PIK3CA mutational status in tissue and plasma as a prognostic biomarker in HR+/HER2- breast cancer.

INTRODUCTION: Hotspots (HS) mutations in the PIK3CA gene may lead to poorer oncological outcomes and endocrine resistance in advanced breast cancer (BC), but their prognostic role in early-stage disease remains controversial. The overall agreement within plasma and tissue methods has not been well explored. Our aim was to correlate tissue and plasma approaches and to analyze the prognostic impact of PIK3CA mutations (PIK3CAm) in HR+/HER2- BC. METHODS: A retrospective and unicentric analysis of PIK3CA mutational status in tissue and plasma samples by Cobas®PIK3CA Mutation Kit in patients with HR+/HER2- BC. RESULTS: We analyzed 225 samples from 161 patients with luminal BC. PIK3CA mutations were identified in 62 patients (38.5%), of which 39.6% were found in tissue and 11.8% in plasma. In advanced disease, plasma and tissue correlation rate was performed in 64 cases, with an overall agreement of 70.3%. Eighty patients were treated with CDK4/6 inhibitors + endocrine therapy. We observed a moderately worse progression-free survival (PFS) in PIK3CAm versus wild-type (WT) (24 m vs. 30 m; HR = 1.39, p = 0.26). A subanalysis was carried out based on exons 9 and 20, which showed a statistically poorer PFS in PIK3CAm exon 9 versus 20 population (9.7 m vs. 30.3 m; HR = 2.84; p = 0.024). Furthermore, detection of PIK3CAm in plasma was linked to a worse PFS vs PIK3CAm detection just in tissue (12.4 vs. 29.3; HR = 2.4; p = 0.08). CONCLUSIONS: Our findings suggest the PIK3CA evaluation in tissue as the diagnostic method of choice, however, additional investigations are required to improve the role of liquid biopsy in the PIK3CA assessment. PIK3CAm show worse outcomes in advanced luminal BC, especially in exon 9 mutation carriers, despite visceral involvement, prior exposure to endocrine therapy or detection of PIK3CAm in plasma, with an unclear prognosis in early-stage disease. Nonetheless, this should be validated in a prospective cohort study.

Clinical presentation and microbiological characteristics of community-acquired Staphylococcus aureus bacteraemia at a tertiary hospital in Costa Rica.

Introduction. Staphylococcus aureus is a leading agent in community-acquired bacteraemia (CAB) and has been linked to elevated mortality rates and methicillin resistance in Costa Rica.Gap statement and aim. To update and enhance previous data obtained in this country, we analysed the clinical manifestations of 54 S. aureus CAB cases in a tertiary hospital and delineated the sequence types (STs), virulome, and resistome of the implicated isolates.Methodology. Clinical information was retrieved from patient files. Antibiotic susceptibility profiles were obtained with disc diffusion and automated phenotypic tests. Genomic data were exploited to type the isolates and for detection of resistance and virulence genes.Results. Primary infections predominantly manifested as bone and joint infections, followed by skin and soft tissue infections. Alarmingly, 70% of patients continued to exhibit positive haemocultures beyond 48 h of treatment modification, with nearly a quarter requiring mechanical ventilation or developing septic shock. The 30-day mortality rate reached an alarming 40%. More than 60% of the patients were found to have received suboptimal or inappropriate antibiotic treatment, and there was an alarming tendency towards the overuse of third-generation cephalosporins as empirical treatment. Laboratory tests indicated elevated creatinine levels, leukocytosis, and bandaemia within the first 24 h of hospitalization. However, most showed improvement after 48 h. The isolates were categorized into 13 STs, with a predominance of representatives from the clonal complexes CC72 (ST72), CC8 (ST8), CC5 (ST5, ST6), and CC1 (ST188). Twenty-four isolates tested positive for mecA, with ST72 strains accounting for 20. In addition, we detected genes conferring acquired resistance to aminoglycosides, MLSB antibiotics, trimethoprim/sulfamethoxazole, and mutations for fluoroquinolone resistance in the isolate collection. Genes associated with biofilm formation, capsule synthesis, and exotoxin production were prevalent, in contrast to the infrequent detection of enterotoxins or exfoliative toxin genes.Conclusions. Our findings broaden our understanding of S. aureus infections in a largely understudied region and can enhance patient management and treatment strategies.

Multiple Myeloma Risk and Outcomes are Associated with Pathogenic Germline Variants in DNA Repair Genes.

First-degree relatives of multiple myeloma (MM) patients are at increased risk for MM, but the contribution of pathogenic germline variants (PGVs) in hereditary cancer genes to MM risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 MM patients. PGVs were identified in 8.6% of the discovery cohort and 11.5% of the replication cohort, with a notable presence of high or moderate-penetrance PGVs (PGV-As) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR=3.9, FDR<0.01) and BRCA2 (OR=7.0, FDR<0.001) were significantly enriched in MM patients compared to 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGV-As were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem cell transplant (p<0.01).

Genomic Insights into Pseudomonas protegens E1BL2 from Giant Jala Maize: A Novel Bioresource for Sustainable Agriculture and Efficient Management of Fungal Phytopathogens.

The relationships between plants and bacteria are essential in agroecosystems and bioinoculant development. The leaf endophytic Pseudomonas protegens E1BL2 was previously isolated from giant Jala maize, which is a native Zea mays landrace of Nayarit, Mexico. Using different Mexican maize landraces, this work evaluated the strain's plant growth promotion and biocontrol against eight phytopathogenic fungi in vitro and greenhouse conditions. Also, a plant field trial was conducted on irrigated fields using the hybrid maize Supremo. The grain productivity in this assay increased compared with the control treatment. The genome analysis of P. protegens E1BL2 showed putative genes involved in metabolite synthesis that facilitated its beneficial roles in plant health and environmental adaptation (bdhA, acoR, trpE, speE, potA); siderophores (ptaA, pchC); and extracellular enzymes relevant for PGPB mechanisms (cel3, chi14), protection against oxidative stress (hscA, htpG), nitrogen metabolism (nirD, nit1, hmpA), inductors of plant-induced systemic resistance (ISR) (flaA, flaG, rffA, rfaP), fungal biocontrol (phlD, prtD, prnD, hcnA-1), pest control (vgrG-1, higB-2, aprE, pslA, ppkA), and the establishment of plant-bacteria symbiosis (pgaA, pgaB, pgaC, exbD). Our findings suggest that P. protegens E1BL2 significantly promotes maize growth and offers biocontrol benefits, which highlights its potential as a bioinoculant.

Beyond the Buzz: Do Energy Drinks Offer More Than Caffeine for Mental and Physical Tasks?

Energy drinks are marketed for enhancing mental and physical performance, often containing ingredients beyond caffeine. This study investigated whether an energy drink (ED), Gorilla Mind, exerted greater effects on sustained attention, mood, handgrip strength, and push-up performance than a caffeine-matched control drink (CAF) in exercise-trained individuals (n = 21, age: 22 ± 5.9 years). In a randomized, counterbalanced, crossover design, participants first completed tests assessing mood (Profile of Mood States; POMS), sustained attention (Psychomotor Vigilance Test; PVT), handgrip strength (HG), and 1-minute maximum push-up performance (PU). They then consumed either an ED or CAF drink (200mg caffeine) in a randomized order. After 45 minutes, the tests were repeated. Following a 1-week washout period, participants returned to consume the other drink and completed the same protocol. While the ED group improved reaction time (PVT), the Delta score between ED and CAF was not statistically significant (p = 0.3391). No significant differences were found between ED and CAF groups for other measures (POMS: p = 0.152, HG: p = 0.499, PU: p = 0.209). These findings suggest that the additional ingredients in the ED may not offer substantial benefits beyond caffeine for these measures in active individuals. It is important to note that the caffeine dose was, on average, less than 3.0 mg/kg body mass, which may have influenced the outcomes.

Real-world experience with clinical management of talquetamab in relapsed/refractory multiple myeloma: a qualitative study of US healthcare providers.

OBJECTIVE: Talquetamab is the first-in-class GPRC5DxCD3 bispecific antibody for relapsed/refractory multiple myeloma. Given limited real-world data, this study was conducted with US healthcare providers (HCPs) to understand real-world talquetamab dosing and symptom management. METHODS: In February/March 2024, individual in-depth interviews (IDIs; n = 10) were conducted with HCPs administering talquetamab in real-world settings. A subsequent expert panel (n = 6) further discussed current practices. RESULTS: The IDIs reported a variety of settings for step-up dosing (SUD), including inpatient (n = 5), outpatient (n = 3), and hybrid models (n = 2), with a trend toward shorter SUD length to reduce healthcare resource utilization. Most HCPs used a biweekly (Q2W) schedule in SUD (n = 7) and treatment phases (n = 8). Six participants explored reducing dose frequency to every 4 weeks (Q4W) in patients following positive disease response to treatment, considering patient convenience and relieving GPRC5D-related symptoms. Panelists recommended symptom management and prophylactic strategies, such as dexamethasone and nystatin mouthwash or zinc and vitamin B complex for oral symptoms, and topical steroids and cosmetic products for skin and nail symptoms. CONCLUSION: This study outlines current real-world practices for talquetamab. Findings indicate variation in the SUD care setting. The 0.8 mg/kg Q2W dosing schedule was most common, although switching to Q4W is a real-world symptom management strategy for some patients with responses to therapy. GPRC5D-related symptom management approaches are evolving; prophylactic use of dexamethasone and nystatin mouthwash or zinc and vitamin B complex may be effective strategies to alleviate oral symptoms. Further real-world evidence is needed to inform optimal dosing schedules while mitigating symptom impact.

Talquetamab is a new treatment that was approved in the United States in 2023 for a type of blood cancer called multiple myeloma. This drug is administered at one of two doses, each of which includes a defined step-up dosing schedule where patients first receive smaller amounts of the drug to help avoid serious side effects. Because talquetamab is new and associated with treatment-related symptoms not normally seen with other multiple myeloma treatments, doctors and patients need more guidance on drug administration and symptom management. In this study, we describe findings from interviews and an expert panel discussion with healthcare professionals who have experience using talquetamab. This study found that most healthcare professionals administered step-up dosing with patients staying overnight in the hospital, while other providers administered these doses during outpatient visits. Most providers administered talquetamab once every 2 weeks after utilizing the associated step-up dosing schedule. Additionally, healthcare providers described transitioning some patients, who had responded positively to treatment, to a less frequent dosing schedule of once per month to help reduce the effect of treatment-related symptoms. Participants in the expert panel described approaches for managing or preventing these symptoms, such as dexamethasone and nystatin mouthwashes or zinc and vitamin B complex for oral symptoms, and topical steroids and cosmetic products for skin and nail symptoms. In summary, this study provides valuable real-world information from healthcare providers who have experience treating patients with multiple myeloma with talquetamab.

An outbreak of severe or lethal infections by a multidrug-resistant Acinetobacter baumannii ST126 strain carrying a plasmid with blaNDM-1 and blaOXA-58 carbapenemases.

Acinetobacter baumannii poses a significant health threat because of its frequent implications in hospital outbreaks and multidrug resistance (MDR). Here, we studied four A. baumannii isolates recovered during a hospital outbreak of severe or fatal cases to elucidate their diversity and factors contributing to their increased virulence and antibiotic resistance. The isolates were identified using MALDI-ToF and characterized using comparative genomics, PCR, and antimicrobial susceptibility tests. They were classified as ST126 and exhibited fewer than five chromosomal single-nucleotide variants and the same extrachromosomal content, indicating that they are a single strain (A. baumannii AB01). A. baumannii AB01 showed an MDR phenotype that could be linked to the carriage of parC and gyrA mutations, efflux transporters, aminoglycoside resistance genes, a class C beta-lactamase, and three carbapenemases, some of which are encoded on a 72 kb plasmid. ST126 is infrequent and has not been reported in Latin America, and our genomic data indicate a plausible origin for A. baumannii AB01 within the Pan Pacific region.

A Pilot Study on Proteomic Predictors of Mortality in Stable COPD.

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality. Despite clinical predictors (age, severity, comorbidities, etc.) being established, proteomics offers comprehensive biological profiling to obtain deeper insights into COPD pathophysiology and survival prognoses. This pilot study aimed to identify proteomic footprints that could be potentially useful in predicting mortality in stable COPD patients. Plasma samples from 40 patients were subjected to both blind (liquid chromatography-mass spectrometry) and hypothesis-driven (multiplex immunoassays) proteomic analyses supported by artificial intelligence (AI) before a 4-year clinical follow-up. Among the 34 patients whose survival status was confirmed (mean age 69 ± 9 years, 29.5% women, FEV1 42 ± 15.3% ref.), 32% were dead in the fourth year. The analysis identified 363 proteins/peptides, with 31 showing significant differences between the survivors and non-survivors. These proteins predominantly belonged to different aspects of the immune response (12 proteins), hemostasis (9), and proinflammatory cytokines (5). The predictive modeling achieved excellent accuracy for mortality (90%) but a weaker performance for days of survival (Q2 0.18), improving mildly with AI-mediated blind selection of proteins (accuracy of 95%, Q2 of 0.52). Further stratification by protein groups highlighted the predictive value for mortality of either hemostasis or pro-inflammatory markers alone (accuracies of 95 and 89%, respectively). Therefore, stable COPD patients' proteomic footprints can effectively forecast 4-year mortality, emphasizing the role of inflammatory, immune, and cardiovascular events. Future applications may enhance the prognostic precision and guide preventive interventions.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

Removal of mobile genetic elements from the genome of Clostridioides difficile and the implications for the organism's biology.

Clostridioides difficile is an emerging pathogen of One Health significance. Its highly variable genome contains mobile genetic elements (MGEs) such as transposons and prophages that influence its biology. Systematic deletion of each genetic element is required to determine their precise role in C. difficile biology and contribution to the wider mobilome. Here, Tn5397 (21 kb) and ϕ027 (56 kb) were deleted from C. difficile 630 and R20291, respectively, using allele replacement facilitated by CRISPR-Cas9. The 630 Tn5397 deletant transferred PaLoc at the same frequency (1 × 10-7) as 630 harboring Tn5397, indicating that Tn5397 alone did not mediate conjugative transfer of PaLoc. The R20291 ϕ027 deletant was sensitive to ϕ027 infection, and contained two unexpected features, a 2.7 kb remnant of the mutagenesis plasmid, and a putative catalase gene adjacent to the deleted prophage was also deleted. Growth kinetics of R20291 ϕ027 deletant was similar to wild type (WT) in rich medium but marginally reduced compared with WT in minimal medium. This work indicates the commonly used pMTL8000 plasmid series works well for CRISPR-Cas9-mediated gene deletion, resulting in the largest deleted locus (56.8 kb) described in C. difficile. Removal of MGEs was achieved by targeting conjugative/integrative regions to promote excision and permanent loss. The deletants created will be useful strains for investigating Tn5397 or ϕ027 prophage contribution to host virulence, fitness, and physiology, and a platform for other mutagenesis studies aimed at functional gene analysis without native transposon or phage interference in C. difficile 630 and R20291.

Alliance A061202: Ixazomib, pomalidomide and dexamethasone for lenalidomide-refractory multiple myeloma in first relapse.

Optimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma (MM) in first relapse remains poorly defined. We therefore undertook a randomized phase II study evaluating the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) for this patient population. The overall response rate (ORR) for POM-DEX was 43.6% and 63.2% for IXA-POM-DEX. Depth of response, as measured by attainment of a very good partial response or better favored the triplet over the doublet, 28.9% vs 5.1%, respectively (p = 0.0063). A pre-planned interim analysis after 75% of the progression events had occurred demonstrated a progression-free survival (PFS) advantage favoring IXA-POM-DEX that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI] 4.8 - 13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI 7.7 - 26.0 months, hazard ratio 0.437 [upper 90% bound = 0.657]). ORR and median PFS for the 26 of 30 eligible patients who crossed over from the doublet to the triplet at progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the two groups. More hematologic toxicities were seen with the triplet, but non-hematologic adverse events were similar between the two arms. Our data support further testing of this all-oral triplet vs current standard triplet therapy in the context of phase III studies for patients with LEN-refractory disease in first relapse. This trial is registered at www.clinicaltrials.gov as NCT02004275.

An iterative neural network approach applied to human-induced force reconstruction using a non-linear electrodynamic shaker.

Human-induced force analysis plays an important role across a wide range of disciplines, including biomechanics, sport engineering, health monitoring or structural engineering. Specifically, this paper focuses on the replication of ground reaction forces (GRF) generated by humans during movement. They can provide critical information about human-mechanics and be used to optimize athletic performance, prevent and rehabilitate injuries and assess structural vibrations in engineering applications. It is presented an experimental approach that uses an electrodynamic shaker (APS 400) to replicate GRFs generated by humans during movement, with a high degree of accuracy. Successful force reconstruction implies a high fidelity in signal reproduction with the electrodynamic shaker, which leads to an inverse problem, where a reference signal must be replicated with a nonlinear and non-invertible system. The solution presented in this paper relies on the development of an iterative neural network and an inversion-free approach, which aims to generate the most effective drive signal that minimizes the error between the experimental force signal exerted by the shaker and the reference. After the optimization process, the weights of the neural network are updated to make the shaker behave as desired, achieving excellent results in both time and frequency domains.

Comparative Genomics of the First Resistant Candida auris Strain Isolated in Mexico: Phylogenomic and Pan-Genomic Analysis and Mutations Associated with Antifungal Resistance.

Candida auris is an emerging multidrug-resistant and opportunistic pathogenic yeast. Whole-genome sequencing analysis has defined five major clades, each from a distinct geographic region. The current study aimed to examine the genome of the C. auris 20-1498 strain, which is the first isolate of this fungus identified in Mexico. Based on whole-genome sequencing, the draft genome was found to contain 70 contigs. It had a total genome size of 12.86 Mbp, an N50 value of 1.6 Mbp, and an average guanine-cytosine (GC) content of 45.5%. Genome annotation revealed a total of 5432 genes encoding 5515 proteins. According to the genomic analysis, the C. auris 20-1498 strain belongs to clade IV (containing strains endemic to South America). Of the two genes (ERG11 and FKS1) associated with drug resistance in C. auris, a mutation was detected in K143R, a gene located in a mutation hotspot of ERG11 (lanosterol 14-α-demethylase), an antifungal drug target. The focus on whole-genome sequencing and the identification of mutations linked to the drug resistance of fungi could lead to the discovery of new therapeutic targets and new antifungal compounds.

Portal vein Doppler tracks volume status in patients with severe tricuspid regurgitation: a proof-of-concept study.

AIMS: Renal and liver congestion are associated with adverse outcomes in patients with tricuspid regurgitation (TR). Currently, there are no valid sonographic indicators of fluid status in this population. Intra-renal venous Doppler (IRVD) is a novel method for quantifying renal congestion but its interpretation can be challenging in severe TR due to altered haemodynamics. This study explores the potential of portal vein Doppler (PVD) as an alternative marker for decongestion during volume removal in patients with severe TR. METHODS AND RESULTS: Forty-two patients with severe TR undergoing decongestive therapy were prospectively enrolled. Inferior vena cava diameter, PVD, and IRVD were sequentially assessed during volume removal. Improvement criteria were portal vein pulsatility fraction (PVPF) < 70% and renal venous stasis index (RVSI) < 0.5 for partial improvement, and PVPF < 30% and RVSI < 0.2 for complete improvement. After volume removal, PVPF significantly improved from 130 ± 39% to 47 ± 44% (P < 0.001), while IRVD improved from 0.72 ± 0.08 to 0.54 ± 0.22 (P < 0.001). A higher proportion of patients displayed improvement in PVD compared to IRVD (partial: 38% vs. 29%, complete: 41% vs. 7%) (P < 0.001). Intra-renal venous Doppler only improved in patients with concomitant improvement in severe TR. Portal vein Doppler was the only predictor of achieving ≥5 L of negative fluid balance [area under the ROC curve (AUC) 0.83 P = 0.001]. CONCLUSION: This proof-of-concept study suggests that PVD is the only sonographic marker that can track volume removal in severe TR, offering a potential indicator for decongestion in this population. Further intervention trials are warranted to determine if PVD-guided decongestion improves patient outcomes in severe TR.

Proteomic Blood Profiles Obtained by Totally Blind Biological Clustering in Stable and Exacerbated COPD Patients.

Although Chronic Obstructive Pulmonary Disease (COPD) is highly prevalent, it is often underdiagnosed. One of the main characteristics of this heterogeneous disease is the presence of periods of acute clinical impairment (exacerbations). Obtaining blood biomarkers for either COPD as a chronic entity or its exacerbations (AECOPD) will be particularly useful for the clinical management of patients. However, most of the earlier studies have been characterized by potential biases derived from pre-existing hypotheses in one or more of their analysis steps: some studies have only targeted molecules already suggested by pre-existing knowledge, and others had initially carried out a blind search but later compared the detected biomarkers among well-predefined clinical groups. We hypothesized that a clinically blind cluster analysis on the results of a non-hypothesis-driven wide proteomic search would determine an unbiased grouping of patients, potentially reflecting their endotypes and/or clinical characteristics. To check this hypothesis, we included the plasma samples from 24 clinically stable COPD patients, 10 additional patients with AECOPD, and 10 healthy controls. The samples were analyzed through label-free liquid chromatography/tandem mass spectrometry. Subsequently, the Scikit-learn machine learning module and K-means were used for clustering the individuals based solely on their proteomic profiles. The obtained clusters were confronted with clinical groups only at the end of the entire procedure. Although our clusters were unable to differentiate stable COPD patients from healthy individuals, they segregated those patients with AECOPD from the patients in stable conditions (sensitivity 80%, specificity 79%, and global accuracy, 79.4%). Moreover, the proteins involved in the blind grouping process to identify AECOPD were associated with five biological processes: inflammation, humoral immune response, blood coagulation, modulation of lipid metabolism, and complement system pathways. Even though the present results merit an external validation, our results suggest that the present blinded approach may be useful to segregate AECOPD from stability in both the clinical setting and trials, favoring more personalized medicine and clinical research.

Global mercury concentrations in biota: their use as a basis for a global biomonitoring framework.

An important provision of the Minamata Convention on Mercury is to monitor and evaluate the effectiveness of the adopted measures and its implementation. Here, we describe for the first time currently available biotic mercury (Hg) data on a global scale to improve the understanding of global efforts to reduce the impact of Hg pollution on people and the environment. Data from the peer-reviewed literature were compiled in the Global Biotic Mercury Synthesis (GBMS) database (>550,000 data points). These data provide a foundation for establishing a biomonitoring framework needed to track Hg concentrations in biota globally. We describe Hg exposure in the taxa identified by the Minamata Convention: fish, sea turtles, birds, and marine mammals. Based on the GBMS database, Hg concentrations are presented at relevant geographic scales for continents and oceanic basins. We identify some effective regional templates for monitoring methylmercury (MeHg) availability in the environment, but overall illustrate that there is a general lack of regional biomonitoring initiatives around the world, especially in Africa, Australia, Indo-Pacific, Middle East, and South Atlantic and Pacific Oceans. Temporal trend data for Hg in biota are generally limited. Ecologically sensitive sites (where biota have above average MeHg tissue concentrations) have been identified throughout the world. Efforts to model and quantify ecosystem sensitivity locally, regionally, and globally could help establish effective and efficient biomonitoring programs. We present a framework for a global Hg biomonitoring network that includes a three-step continental and oceanic approach to integrate existing biomonitoring efforts and prioritize filling regional data gaps linked with key Hg sources. We describe a standardized approach that builds on an evidence-based evaluation to assess the Minamata Convention's progress to reduce the impact of global Hg pollution on people and the environment.

Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient-reported outcomes from GRIFFIN.

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D-RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D-RVd and RVd. These improvements in health-related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D-RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

A Step towards understanding coronary artery disease: a complication in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a relatively rare disease with increasing incidence trends. Cardiovascular disease is a significant complication in IPF patients due to the role of common proatherogenic immune mediators. The prevalence of coronary artery disease (CAD) in IPF and the association between these distinct pathologies with overlapping pathophysiology remain less studied. RESEARCH QUESTION: We hypothesised that IPF is an independent risk factor for CAD. METHODS: We conducted a retrospective case-control study using the national inpatient sample (2017-2019). We included adult hospitalisations with IPF after excluding other interstitial lung diseases and other endpoints of CAD, acute coronary syndrome and old myocardial infarction. We examined their baseline characteristics, such as demographic data, hospital characteristics and socioeconomic status. The prevalence of cardiac risk factors and CAD was also compared between hospitalisations with and without IPF. Univariate and multivariate regression analysis was further performed to study the odds of CAD with IPF. The cases of IPF in the study population were propensity-matched, after which generalised linear modelling analysis was performed to validate the findings. RESULTS: A total of 116 010 admissions were hospitalised in 2017-2019 with IPF, of which 55.6% were men with a mean age of 73 years. Adult hospitalisations with IPF were found to have a higher prevalence of diabetes mellitus (29.3% vs 24.0%; p<0.001), hypertension (35.6% vs 33.8%; p<0.001), hyperlipidaemia (47.7% vs 30.2%; p<0.0001) and tobacco abuse (41.7% vs 20.9%; p<0.001), while they had a lower prevalence of obesity (11.7% vs 15.3%; p<0.0001) compared with hospitalisations without IPF. Multivariate logistic regression analysis revealed 28% higher odds of developing CAD in IPF hospitalisations (OR -1.28; CI 1.22 to 1.33; p<0.001). Postpropensity matching, generalised linear modelling analysis revealed even higher odds of CAD with IPF (OR -1.77; CI 1.54 to 2.02; p<0.001) CONCLUSIONS: Our study found a higher prevalence of CAD in IPF hospitalisations and significantly higher odds of CAD among IPF cases. IPF remains a terminal lung disease that portends a poor prognosis, but addressing the cardiovascular risk factors in these patients can help reduce the case fatality rate due to the latter and potentially add to quality-adjusted life years.

COPD: systemic proteomic profiles in frequent and infrequent exacerbators.

Background: Some patients with COPD suffer frequent exacerbations (FE). We hypothesised that their systemic proteomic profile would be different from that of non-frequent exacerbators (NFE). The objective of the present study was to contrast the systemic proteomic profile in FE versus NFE. As a reference, we also determined the systemic proteomic profile of healthy controls (HC) and COPD patients during an actual episode of exacerbation (AE). Methods: In the analysis we included 40 clinically stable COPD patients (20 FE and 20 NFE), and 20 HC and 10 AE patients. Their plasma samples were analysed by combining two complementary proteomic approaches: label-free liquid chromatography-tandem mass spectrometry and multiplex immunoassays. Gene Ontology annotation, pathway enrichment and network analyses were used to investigate molecular pathways associated with differentially abundant proteins/peptides (DAPs). Results: Compared with HC, we identified 40 DAPs in FE, 10 in NFE and 63 in AE. Also compared to HC, pathway functional and protein-protein network analyses revealed dysregulation of inflammatory responses involving innate and antibody-mediated immunity in COPD, particularly in the FE group, as well as during an AE episode. Besides, we only identified alterations in the complement and coagulation cascades in AE. Conclusion: There are specific plasma proteome profiles associated with FE, which are partially shared with findings observed during AE, albeit others are uniquely present during the actual episode of AE.