Global invasion and biosecurity risk from the online trade in ornamental crayfish.

Trade in undomesticated ornamental animals has rapidly expanded beyond brick-and-mortar retail stores to now include growing numbers of internet marketplaces. The growing volume, diversity, and origins of invasive non-native species in trade challenge already weak national biosecurity policies. Despite widespread focus on vertebrates, many knowledge gaps exist regarding the online global trade of ornamental invertebrates. We conducted the first global assessment of the online trade in and associated invasion risk of freshwater crayfishes, which are increasingly popular aquarium animals. We systematically examined e-commerce marketplaces in multiple languages, scrapping information that included species identity, price, quantity, and shipping designation from each crayfish listing. Next, we combined geographic pathways of shipping associated with online trade (introduction risk) and environmental suitability modeling (establishment risk) to estimate global risk of non-native crayfish invasion risk. We identified hundreds of online marketplaces and thousands of sale listings in 33 countries (5 continents) involving 60 species and representing a selling value of ∼US$1.5 million. Invasion risk of non-native crayfish in trade was widespread, with geographic hotspots coinciding with both elevated opportunities for introduction (greater shipping offerings) and establishment. Precise characterization of the online species trade is fundamental to support new and reformed biosecurity policies, build industry partnerships, and design educational campaigns to prevent species invasions through trade. We found that the taxonomy, geography, and economics of the global online ornamental crayfish trade are vast and require greater attention.

Invasión global y riesgos de bioseguridad a partir del mercado virtual de langostinos de ornato Resumen El comercio de animales ornamentales silvestres se ha expandido rápidamente más allá de las tiendas minoristas para incluir un número creciente de tiendas en línea. El creciente volumen, diversidad y origen de las especies no nativas invasoras en el comercio suponen un reto para las ya débiles políticas nacionales de bioseguridad. A pesar de la gran atención que se presta a los vertebrados, existen muchos vacíos en el conocimiento sobre el comercio mundial en línea de invertebrados ornamentales. Realizamos la primera evaluación mundial del comercio virtual de langostinos de agua dulce, animales de ornato cada vez más populares, y el riesgo de invasión asociado. Analizamos sistemáticamente los mercados de comercio electrónico en varios idiomas, recopilando información que incluía la identidad de las especies, el precio, la cantidad y la designación de envío de cada listado de langostinos. Después combinamos las vías geográficas de envío asociadas al comercio en línea (riesgo de introducción) y los modelos de idoneidad ambiental (riesgo de establecimiento) para estimar el riesgo global de invasión de los langostinos no nativos. Identificamos cientos de mercados en línea y miles de listados de venta en 33 países (cinco continentes) que afectaban a 60 especies y representaban un valor de venta de ∼1.5 millones de dólares estadunidenses. El riesgo de invasión de langostinos no nativos en el comercio fue extenso, con puntos geográficos críticos que coincidían con elevadas oportunidades de introducción (mayores ofertas de envío) y de establecimiento. La caracterización precisa del comercio virtual de especies es fundamental para respaldar políticas de bioseguridad nuevas y reformadas, establecer alianzas con la industria y diseñar campañas educativas para prevenir las invasiones de especies a través del comercio. Descubrimos que la taxonomía, la geografía y la economía del comercio mundial en línea de langostinos de ornato es amplio y requiere mayor atención.

Resilience in the aftermath of trauma: Classes of adjustment in at-risk youth.

OBJECTIVE: Youth who have been exposed to potentially traumatic events are at risk of developing chronic and severe adjustment problems. However, some youth exposed to potentially traumatic events exhibit better-than-expected adaptation. Person-centered analyses, based on multiple criteria for adaptive behavior and adversity, are well-suited to empirically identifying different patterns of adaptation among high-risk youth. METHOD: Data from 381 youth from three at-risk subgroups in Portugal were collected using self-reported measures of trauma history, trauma-related symptomatology, coping skills, and perceived social support. Distinct classes of adaptation after traumatic experiences were examined with latent class analysis. RESULTS: Four classes were identified: (a) trauma-related psychopathology class (13.6%), (b) adaptive resilience class (36.8%), (c) low resources class (11.4%), and (d) high resources class (38.2%). Trauma-related psychopathology class and low resources class were characterized by high levels of maladjustment. Similarly to the low resources class, the trauma-related psychopathology class reported a significantly higher likelihood of trauma-related psychopathology and higher levels of problem-solving skills. The adaptive resilience class and high resources class also reported lower levels of maladjustment, and the high resources class reported higher levels of coping skills and lower levels of externalizing problems than any other class. CONCLUSION: Clinicians treating children's internalizing mental health or externalizing behavior problems should assess trauma history and trauma-related psychopathology, as well as protective resources that may enhance resilience such as skills for problem solving and social support seeking. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

PM2.5 exposure disparities persist despite strict vehicle emissions controls in California.

As policymakers increasingly focus on environmental justice, a key question is whether emissions reductions aimed at addressing air quality or climate change can also ameliorate persistent air pollution exposure disparities. We examine evidence from California's aggressive vehicle emissions control policy from 2000 to 2019. We find a 65% reduction in modeled statewide average exposure to PM2.5 from on-road vehicles, yet for people of color and overburdened community residents, relative exposure disparities increased. Light-duty vehicle emissions are the main driver of the exposure and exposure disparity, although smaller contributions from heavy-duty vehicles especially affect some overburdened groups. Our findings suggest that a continued trend of emissions reductions will likely reduce concentrations and absolute disparity but may not reduce relative disparities without greater attention to the systemic factors leading to this disparity.

Redefining Cardiac Involvement and Targets of Treatment in Systemic Immunoglobulin AL Amyloidosis.

Importance: Cardiac amyloid infiltration is the key determinant of survival in systemic light-chain (AL) amyloidosis. Current guidelines recommend early switching therapy in patients with a nonoptimal or suboptimal response regardless of the extent of cardiac amyloid infiltration. Objective: To assess the differences between serum biomarkers, echocardiography, and cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping in characterizing cardiac amyloid, the independent prognostic role of these approaches, and the role of ECV mapping to guide treatment strategies. Design, Setting, and Participants: Consecutive patients newly diagnosed with systemic AL amyloidosis (2015-2021) underwent echocardiography, cardiac biomarkers, and CMR with ECV mapping at diagnosis. Data were analyzed from January to June 2024. Main Outcomes and Measures: The primary outcomes of the study were all-cause mortality and hematological response as defined according to validated criteria: no response (NR), partial response (PR), very good partial response (VGPR), and complete response (CR). Secondary outcomes were the depth and speed of hematological response and overall survival according to ECV. Results: Of 560 patients with AL amyloidosis, the median (IQR) age was 68 years (59-74 years); 346 patients were male (61.8%) and 214 female (38.2%). Over a median (IQR) 40.5 months 9-58 months), ECV was independently associated with mortality. In the landmark analysis at 1 month, long-term survival was independent of the achieved hematological response in ECV less than 0.30% and ECV of 0.31% to 0.40%, while it was dependent on the depth of the hematological response in ECV greater than 0.40%. In the landmark analysis at 6 months, survival was independent of the achieved hematological response in ECV less than 0.30% and dependent on achieving at least PR in ECV of 0.31% to 0.40%. Survival was dependent on achieving CR in ECV of 0.41% to 0.50% and ECV greater than 0.50%. Achieving a deep hematological response at 1 month was associated with better survival compared with 6 months in patients with ECV greater than 0.40% but not with ECV less than 0.40%. Conclusions and Relevance: This study found that ECV mapping, in systemic AL amyloidosis, is an independent predictor of prognosis, can help define the hematological response associated with better long-term outcomes for each patient and potentially inform treatment strategies.

Beyond Pearson's Correlation: Modern Nonparametric Independence Tests for Psychological Research.

When examining whether two continuous variables are associated, tests based on Pearson's, Kendall's, and Spearman's correlation coefficients are typically used. This paper explores modern nonparametric independence tests as an alternative, which, unlike traditional tests, have the ability to potentially detect any type of relationship. In addition to existing modern nonparametric independence tests, we developed and considered two novel variants of existing tests, most notably the Heller-Heller-Gorfine-Pearson (HHG-Pearson) test. We conducted a simulation study to compare traditional independence tests, such as Pearson's correlation, and the modern nonparametric independence tests in situations commonly encountered in psychological research. As expected, no test had the highest power across all relationships. However, the distance correlation and the HHG-Pearson tests were found to have substantially greater power than all traditional tests for many relationships and only slightly less power in the worst case. A similar pattern was found in favor of the HHG-Pearson test compared to the distance correlation test. However, given that distance correlation performed better for linear relationships and is more widely accepted, we suggest considering its use in place or additional to traditional methods when there is no prior knowledge of the relationship type, as is often the case in psychological research.

Adolescent girls' and young mothers' knowledge and use of antenatal care in the Ahafo Region, Ghana: A cross-sectional study.

BACKGROUND:  Antenatal care (ANC) is crucial to reducing maternal and neonatal deaths, but few studies examined adolescent girls' and young women's ANC utilisation and knowledge in Ghana. AIM:  To assess adolescents' and young mothers' knowledge of ANC, utilisation and factors influencing its use in Ghana. SETTING:  Tano North Municipality, Ahafo Region. METHODS:  This community-based, cross-sectional study involved 440 adolescent and young mothers (between 10 and 24 years). A structured questionnaire was employed to collect data face-to-face. Descriptive and statistical analyses were performed, and p  0.05 was considered statistically significant. RESULTS:  Of the 440 respondents, most were aged 20-24 years (61.2%), married (30.0%), Christians (78.2%), completed junior high school (JHS) (47.8%) and traders (38.9%). Postnatal mothers were 71.6% (315), and all had utilised ANC services. Antenatal care knowledge was good among 75% (330) respondents, with no significant variation by age. Religion influenced knowledge, with Muslims having lower knowledge. Antenatal care utilisation was high ( 50%) among those aged 15-19 years, married, Christians, JHS graduates and traders. Age, marital status and employment type significantly influenced ANC utilisation. Individuals in the age group 15-19 years and married women demonstrated higher odds of utilising ANC services. Casual workers and unemployed respondents were found to have lower odds of utilising ANC services compared to traders. CONCLUSION:  Age, marital status, and employment type influenced ANC utilisation in the Ahafo Region. Adolescent mothers under 15 years had lower rates, requiring targeted interventions to improve pregnancy outcomes.Contribution: This study highlights the knowledge and factors influencing ANC use in Ahafo Region and adds to the existing research evidence on ANC.

Antiferromagnetic Ising model in a triangular vortex lattice of quantum fluids of light.

Vortices are topologically distinctive objects appearing as phase twists in coherent fields of optical beams and Bose-Einstein condensates. Structured networks and artificial lattices of coupled vortices could offer a powerful platform to study and simulate interaction mechanisms between constituents of condensed matter systems, such as antiferromagnetic interactions, by replacement of spin angular momentum with orbital angular momentum. Here, we realize such a platform using a macroscopic quantum fluid of light based on exciton-polariton condensates. We imprint all-optical hexagonal lattice that results into a triangular vortex lattice, with each cell having a vortex of charge l = ±1. We reveal that pairs of coupled condensates spontaneously arrange their orbital angular momentum antiparallel, implying a form of artificial orbital "antiferromagnetism." We discover that correlation exists between the emergent vortex patterns in triangular condensate lattices and the low-energy solutions of the corresponding antiferromagnetic Ising system. Our study offers a path toward spontaneously ordered vortex arrays with nearly arbitrary configurations and controlled couplings.

Structure Prediction and Protein Engineering Yield New Insights into Microcin J25 Precursor Recognition.

Microcin J25 (MccJ25), a lasso peptide antibiotic with a unique structure that resembles the lariat knot, has been a topic of intense interest since its discovery in 1992. The precursor (McjA) contains a leader and a core segment. McjB is a protease activated upon binding to the leader, and McjC converts the core segment into the mature MccJ25. Previous studies suggested that these biosynthetic steps likely proceed in a (nearly) concerted fashion; however, there is only limited information regarding the structural and molecular intricacies of MccJ25 biosynthesis. To close this knowledge gap, we used AlphaFold2 to predict the structure of the precursor (McjA) in complex with its biosynthetic enzymes (McjB and McjC) and queried the critical predicted features by protein engineering. Based on the predicted structure, we designed protein variants to show that McjB can still be functional and form a proficient biosynthetic complex with McjC when its recognition and protease domains were circularly permutated or split into separate proteins. Specific residues important for McjA recognition were also identified, which permitted us to pinpoint a compensatory mutation (McjBM108T) to restore McjA/McjB interaction that rescued an otherwise nearly nonproductive precursor variant (McjAT-2M). Studies of McjA, McjB, and McjC have long been mired by them being extremely difficult to handle experimentally, and our results suggest that the AF2 predicted ternary complex structure may serve as a reasonable starting point for understanding MccJ25 biosynthesis. The prediction-validation workflow presented herein combined artificial intelligence and laboratory experiments constructively to gain new insights.

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. RESULTS: A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. CONCLUSIONS: Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

Ecosystem synchrony: an emerging property to elucidate ecosystem responses to global change.

Understanding ecosystem responses to global change have long challenged scientists due to notoriously complex properties arising from the interplay between biological and environmental factors. We propose the concept of ecosystem synchrony - that is, similarity in the temporal fluctuations of an ecosystem function between multiple ecosystems - to overcome this challenge. Ecosystem synchrony can manifest due to spatially correlated environmental fluctuations (Moran effect), exchange of energy, nutrients, and organic matter and similarity in biotic characteristics across ecosystems. By taking advantage of long-term surveys, remote sensing and the increased use of high-frequency sensors to assess ecosystem functions, ecosystem synchrony can foster our understanding of the coordinated ecosystem responses at unexplored spatiotemporal scales, identify emerging portfolio effects among ecosystems, and deliver signals of ecosystem perturbations.

Interdomain-linkers control conformational transitions in the SLC23 elevator transporter UraA.

Uptake of nucleobases and ascorbate is an essential process in all living organisms mediated by SLC23 transport proteins. These transmembrane carriers operate via the elevator alternating-access mechanism, and are composed of two rigid domains whose relative motion drives transport. The lack of large conformational changes within these domains suggests that the interdomain-linkers act as flexible tethers. Here, we show that interdomain-linkers are not mere tethers, but have a key regulatory role in dictating the conformational space of the transporter and defining the rotation axis of the mobile transport domain. By resolving a wide inward-open conformation of the SLC23 elevator transporter UraA and combining biochemical studies using a synthetic nanobody as conformational probe with hydrogen-deuterium exchange mass spectrometry, we demonstrate that interdomain-linkers control the function of transport proteins by influencing substrate affinity and transport rate. These findings open the possibility to allosterically modulate the activity of elevator proteins by targeting their linkers.

Selecting the Most Relevant Mouse Strains for Evaluating Radiation-Induced Multiple Tissue Injury after Leg-Shielded Partial-Body Gamma Irradiation.

Animal studies are needed that best simulate a large-scale, inhomogeneous body exposure after a radiological or nuclear incident and that provides a platform for future development of medical countermeasures. A partial-body irradiation (PBI) model using 137Cs gamma rays with hind limb (tibia) shielding was developed and assessed for the sequalae of radiation injuries to gastrointestinal tract, bone marrow (BM) and lung and among different genetic mouse strains (C57BL/6J, C57L/J, CBA/J and FVB/NJ). In this case, a marginal level of BM shielding (∼2%) provided adequate protection against lethality from infection and hemorrhage and enabled escalation of radiation doses with evaluation of both acute and delayed radiation syndromes. A steep radiation dose-dependent body weight loss was observed over the first 5 days attributed to enteritis with C57BL/6J mice appearing to be the most sensitive strain. Peripheral blood cell analysis revealed significant depression and recovery of leukocytes and platelets over the first month after PBI and were comparable among the four different mouse strains. Latent pulmonary injury was observed on micro-CT imaging at 4 months in C57L/J mice and confirmed histologically as severe pneumonitis that was lethal at 12 Gy. The lethality and radiological densitometry (HUs) dose responses were comparable to previous studies on C57L/J mice after total-body irradiation (TBI) and BM transplant rescue as well as after localized whole-thorax irradiation (WTI). Indeed, the lethal radiation doses and latency appeared similar for pneumonitis appearing in rhesus macaques after WTI or PBI as well as predicted for patients given systemic radiotherapy. In contrast, PBI treatment of C57BL/6 mice at a higher dose of 14 Gy had far longer survival times and developed extreme and debilitating pIeural effusions; an anomaly as similarly reported in previous thorax irradiation studies on this mouse strain. In summary, a radiation exposure model that delivers PBI to unanesthetized mice in a device that provides consistent shielding of the hind limb BM was developed for 137Cs gamma rays with physical characteristics and relevance to relatively high photon energies expected from the detonation of a nuclear device or accidental release of ionizing radiation. Standard strains such as C57BL/6J mice may be used reliably for early GI or hematological radiation syndromes while the C57L/J mouse strain stands out as the most appropriate for evaluating the delayed pulmonary effects of acute radiation exposure and recapitulating this disease in humans.

Dual nationality, anti-citizenship, and xeno-racism: Online tropes on migrant (in)gratitude, and (in)adequate Britishness of Nazanin Zaghari-Ratcliffe.

Nazanin Zaghari-Ratcliffe, an Iranian-British dual citizen, was detained by the Iranian state from April 2016 to March 2022 and charged with spying and propaganda activities against the Iranian state without due process. After her release and return to the UK, Zaghari-Ratcliffe criticized the UK government in a press conference, which triggered a Twitter campaign using the hashtags "sendherback" and "ungrateful." This campaign claimed that she did not show "enough gratitude" to Britain, the country that "saved" her. In this paper, we investigate the content of the Twitter campaign. Using the concept of anti-citizenship, we focus on xeno-racist discourses around Zaghari-Ratcliffe's dual nationality and how her belonging in Britain is challenged. We explore the role Zaghari-Ratcliffe's Iranian background plays in how her Britishness is rendered suspect, which then enables the racialized tropes in the #sendherback campaign.

A voice and speech corpus of patients who underwent upper airway surgery in pre- and post-operative states.

Many research articles have explored the impact of surgical interventions on voice and speech evaluations, but advances are limited by the lack of publicly accessible datasets. To address this, a comprehensive corpus of 107 Spanish Castilian speakers was recorded, including control speakers and patients who underwent upper airway surgeries such as Tonsillectomy, Functional Endoscopic Sinus Surgery, and Septoplasty. The dataset contains 3,800 audio files, averaging 35.51 ± 5.91 recordings per patient. This resource enables systematic investigation of the effects of upper respiratory tract surgery on voice and speech. Previous studies using this corpus have shown no relevant changes in key acoustic parameters for sustained vowel phonation, consistent with initial hypotheses. However, the analysis of speech recordings, particularly nasalised segments, remains open for further research. Additionally, this dataset facilitates the study of the impact of upper airway surgery on speaker recognition and identification methods, and testing of anti-spoofing methodologies for improved robustness.

A Comparison of Measures for Assessing Profile Similarity in Dyads.

Profile similarity measures are used to quantify the similarity of two sets of ratings on multiple variables. Yet, it remains unclear how different measures are distinct or overlap and what type of information they precisely convey, making it unclear what measures are best applied under varying circumstances. With this study, we aim to provide clarity with respect to how existing measures interrelate and provide recommendations for their use by comparing a wide range of profile similarity measures. We have taken four steps. First, we reviewed 88 similarity measures by applying them to multiple cross-sectional and intensive longitudinal data sets on emotional experience and retained 43 useful profile similarity measures after eliminating duplicates, complements, or measures that were unsuitable for the intended purpose. Second, we have clustered these 43 measures into similarly behaving groups, and found three general clusters: one cluster with difference measures, one cluster with product measures that could be split into four more nuanced groups and one miscellaneous cluster that could be split into two more nuanced groups. Third, we have interpreted what unifies these groups and their subgroups and what information they convey based on theory and formulas. Last, based on our findings, we discuss recommendations with respect to the choice of measure, propose to avoid using the Pearson correlation, and suggest to center profile items when stereotypical patterns threaten to confound the computation of similarity.

Integrating Mobile and Fixed-Site Black Carbon Measurements to Bridge Spatiotemporal Gaps in Urban Air Quality.

Urban air pollution can vary sharply in space and time. However, few monitoring strategies can concurrently resolve spatial and temporal variation at fine scales. Here, we present a new measurement-driven spatiotemporal modeling approach that transcends the individual limitations of two complementary sampling paradigms: mobile monitoring and fixed-site sensor networks. We develop, validate, and apply this model to predict black carbon (BC) using data from an intensive, 100-day field study in West Oakland, CA. Our spatiotemporal model exploits coherent spatial patterns derived from a multipollutant mobile monitoring campaign to fill spatial gaps in time-complete BC data from a low-cost sensor network. Our model performs well in reconstructing patterns at fine spatial and temporal resolution (30 m, 15 min), demonstrating strong out-of-sample correlations for both mobile (Pearson's R ∼ 0.77) and fixed-site measurements (R ∼ 0.95) while revealing features that are not effectively captured by a single monitoring approach in isolation. The model reveals sharp concentration gradients near major emission sources while capturing their temporal variability, offering valuable insights into pollution sources and dynamics.

Effect of beta-blockade on mortality in patients with cardiac amyloidosis: A systematic review and meta-analysis.

AIMS: The efficacy of beta-blockers in cardiac amyloidosis (CA) is unclear, and concerns persist that neurohormonal blockade could worsen symptoms of heart failure. We aimed to assess whether beta-blocker therapy is associated with improved survival in patients with CA. METHODS AND RESULTS: We conducted a systematic review and meta-analysis to examine the impact of beta-blocker therapy on mortality in patients with CA. A search of MEDLINE and EMBASE was performed in August 2023. Data were extracted from observational studies and synthesized with pooling and random effects meta-analysis. Thirteen studies including 4215 patients with CA were incorporated in this review (3688 transthyretin amyloid cardiomyopathy (ATTR-CM), 502 light chain amyloid cardiomyopathy (AL-CM), 25 not specified; age 74.8 ± 5.5 years, 76% male). Over half of the cohort (52%) received beta-blockers and the rate of beta-blocker withdrawal was 28%. All-cause mortality was 33% (range: 13-51%) after a median follow-up ranging from 13 to 36 months. There was an inverse association between the pooled risk of mortality and the use of beta-blocker therapy at any time point (RR 0.48, 95% CI 0.29-0.80, I2 = 83%, P = 0.005, seven studies). There was no association between mortality and beta-blocker use (RR 0.65, 95% CI 0.29-1.47, I2 = 88%, P = 0.30) in the three studies that only included patients with ATTR-CM. The three studies that included patients with both ATTR-CM and AL demonstrated an association of beta-blocker use with reduced mortality (OR 0.43, 95% CI 0.29-0.63, I2 = 4%, P < 0.001). The only study that solely included 53 patients with AL-CM, demonstrated improved survival among the 53% who were able to tolerate beta-blocker therapy (RR 0.26, 95% CI 0.08-0.79, P = 0.02). The absence of information on staging of CA is an important limitation of this study. CONCLUSIONS: Treatment with beta-blockers may be associated with a survival benefit in patients with CA, but these findings are subject to selection and survivor biases. Definitive prospective randomized trials of conventional heart failure therapies are needed in CA.

Antifungal efficacy and immunomodulatory effect of PLGA nanoparticle-encapsulated itraconazole in histoplasmosis in vivo model.

INTRODUCTION: Histoplasma capsulatum is the etiological agent of histoplasmosis, the most common endemic pulmonary mycosis. Itraconazole (ITZ) is the choice for mild disease and a step-down therapy in severe and disseminated clinical presentations. Drug encapsulation into nanoparticles (NPs) is an alternative to improve drug solubility and bioavailability, reducing undesirable interactions and drug degradation and reaching the specific therapeutic target with lower doses. OBJECTIVE: evaluate the antifungal and immunomodulatory effect of ITZ encapsulated into poly(lactic-co-glycolic acid) (PLGA) NPs, administrated orally and intraperitoneally in an in vivo histoplasmosis model. RESULTS: After intranasal infection and treatment of animals with encapsulated ITZ by intraperitoneal and oral route, fungal burden control, biodistribution, immune response, and histopathology were evaluated. The results showed that the intraperitoneal administered and encapsulated ITZ has an effective antifungal effect, significantly reducing the Colony-Forming-Units (CFU) after the first doses and controlling the infection dissemination, with a higher concentration in the liver, spleen, and lung compared to the oral treatment. In addition, it produced a substantial immunomodulatory effect on pro- and anti-inflammatory cytokines and immune cell infiltrates confirmed by histopathology. CONCLUSIONS: Overall, results suggest a synergistic effect of the encapsulated drug and the immunomodulatory effect contributing to infection control, preventing their dissemination.

Expansion of the National Amyloidosis Centre staging system to detect early mortality in transthyretin cardiac amyloidosis.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is stratified into prognostic categories using the National Amyloidosis Centre (NAC) staging system. The aims of this study were to further expand the existing NAC staging system to incorporate an additional disease stage that would identify patients at high risk of early mortality. METHODS AND RESULTS: The traditional NAC staging system (stage 1: N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≤3000 ng/L and estimated glomerular filtration rate [eGFR] ≥45 ml/min; stage 3: NT-proBNP >3000 ng/L and eGFR <45 ml/min; stage 2: remainder) was expanded by the introduction of a new stage 4 (defined as NT-proBNP ≥10 000 ng/L irrespective of eGFR) and studied in 2042 patients. The optimal NT-proBNP cut-point was established using time-dependent receiver operating characteristic curves in the subgroup of patients with NAC stage 3 disease. Mortality at 1 year according to NAC stage was 2.3% (n = 20/886) for stage 1, 8.8% (n = 62/706) for stage 2, 10.4% (n = 28/270) for stage 3, and 30.6% (n = 55/180) for stage 4 (log-rank p < 0.001). After adjustment for age, mortality hazard for stage 4 was >15-fold higher than that of stage 1 (hazard ratio [HR] 15.5; 95% confidence interval [CI] 9.3-26.1) and >3-fold higher than that of stage 3 (HR 3.4; 95% CI 2.2-5.4). The increased risk of early mortality was consistent across the different genotypes and subclasses of patients based on the severity of heart failure symptoms and echocardiographic parameters. CONCLUSIONS: The proposed modification of the NAC staging system identifies patients with ATTR-CA at a high risk of early mortality, who may benefit from a more intensive treatment strategy, and who are most likely to experience an event early in the course of a clinical trial.

SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i). OBJECTIVES: This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM. METHODS: Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different-age and N-terminal pro-B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables. RESULTS: The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). CONCLUSIONS: SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM.