuable information about the presence and properties of the third body, including its mass and distance. Furthermore, unmodeled 1PN effects significantly bias the tertiary's mass and distance. Finally, we assess the detectability of GW bursts from such perturbed systems and demonstrate that the inclusion of PN corrections is crucial for accurately capturing the orbital dynamics of hierarchical triples
Electroconvulsive therapy and occupational functioning in individuals with major depression
No full textPurposeElectroconvulsive therapy (ECT) is a well-established treatment for severe depressive episodes, but its effect on subsequent occupational functioning remains unclear. This study examined labour market trajectories among individuals with major depression treated with ECT, compared to similar individuals with depression who did not receive ECT.MethodsThis population-based cohort study included all patients aged 15–55 with a first-time hospital contact for major depression (ICD-10 codes F32 and F33) in Denmark between 2000 and 2022. Patients treated with ECT were identified using the Danish National Patient Registry and matched 1:5 by age and sex to patients not treated with ECT. Labour market outcomes were assessed using data from the Danish Register for Evaluation of Marginalisation, tracking changes in employment and social transfer payments from one year before to three years after ECT/matching. Sequence analysis and Cox proportional hazards regression were used to evaluate time to regained employment, categorized as ≤6 months, 7–12 months, and 1–3 years.ResultsWe included 6672 ECT-treated patients and 27,940 matched non-ECT individuals. At baseline, ECT patients had lower employment rates (6.9 % vs. 39.5 %) but higher education and marriage rates. ECT was associated with slower return to work within 6 months (adjusted HR: 0.59, 95 % CI: 0.54–0.64), but similar or faster return at 7–12 months (HR: 1.12, 95 % CI: 1.01–1.24) and 1–3 years (HR: 1.05, 95 % CI: 0.96–1.14).ConclusionECT was linked to delayed short-term occupational recovery, but comparable or improved long-term return to work, supporting its continued use in treating major depression.Purpose Electroconvulsive therapy (ECT) is a well-established treatment for severe depressive episodes, but its effect on subsequent occupational functioning remains unclear. This study examined labour market trajectories among individuals with major depression treated with ECT, compared to similar individuals with depression who did not receive ECT. Methods This population-based cohort study included all patients aged 15–55 with a first-time hospital contact for major depression (ICD-10 codes F32 and F33) in Denmark between 2000 and 2022. Patients treated with ECT were identified using the Danish National Patient Registry and matched 1:5 by age and sex to patients not treated with ECT. Labour market outcomes were assessed using data from the Danish Register for Evaluation of Marginalisation, tracking changes in employment and social transfer payments from one year before to three years after ECT/matching. Sequence analysis and Cox proportional hazards regression were used to evaluate time to regained employment, categorized as ≤6 months, 7–12 months, and 1–3 years. Results We included 6672 ECT-treated patients and 27,940 matched non-ECT individuals. At baseline, ECT patients had lower employment rates (6.9 % vs. 39.5 %) but higher education and marriage rates. ECT was associated with slower return to work within 6 months (adjusted HR: 0.59, 95 % CI: 0.54–0.64), but similar or faster return at 7–12 months (HR: 1.12, 95 % CI: 1.01–1.24) and 1–3 years (HR: 1.05, 95 % CI: 0.96–1.14). Conclusion ECT was linked to delayed short-term occupational recovery, but comparable or improved long-term return to work, supporting its continued use in treating major depression.</p
Antifungal Resistance Surveillance:Insights From National Mycology Reference Centers and Expert Mycology Laboratories
No full textFungal pathogens and the infections they cause are notoriously understudied and underrepresented in public health surveillance programs. Recent initiatives, such as that of the Joint Programming Initiative on Anti-Microbial Resistance (JPIAMR), recognize these gaps and have supported the development of a fungal surveillance resistance network. The International Fungal Network for One-Health Resistance Surveillance: Antifungal Resistance (INFORM-AFR) network sought to enhance understanding of existing surveillance programs, with the ultimate goal of developing standardized fungal surveillance strategies that enable international comparisons. A survey was conducted involving mycology reference centers or public health institutes (n = 15) from 12 countries, each responsible for nationwide or regional surveillance programs on fungal infections or pathogens. The ongoing programs were heterogenous, not only in terms of the epidemiological focus of surveillance (pathogen vs disease based), but also in relation to the mycological procedures used (identification and antifungal susceptibility testing methods). Funding dedicated to surveillance was variable and often lacked long-term stability, resulting in suboptimal surveillance data in many centers and limiting the generation of accurate and consistent knowledge. With the expanding number of fungal disease cases and increasing reports of antifungal resistance, we strongly advocate for improved integration of fungal infections into nationwide health surveillance programs as well as international standardization.Fungal pathogens and the infections they cause are notoriously understudied and underrepresented in public health surveillance programs. Recent initiatives, such as that of the Joint Programming Initiative on Anti-Microbial Resistance (JPIAMR), recognize these gaps and have supported the development of a fungal surveillance resistance network. The International Fungal Network for One-Health Resistance Surveillance: Antifungal Resistance (INFORM-AFR) network sought to enhance understanding of existing surveillance programs, with the ultimate goal of developing standardized fungal surveillance strategies that enable international comparisons. A survey was conducted involving mycology reference centers or public health institutes (n = 15) from 12 countries, each responsible for nationwide or regional surveillance programs on fungal infections or pathogens. The ongoing programs were heterogenous, not only in terms of the epidemiological focus of surveillance (pathogen vs disease based), but also in relation to the mycological procedures used (identification and antifungal susceptibility testing methods). Funding dedicated to surveillance was variable and often lacked long-term stability, resulting in suboptimal surveillance data in many centers and limiting the generation of accurate and consistent knowledge. With the expanding number of fungal disease cases and increasing reports of antifungal resistance, we strongly advocate for improved integration of fungal infections into nationwide health surveillance programs as well as international standardization.</p
Bridging veins in Alzheimer's disease:Decoding waste clearance failure
No full textPerivenous tunnels surrounding bridging veins terminate at "arachnoid cuff exit" (ACE) points, which enable waste efflux from the brain. Smyth et al. (https://doi.org/10.1084/jem.20251860) show that amyloid deposits in ACE in Alzheimer's disease mice and human samples identify a potential new therapeutic target.</p
Advancing a restorative blue Economy:A DPSIR–Ecosystem services framework for sustainable seaweed aquaculture
No full textSeaweed aquaculture is rapidly expanding in Europe and the Americas providing engineered ecosystem services (EES) such as nutrient removal, pH buffering, and carbon uptake. Used as a nature-based emission capture-and-utilisation technology, seaweed transforms emissions into revenue streams while delivering non-profit value, making seaweed aquaculture a promising eco-industrial system that fits well to the global agenda of green economic transitions and ecosystem health restoration. However, aquaculture activities may, in some cases, cause unwanted engineered ecosystem disservices (EED) which should be avoided. We argue that an adaptive and cross-sectoral policy framework is imperative to guide the sustainable development of a blue circular bioeconomy, or phyconomy, from primary production to final products, involving actors across multiple governance levels and sectors. We identify likely EES/EED and their potential impacts on natural ecosystem services using the Common International Classification of Ecosystem Services (CICES), and we map stakeholder linkages and policy instruments through a snowball approach. Finally, we adapt the Drivers-Pressures-State-Impact-Response (DPSIR) framework to seaweed aquaculture, redefining Pressure as Progress to recognise restorative outcomes. The resulting model connects EES/EED with relevant policies, supporting integrated and regenerative development of the seaweed sector.</p
Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer
No full textThe breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.</p
Establishment of Adult Stem Cell-Derived Organoid Cultures:General Principles from the Mouse Gut
No full textAdult stem cell (ASC)-derived organoid cultures have become an important model system for studying mammalian epithelial tissues in health and disease, including autoimmune conditions. Somatic stem cells are isolated and embedded into basement membrane-like matrix to allow for the in vitro outgrowth of miniature versions of functional epithelium in the presence of supportive growth factor niche. Organoids derived from tissues affected by autoimmune diseases, such as the intestine in inflammatory bowel disease or salivary glands in Sjögren’s disease, may provide an invaluable platform for exploring disease mechanisms, immune-epithelial interactions, and therapeutic interventions. Here, we describe the basic establishment and maintenance principles of mouse intestinal organoid cultures, suitable for many downstream applications, including for disease modeling, drug discovery, and regenerative medicine.</p
The <i>Pseudomonas aeruginosa sirB2</i> gene is a fitness determinant of anaerobic growth and its inactivation affects virulence and rugose small colony variants emergence
No full textPseudomonas aeruginosa is the leading cause of death in cystic fibrosis (CF) patients, yet the genetic mechanisms driving its fitness in the host remain poorly defined. Previously collected transcriptomic data of clinical samples showed that expression of the gene PA14_RS04555 (sirB2) is stimulated in the CF lung environment. In this work, we show that sirB2 is regulated by the global transcriptional regulators Vfr and AmrZ. Loss of sirB2 markedly enhanced P. aeruginosa pathogenicity, increasing virulence in Galleria mellonella, and promoting bacterial translocation and biofilm formation in a differentiated airway epithelial infection model. Deletion of sirB2 triggered the emergence of biofilm-proficient rugose small colony variants (RSCVs), driven by elevated c-di-GMP and increased Pel polysaccharide production when cultures were grown in static conditions. The RSCV phenotype depends on suppressor mutations in the wsp operon, possibly as a response to redox imbalance caused by the lack of sirB2 under oxygen-limited conditions. Indeed, the sirB2 mutant exhibited impaired fitness during anaerobic respiration when nitrate was the sole electron acceptor, in a manner independent of the ubiquinone pool. Our findings show that sirB2 inactivation promotes RSCV emergence and identify sirB2 as a novel genetic determinant of metabolic fitness under host-relevant conditions, thereby underscoring the role of redox balance in chronic CF infections.</p
The Several Jill Johnston
No full textEveryone is more or less familiar with the American journalist, art critic, performer, and feminist writer Jill Johnston (born Jill Crowe, May 17, 1929–September 18, 2010). The question is which Jill, or “JJ” we are talking about. Is it Johnston the critic, Johnston the dancer or Johnston the lesbian feminist? In dance and performance scholar, Clare Croft’s recent monograph Jill Johnston in Motion: Dance, Writing, and Lesbian Life and the accompanying anthology on Johnston’s writing, The Essential Jill Johnston Reader that she has edited, Johnston is also introduced according to categories such as “audience” and “writer”. The book is structured across these categories, as per which Johnston’s activities are historicized from her engagement as dancer and critic within the circuits of Judson church, to her alteration of spectatorship to performance. Discussing Johnston’s lesbian activities throughout, Clare Croft introduces the notion of ‘lesbian adjacencies’, in compliance with which entanglements across lesbian experiences, subjects and contexts are articulated.1 Reading the monography, it stands out as clear that Croft herself has approached the subject of Johnston in this way. Namely, rather than as an object of study, Jill Johnston is approached as a fellow lesbian. Croft’s resulting way to handle Johnston’s archive, which she is the only one who have accessed to date, stands out in the same manner. Rather than underscoring historical facts, gaps and contradictions in the subjective assembly of traces from Johnston’s eclectic life –that her partner at the time, Ingrid Nyboe, still handles– Croft reflects on every event that is archived, every text that is drafted, as if it was still in action. The title of the monography –Jill Johnston in Motion– is suitable for the purpose. Johnston is indeed in motion, but behind all that activity, it is hard to decipher who she really was. This causes, on the contrary, a problem for Croft’s intimate approach to this figurehead. Is it Johnston that Croft approaches intimately, or is it one of the many images that Johnston created, or let be created by others, of herself