Comparison of the Sensitivity and Specificity of Commercial Anti-Dengue Virus IgG Tests to Identify Persons Eligible for Dengue Vaccination.

The Advisory Committee on Immunization Practices (ACIP) recommended that dengue pre-vaccination screening tests for Dengvaxia administration have at least 98% specificity and 75% sensitivity. This study evaluates the performance of commercial anti-DENV IgG tests to identify tests that could be used for pre-vaccination screening. First, for 7 tests, we evaluated sensitivity and specificity in early convalescent dengue virus (DENV) infection, using 44 samples collected 7-30 days after symptom onset and confirmed by RT-PCR. Next, for the 5 best performing tests and two additional tests (with and without an external test reader) that became available later, we evaluated performance to detect past dengue infection among a panel of 44 specimens collected in 2018-2019 from healthy 9-16-year-old children from Puerto Rico. Finally, a full-scale evaluation was done with the 4 best performing tests using 400 specimens from the same population. We used virus focus reduction neutralization test and an in-house DENV IgG ELISA as reference standards. Of seven tests, five showed ≥75% sensitivity detecting anti-DENV IgG in early convalescent specimens with low cross-reactivity to Zika virus. For the detection of previous DENV infections the tests with the highest performance were the Euroimmun NS1 IgG ELISA (sensitivity 84.5%, specificity 97.1%) and CTK Dengue IgG rapid test R0065C with the test reader (sensitivity 76.2% specificity 98.1%). There are IgG tests available that can be used to accurately classify individuals with previous DENV infection as eligible for dengue vaccination to support safe vaccine implementation.

Gut microbiota, blood metabolites, and left ventricular diastolic dysfunction in US Hispanics/Latinos.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD. RESULTS: We included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 × 10-5, for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC] = 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD. CONCLUSION: In this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity. Video Abstract.

An algorithm for the National Institute of Health Stroke Scale assessment: a multicenter, two-arm and cluster randomized study.

BACKGROUND: The NIH Stroke Scale (NIHSS) is a validated tool for assessing stroke severity, increasingly used by general practitioners in telemedicine services. Mobile apps may enhance its reliability. We aim to validate a digital platform (SPOKES) for NIHSS assessment in telemedicine and healthcare settings. METHODS: Hospitals using a telemedicine service were randomly allocated to control or SPOKES-user groups. The discrepancy between the NIHSS scores reported and those confirmed by experts was evaluated. Healthcare providers from comprehensive stroke centers were invited for interrater validation. Participants were randomized to assess the NIHSS using videos of real patients. Weighted Kappa (wk) statistics analyzed the agreement, and logistic regression determined the correlation with the congruency. RESULTS: A total of 299 telemedicine consultations from 12 hospitals were included. The difference between the NIHSS scores reported and double-checked was lower in the SPOKES group (p=0.03), with a significantly higher level of complete agreement (72.5% vs. 50.4%, p=0.005). Adoption of SPOKES was associated with complete congruency (OR 4.01, 95%CI 1.42-11.35, p=0.009). For interrater validation, 20 participants were considered. In the SPOKES group, almost-perfect and strong agreement occurred in 13.3%(n=6/45) and 84.4%(n=38/45) of ratings, respectively; in the control group, 6.7%(n=3/45) were almost-perfect, 28.9%(n=13/45) strong and 51%(n=23/45) were minimal. CONCLUSION: A free and reliable mobile application for NIHSS assessment can significantly improve interrater agreement between healthcare professionals, and between NIHSS-certified neurologists and general practitioners. Our results underscore the importance of ongoing training and education in enhancing the consistency and reliability of NIHSS scores.

Cardiovascular Disease in Hispanic Women: JACC Review Topic of the Week.

Cardiovascular disease affects 37% of Hispanic women and is the leading cause of death among Hispanic women in the United States. Hispanic women have a higher burden of cardiovascular risk factors, are disproportionally affected by social determinants of health, and face additional barriers related to immigration, such as discrimination, language proficiency, and acculturation. Despite this, Hispanic women show lower rates of cardiovascular disease and mortality compared with non-Hispanic White women. However, this "Hispanic paradox" is challenged by recent studies that account for the diversity in culture, race, genetic background, country of origin, and social determinants of health within Hispanic subpopulations. This review provides a comprehensive overview of the cardiovascular risk factors in Hispanic women, emphasizing the role of social determinants, and proposes a multipronged approach for equitable care.

Rehabilitation of amblyopia using a digital platform for visual training combined with patching in children: a prospective study.

PURPOSE: To assess the possible benefits of the use of perceptual learning and dichoptic therapy combined with patching in children with amblyopia over the use of only patching. METHODS: Quasi-experimental multicentric study including 52 amblyopic children. Patients who improved their visual acuity (VA) by combining spectacles and patching were included in patching group (PG: 20 subjects), whereas those that did not improved with patching performed visual training (perceptual learning + dichoptic therapy) combined with patching, being assigned to the visual treatment group (VT: 32 subjects). Changes in VA, contrast sensitivity (CS), and stereopsis were monitored during a 6-month follow-up in each group. RESULTS: Significant improvements in VA were found in both groups at 1 month (p < 0.01). The total improvement of VA was 0.18 ± 0.16 and 0.31 ± 0.35 logMAR in PG and VT groups, respectively (p = 0.317). The Wilcoxon effect size was slightly higher in VT (0.48 vs. 0.54) at 6 months. An enhancement in CS was observed in the amblyopic eye of the VT group for all spatial frequencies at 1 month (p < 0.001). Likewise, the binocular function score also increased significantly in VT group (p = 0.002). A prediction equation of VA improvement at 1 month in VT group was obtained by multiple linear regression analysis (p < 0.001, R2 = 0.747). CONCLUSIONS: A combined treatment of visual training and patching is effective for obtaining a predictable improvement of VA, CS, and binocularity in patching-resistant amblyopic children.

Ecotoxicological effects of ketoprofen and fluoxetine and their mixture in an aquatic microcosm.

The effects of fluoxetine (antidepressant) and ketoprofen (analgesic) on aquatic ecosystems are largely unknown, particularly as a mixture. This work aimed at determining the effect of sublethal concentrations of both compounds individually (0.050 mg/L) and their mixture (0.025 mg/L each) on aquatic communities at a microcosm scale for a period of 14 d. Several physicochemical parameters were monitored to estimate functional alterations in the ecosystem, while model organisms (Daphnia magna, Lemna sp., Raphidocelis subcapitata) and the sequencing of 16S/18S rRNA genes permitted to determine effects on specific populations and changes in community composition, respectively. Disturbances were more clearly observed after 14 d, and overall, the microcosms containing fluoxetine (alone or in combination with ketoprofen) produced larger alterations on most physicochemical and biological variables, compared to the microcosm containing only ketoprofen, which suffered less severe changes. Differences in nitrogen species suggest alterations in the N-cycle due to the presence of fluoxetine; similarly, all pharmaceutical-containing systems decreased the brood rate of D. magna, while individual compounds inhibited the growth of Lemna sp. No clear trends were observed regarding R. subcapitata, as indirectly determined by chlorophyll quantification. The structure of micro-eukaryotic communities was altered in the fluoxetine-containing systems, whereas the structure of bacterial communities was affected to a greater extent by the mixture. The disruptions to the equilibrium of the microcosm demonstrate the ecological risk these compounds pose to aquatic ecosystems.

Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation.

The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo signaling pathway activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivation. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.

Pilot Study Assessing the Safety and Acceptance of a Novel Virtual Reality System to Improve Visual Function.

PURPOSE: To assess the feasibility of the clinical use of a novel Virtual Reality (VR) training software designed to be used for active vision therapy in amblyopic patients by determining its preliminary safety and acceptance on the visual function of healthy adults. METHODS: Pilot study enrolling 10 individuals (3 men, 7 women, mean age: 31.8 ± 6.5 years) with a best-corrected visual acuity (BCVA) of ≥ .90 (decimal) in both eyes were evaluated before and after 20 minutes of exposure to the NEIVATECH VR system using the HTC Vive Pro Eye head mounted display. Visual function assessment included near (40 cm) and distance (6 m) cover test (CT), stereopsis, binocular accommodative facility (BAF), near point of convergence (NPC), near point of accommodation (NPA), accommodative-convergence over accommodation (AC/A) ratio and positive and negative fusional vergences. Safety was assessed using the VR Sickness Questionnaire (VRSQ) and acceptance using the Technology Acceptance Model ;(TAM). Changes in all these variables after VR exposure were analyzed. RESULTS: Short-term exposure to the NEIVATECH VR system only induced statistically significant changes in distance phoria (p = .016), but these changes were not clinically relevant. No significant changes were observed in VRSQ oculo-motricity and disorientation scores after exposure (p = .197 and .317, respectively). TAM scores showed a good acceptance of the system in terms of perceived enjoyment and perceived ease of use, although some concerns were raised in relation to the intention-to-use domain. CONCLUSION: Exposure to the NEIVATECH VR system does not seem to adversely affect the visual function in healthy adults and its safety and acceptance profile seems to be adequate for supporting its potential use in other populations, such as amblyopic patients.

Latino-White Disparities in Identification and Control of Elevated Blood Pressure Among Adults With Hypertension.

BACKGROUND: Studies analyzing blood pressure (BP) management using the hypertension control cascade have consistently shown disparities in hypertension awareness, treatment, and BP control between Latino patients and non-Latino White patients. We analyze this cascade using electronic health record data from a multistate network of community health centers. METHODS AND RESULTS: Data from 790 clinics in 23 US states from 2012 to 2020, including 1 270 174 patients, were analyzed to compare BP documentation in the electronic health record, clinician acknowledgment (diagnosis or treatment) of incident hypertension (BP ≥140/90), medication prescription, and BP control between non-Latino White patients, English-preferring Latino patients, and Spanish-preferring Latino patients, adjusted for patient-level covariates, and clustered on patients' primary clinics. Among the 429 182 patients with elevated BP (≥140/90) during ambulatory visits from 2012 to 2020, we found that clinician acknowledgment of hypertension was more likely in Spanish-preferring and English-preferring Latino patients versus non-Latino White patients (adjusted odds ratio [aOR], 1.17 [95% CI, 1.11-1.24]; aOR, 1.07 [95% CI, 1.02-1.12], respectively). In addition, Spanish-preferring Latino patients were more likely to receive a medication versus non-Latino White patients (aOR, 1.21 [95% CI, 1.16-1.28]). Among those receiving medication, Latino patients were as likely as non-Latino White patients to have their BP controlled (<140/90). CONCLUSIONS: In a large retrospective study of community health center patients with incident hypertension, the expected disparities in hypertension management between Spanish-preferring Latino, English-preferring Latino, and non-Latino White patients were not identified. These findings add to the hypertension control cascade by examining robust electronic health record data from community health centers and may provide clues to reducing disparities in hypertension management.

Review and meta-analysis of the genetic Minimal Cut Set approach for gene essentiality prediction in cancer metabolism.

Cancer metabolism is a marvellously complex topic, in part, due to the reprogramming of its pathways to self-sustain the malignant phenotype in the disease, to the detriment of its healthy counterpart. Understanding these adjustments can provide novel targeted therapies that could disrupt and impair proliferation of cancerous cells. For this very purpose, genome-scale metabolic models (GEMs) have been developed, with Human1 being the most recent reconstruction of the human metabolism. Based on GEMs, we introduced the genetic Minimal Cut Set (gMCS) approach, an uncontextualized methodology that exploits the concepts of synthetic lethality to predict metabolic vulnerabilities in cancer. gMCSs define a set of genes whose knockout would render the cell unviable by disrupting an essential metabolic task in GEMs, thus, making cellular proliferation impossible. Here, we summarize the gMCS approach and review the current state of the methodology by performing a systematic meta-analysis based on two datasets of gene essentiality in cancer. First, we assess several thresholds and distinct methodologies for discerning highly and lowly expressed genes. Then, we address the premise that gMCSs of distinct length should have the same predictive power. Finally, we question the importance of a gene partaking in multiple gMCSs and analyze the importance of all the essential metabolic tasks defined in Human1. Our meta-analysis resulted in parameter evaluation to increase the predictive power for the gMCS approach, as well as a significant reduction of computation times by only selecting the crucial gMCS lengths, proposing the pertinency of particular parameters for the peak processing of gMCS.

Validation of the Spanish translation Sheffield Profile for Assessment and Referral for Care (SPARC-Sp) at the Hospital Universitario San Jose of Popayan, Colombia.

OBJECTIVES: We determined the validity and reliability of the Spanish translation Sheffield Profile for Assessment and Referral for Care (SPARC-Sp) questionnaire to identify the palliative care (PC) needs of patients with chronic noncommunicable diseases (NCDs) in Colombia. METHODS: We developed a cross-sectional observational study of scale assessment in adults with the aim of determining the validity and reliability of the SPARC-Sp questionnaire to identify the PC needs of patients with NCDs receiving outpatient or inpatient care at the Hospital Universitario San Jose of Popayan - ESE, Colombia, from 2021 to 2022. RESULTS: We applied a questionnaire consisting of demographic, clinical data, and SPARC-Sp to 507 participants. The constructed model explained 75% of the variance with an adequate fit according to the root mean square residual (0.03), the comparative fit index (0.98), and acceptable reliability (McDonald's total omega 0.4-0.9). Opportunities for improvement are the reformulation and inclusion of particular words to improve the representativeness and clarity of the domains of communication and information, religious, and spiritual issues. SIGNIFICANCE OF RESULTS: This research represents the first validation of SPARC in Spanish. SPARC-Sp is an instrument that allows initiating a conversation of the patient's main needs through a systematic assessment of the patients' main needs. Its psychometric validation demonstrated good fit and acceptable reliability.

RapidpulseTM cyclic aspiration system for acute ischemic stroke due to large vessel occlusions.

BACKGROUND: The best strategy to achieve optimal reperfusion outcomes during mechanical thrombectomy remains to be defined. The RapidPulseTM Cyclic Aspiration System is a novel technology, delivering high-frequency pulsed vacuum forces to increase the efficiency of aspiration thrombectomy. METHODS: Prospective, multicenter, open-label, core lab-adjudicated, two-arm study comparing safety and efficacy of a feasibility version of the RapidPulseTM system compared with contemporary controls. Primary endpoint was the rate of mTICI ≥ 2c after first-pass effect (FPE). Additional efficacy endpoints were the rates of mTICI ≥ 2b after first pass (modified FPE (mFPE)), last pass with study device defined as frontline technical success, and after all passes including rescue therapy. The primary safety endpoints included symptomatic ICH (sICH) within 24 h post-procedure. RESULTS: Between February 2022 to December 2022, 80 subjects were consented and enrolled in the study (n = 40 treatment arm, n = 40 control arm). In the intent to treat (ITT) population, mean age was 67.8 ± 11.5 years; 19 (47.5%) were male. Median NIHSS score was 16 (IQR: 13-22). Median ASPECTS score was 9 (IQR: 8-10). The rate of mTICI ≥ 2c after first pass was 53.9% in ITT population (60.0% in per-protocol population) versus 38.5% in the corresponding control population. Functional independence (mRS 0-2) at 90 days was achieved in 61.1% (22/36) in the RapidPulseTM arm and 52.8% (19/36) in the control arm. In the RapidPulseTM arm, no sICH within 24 h and no device-related morbidity or mortality occurred. CONCLUSION: Preliminary data suggests RapidPulseTM Aspiration System is highly effective and safe for recanalization of large vessel occlusions.

Racial Implicit Bias and Communication Among Physicians in a Simulated Environment.

Importance: Racial implicit bias can contribute to health disparities through its negative influence on physician communication with Black patients. Interventions for physicians to address racial implicit bias in their clinical encounters are limited by a lack of high-fidelity (realistic) simulations to provide opportunities for skill development and practice. Objective: To describe the development and initial evaluation of a high-fidelity simulation of conditions under which physicians might be influenced by implicit racial bias. Design, Setting, and Participants: This cross-sectional study, performed on an online platform from March 1 to September 30, 2022, recruited a convenience sample of physician volunteers to pilot an educational simulation. Exposures: In the simulation exercise, physicians saw a 52-year-old male standardized patient (SP) (presenting as Black or White) seeking urgent care for epigastric pain, nausea, and vomiting. The case included cognitive stressors common to clinical environments, including clinical ambiguity, stress, time constraints, and interruptions. Physicians explained their diagnosis and treatment plan to the SP, wrote an assessment and management plan, completed surveys, and took the Race Implicit Association Test (IAT) and Race Medical Cooperativeness IAT. The SPs, blinded to the purpose of the study, assessed each physician's communication using skills checklists and global rating scales. Main Outcomes and Measures: Association between physicians' IAT scores and SP race with SP ratings of communication skills. Results: In 60 physicians (23 [38.3%] Asian, 4 [6.7%] Black, 23 [38.3%] White, and 10 [16.7%] other, including Latina/o/x, Middle Eastern, and multiracial; 31 [51.7%] female, 27 [45.0%] male, and 2 [3.3%] other), the interaction of physicians' Race IAT score and SP race was significant for overall communication (mean [SD] ß = -1.29 [0.41]), all subdomains of communication (mean [SD] ß = -1.17 [0.52] to -1.43 [0.59]), and overall global ratings (mean [SD] ß = -1.09 [0.39]). Black SPs rated physicians lower on communication skills for a given pro-White Race IAT score than White SPs; White SP ratings increased as physicians' pro-White bias increased. Conclusions and Relevance: In this cross-sectional study, a high-fidelity simulation calibrated with cognitive stressors common to clinical environments elicited the expected influence of racial implicit bias on physicians' communication skills. The outlined process and preliminary results can inform the development and evaluation of interventions that seek to address racial implicit bias in clinical encounters and improve physician communication with Black patients.

Physical and respiratory therapy in the critically ill patient with obesity: a narrative review.

Obesity has become increasingly prevalent in the intensive care unit, presenting a significant challenge for healthcare systems and professionals, including rehabilitation teams. Caring for critically ill patients with obesity involves addressing complex issues. Despite the well-established and safe practice of early mobilization during critical illness, in rehabilitation matters, the diverse clinical disturbances and scenarios within the obese patient population necessitate a comprehensive understanding. This includes recognizing the importance of metabolic support, both non-invasive and invasive ventilatory support, and their weaning processes as essential prerequisites. Physiotherapists, working collaboratively with a multidisciplinary team, play a crucial role in ensuring proper assessment and functional rehabilitation in the critical care setting. This review aims to provide critical insights into the key management and rehabilitation principles for obese patients in the intensive care unit.

Violence, Abuse and Neglect in Older Women in Rural and Remote Areas: A Scoping Review and Prevalence Meta-Analysis.

This systematic review addressed the issue of the abuse and neglect of older women (age 60 and over) in rural and remote areas, examining these phenomena's prevalence, risk and protective factors, consequences, and associated perceptions. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Arksey and O'Malley methodological framework, peer-reviewed articles published until September 2023 were identified in six electronic databases. Out of the manuscripts initially identified (n = 219), 28 articles met the selection criteria. The study's quality was assessed using the Mixed Methods Appraisal Tool. The included studies provided a comprehensive overview of this phenomenon, encompassing data from 6,579 older rural women. Prevalence rates of abuse and neglect exhibited wide variability, with an average of 27.3%. Among the risk factors, financial dependence and incapacity stood out, while higher income and education levels were protective factors, among others. Emotional/psychological abuse emerged as the most common form, with significant impacts on older women's physical and mental health. Cultural norms and gender expectations also influenced perceptions of abuse and victims' coping mechanisms. In a context in which access to specialized resources and services is hampered by significant limitations, community awareness and education prove vital to address this issue, which positions social work as key to addressing these challenges. The prevalence of abuse against older rural women is significant. Emotional abuse stands out as a major issue, underscoring the need for comprehensive interventions accounting for cultural and gender factors.

Temporal Outcomes of Patients Diagnosed With Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is increasingly recognized. Clinical outcomes have evolved over time amid changes in the diagnostic pathway and advances in therapeutics. We sought to evaluate clinical outcomes over time of patients with ATTR-CA with access to disease-modifying therapy. METHODS AND RESULTS: This is a retrospective cohort study of 419 patients diagnosed with ATTR-CA during 2001-2021, comparing clinical characteristics across eras. The primary end point was composite all-cause mortality or orthotopic heart transplantation (OHT). Time-to-event analysis was performed using Cox proportional hazard modeling controlling for differences among cohorts. Patients diagnosed in the more recent years had higher median age (2017-2021, 78 years; 2014-2016, 75 years; 2001-2013, 74 years) and more often had wild-type ATTR (81.9% vs 82.5% vs 56.4%), but less severe phenotypes as evidenced by more individuals with Columbia stage I disease (47.6% vs 35.9% vs 22.4%), owing to lower biomarkers, more patients in New York Heart Association functional classes I and II (68.9% vs 47.6% vs 43.6%), and lower use of loop diuretics (67.0% vs 78.6% vs 89.1%). Over time, patients were treated more frequently with tafamidis (74% vs 37% vs 32%). On multivariable analysis, greater Columbia score (hazard ratio 1.42, 95% confidence interval 1.30-1.54, P < .001) was predictive of death or OHT, whereas tafamidis (hazard ratio 0.31, 95% confidence interval 0.22-0.44, P < .001) was associated with greater survival and freedom from OHT. CONCLUSIONS: Patients recently diagnosed with ATTR-CA have earlier stage disease and substantially lower mortality. Tafamidis is associated with significantly improved survival and freedom from OHT.

Metabolomic Association and Risk Prediction With Heart Failure in Older Adults.

BACKGROUND: Older adults have markedly increased risks of heart failure (HF), specifically HF with preserved ejection fraction (HFpEF). Identifying novel biomarkers can help in understanding HF pathogenesis and improve at-risk population identification. This study aimed to identify metabolites associated with incident HF, HFpEF, and HF with reduced ejection fraction and examine risk prediction in older adults. METHODS: Untargeted metabolomic profiling was performed in Black and White adults from the ARIC study (Atherosclerosis Risk in Communities) visit 5 (n=3719; mean age, 75 years). We applied Cox regressions to identify metabolites associated with incident HF and its subtypes. The metabolite risk score (MRS) was constructed and examined for associations with HF, echocardiographic measures, and HF risk prediction. Independent samples from visit 3 (n=1929; mean age, 58 years) were used for replication. RESULTS: Sixty metabolites (hazard ratios range, 0.79-1.49; false discovery rate, <0.05) were associated with incident HF after adjusting for clinical risk factors, eGFR, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Mannonate, a hydroxy acid, was replicated (hazard ratio, 1.36 [95% CI, 1.19-1.56]) with full adjustments. MRS was associated with an 80% increased risk of HF per SD increment, and the highest MRS quartile had 8.7× the risk of developing HFpEF than the lowest quartile. High MRS was also associated with unfavorable values of cardiac structure and function. Adding MRS over clinical risk factors and NT-proBNP improved 5-year HF risk prediction C statistics from 0.817 to 0.850 (∆C, 0.033 [95% CI, 0.017-0.047]). The association between MRS and incident HF was replicated after accounting for clinical risk factors (P<0.05). CONCLUSIONS: Novel metabolites associated with HF risk were identified, elucidating disease pathways, specifically HFpEF. An MRS was associated with HF risk and improved 5-year risk prediction in older adults, which may assist at at-risk population identification.

Oligomerization mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.

Deltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognize ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerization, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function. While DTX3L and PARP9 are known to heterodimerize, and assemble into a high molecular weight oligomeric complex, the nature of the oligomeric structure, including whether this contributes to the ADP-ribose reader function is unknown. Here, we report a crystal structure of the DTX3L N-terminal D2 domain and show that it forms a tetramer with, conveniently, D2 symmetry. We identified two interfaces in the structure: a major, conserved interface with a surface of 973 Å2 and a smaller one of 415 Å2. Using native mass spectrometry, we observed molecular species that correspond to monomers, dimers and tetramers of the D2 domain. Reconstitution of DTX3L knockout cells with a D1-D2 deletion mutant showed the domain is dispensable for DTX3L-PARP9 heterodimer formation, but necessary to assemble an oligomeric complex with efficient reader function for ADP-ribosylated androgen receptor. Our results suggest that homo-oligomerization of DTX3L is important for the DTX3L-PARP9 complex to read mono-ADP-ribosylation on a ligand-regulated transcription factor.

Clinical Trial Diversity, Equity, and Inclusion: Roadmap of the Cardiothoracic Surgical Trials Network.

BACKGROUND: There is a recognized lack of diversity among patients enrolled in cardiovascular interventional and surgical trials. Diverse patient representation in clinical trials is necessary to enhance generalizability of findings, which may lead to better outcomes across broader populations. The Cardiothoracic Surgical Trials Network (CTSN) recently developed a plan of action to increase diversity among participating investigators and trial participants and is the focus of this review. METHODS: A review of literature and enrollment data from CTSN trials was conducted. RESULTS: CTSN completed more than a dozen major clinical trials (2008-2022), enrolling >4000 patients, of whom 30% were women, 11% were non-White, and 5.6% were Hispanic. CTSN also completed trials of hospitalized patients with coronavirus disease 2019, wherein enrollment was more diverse, with 42% women, and 58% were Asian, Black, Hispanic, or from another underrepresented racial group. The discrepancy in diversity of enrollment between cardiac surgery trials and coronavirus disease trials highlights the need for a more comprehensive understanding of (1) the prevalence of underlying disease requiring cardiac interventions across broad populations, (2) differences in access to care and referral for cardiac surgery, and (3) barriers to enrollment in cardiac surgery trials. CONCLUSIONS: Committed to diversity, CTSN's multifaceted action plan includes developing site-specific enrollment targets, collecting social determinants of health data, understanding reasons for nonparticipation, recruiting sites that serve diverse populations, emphasizing greater diversity among clinical trial teams, and implicit bias training. The CTSN will prospectively assess how these interventions influence enrollment as we work to ensure trial participants are more representative of the communities we serve.

Biological treatment of pesticide-containing wastewater from coffee crops: selection and optimization of a biomixture and biobed design.

The biopurification systems (BPS) or biobeds are employed for the treatment of pesticide-containing wastewater of agricultural origin. The use of these devices for pesticide removal requires the proper optimization of the composition of biomixtures (BPS active matrix) according to the target pesticides applied on a specific crop and the available materials used in their elaboration. This work aims to design a biomixture for the simultaneous treatment of several pesticides applied in coffee crops, according to local practices in Costa Rica. Three biomixtures containing either coffee husk, coconut fiber or rice husk (as the lignocellulosic substrate) were applied for the removal of 12 pesticides. The profiles of pesticide elimination and the mineralization of radiolabeled chlorpyrifos (14C-chlorpyrifos) revealed that the best performance was achieved with the coconut fiber biomixture, even though similar detoxification patterns were determined in every biomixture (according to immobilization in Daphnia magna and germination tests in Lactuca sativa). The optimization of this biomixture's composition by means of a central composite design permitted the definition of two optimal compositions (compost:soil:coconut fiber, % v/v) that maximized pesticide removal: i. 29:7.3:63.7 and ii. 11:7.3:81.7. The validation of these optimized compositions also included the use of an alternative soil from another coffee farm and resulted in overall DT50 values of 7.8-9.0 d for the pesticide mixture. Considering the removal kinetics in the optimized biomixture, a 1 m3 BPS prototype was dimensioned to be eventually used in local coffee farms. This work provides relevant information for the design and implementation of BPS at on-farm conditions for the treatment of pesticide-containing wastewater of a major crop.