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BackgroundStandard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management.MethodsThis prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results.ResultsPositive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases.Clinical trials registrationNCT02912117.ConclusionKT shows promise in the diagnosis and treatment optimization of FN.

In tropical environments, and especially tropical rainforests, a major part of pollination services is provided by diverse insect lineages. Unbeknownst to most, beetles, and more specifically hyperdiverse weevils (Coleoptera: Curculionoidea), play a substantial role there as specialized mutualist brood pollinators. The latter contrasts with a common view where they are only regarded as plant antagonists. This study aims to provide a comprehensive understanding of what is known about plant-weevil brood-site mutualistic interactions, through a review of the known behavioral, morphological and physiological features found in these systems, and the identification of potential knowledge gaps. To date, plant-weevil associations have been described or indicated in no less than 600 instances. Representatives of major plant lineages are involved in these interactions, which have emerged independently at least a dozen times. Strikingly, these mutualistic interactions are associated with a range of convergent traits in plants and weevils. Plants engaged in weevil-mediated pollination are generally of typical cantharophilous type exhibiting large, white and fragrant flowers or inflorescences and they also show specific structures to host the larval stages of their specialist pollinators. Another characteristic feature is that flowers often perform thermogenesis and exhibit a range of strategies to separate sexual phases, either spatially or temporally. Conversely, lineages of brood-site weevil pollinators present numerous shared behavioral and physiological traits, and often form multispecific assemblages of closely related species on a single host; recent studies also revealed that they generally display a high degree of phylogenetic niche conservatism. This pollination mutualism occurs in all tropical regions, and the contrasts between the known and expected diversity of these systems suggests that a wide range of interactions remain to be described globally. Our early estimates of the species richness of the corresponding weevil clades and the marked pattern of phylogenetic niche conservatism of host use further suggest that weevil-based pollination far exceeds the diversity of other brood-site mutualistic systems, which are generally restricted to one or a few groups of plants. As such, weevil pollinators constitute a relevant model to explore the emergence and evolution of specialized brood-site pollination systems in the tropics.

Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with acute myeloid leukemia (AML). Monitoring patients for measurable residual disease (MRD) is helpful to identify those at risk for relapse. Hypomethylating agents are being investigated as post-remission therapy. Identification of recurrent genetic alterations that drive disease progression has enabled the design of new, personalized approaches to therapy for patients with AML. Emerging data suggest that targeted post-remission therapy, alone or in combination with chemotherapy, may improve outcomes. Results of ongoing clinical trials will further define potential clinical benefits.

The genetic diversity of Breton horses in Brazil is a critical concern, mainly due to the small population size and low number of births per year. Given that the inbreeding was overlooked by breeders for multiple generations, we estimated the genetic diversity of this population utilizing pedigree‐based measures of population diversity. A total of 1394 six‐generation pedigrees representing the full population of registered Breton horses in Brazil defined a total population (TP, N = 2679), with horses born between 2000 and 2022, reproductively active and alive, as reported by the breed association, representing the reference population (RP, N = 731). Using the R package PurgeR, we estimated inbreeding coefficient (Fped), maternal inbreeding coefficient (Fda m), paternal inbreeding coefficient (Fsire), individual reproductive values, number of equivalents to complete generations (t), and unbiased ancestral inbreeding coefficient (Fa). We established the equivalent complete generations (ECG), effective population size (Ne), total number of founders (Nf), effective number of founders (Nfe), total number of ancestors (Na), effective number of ancestors (Nae), founder genomes (Ng), and the inbreeding coefficient estimated with effective population size (Ne) and generation numbers (t) (FNe:t), as well as Nfe/Nae and Nfe/Ng ratios for the RP. The RP inbreeding levels have stabilized, although they are still significantly rising by generation (t), and the Nfe/Ng ratio strongly suggests genetic drift. Pedigree‐based analysis demonstrates that only five stallions have sired 52.83% of the RP individuals, which along with the Nae value of 36.73 implies that the observed inbreeding can be arising from patrilines. Our results suggest that observed inbreeding is due to Popular Sire Effect, highlighting the importance of monitoring breeding schemes and genetic diversity to maintain health. [ABSTRACT FROM AUTHOR]

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Udeus Champion, 1902 is a weevil genus in the tribe Eugnomini associated with the inflorescences of Cecropia Loefl. (Urticaceae), with 11 valid species distributed in the Neotropics. Species of Udeus are generally rare in collections and their biology is poorly known, despite a high abundance in nature. Here, we describe Udeus cerradensis Lira, de Medeiros & Grossi, sp. nov. from the Brazilian Cerrado, including the first descriptions of larvae and pupae for a Neotropical eugnomine. We assess their role as potential pollinators of their host plant Cecropia saxatilis Snethl. and find that adults do not visit pistillate flowers and therefore are unlikely to be pollinators. This contrasts with previous reports in a different pair of species in Cecropia‐Udeus, suggesting that pollinator agents vary between species in this plant genus. Finally, we provide notes about the predation of larvae of U. cerradensis by social wasps Synoeca surinama (L.) and Protopolybia aff. sedula (Saussure), revealing that, in this instance, an endophytic larva does not prevent predation by a behaviourally flexible predator. This study is the first of a series on the natural history of Udeus and their specialised interactions with host plants. [ABSTRACT FROM AUTHOR]

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A better understanding of factors associated with early death and survival among children, adolescents and young adults with acute myeloid leukaemia (AML) may guide health policy aimed at improving outcomes in these patients. We examined trends in early death and survival among 3935 patients aged 0-39 years with de novo AML in California during 1988-2011 and investigated the associations between sociodemographic and selected clinical factors and outcomes. Early death declined from 9·7% in 1988-1995 to 7·1% in 2004-2011 (P = 0·062), and survival improved substantially over time. However, 5-year survival was still only 50% (95% confidence interval 47-53%) even in the most recent treatment period (2004-2011). Overall, the main factors associated with poor outcomes were older age at diagnosis, treatment at hospitals not affiliated with National Cancer Institute-designated cancer centres, and black race/ethnicity. For patients diagnosed during 1996-2011, survival was lower among those who lacked health insurance compared to those with public or private insurance. We conclude that mortality after AML remained strikingly high in California and increased with age. Possible strategies to improve outcomes include wider insurance coverage and treatment at specialized cancer centres.

Abstract Background A better understanding of factors associated with early death and survival may guide future health policy aimed at improving outcomes among children, adolescents and young adults with acute myeloid leukemia (AML). Methods We examined trends in early death and survival among 3,935 patients aged 0-39 years diagnosed with de novo AML in California during 1988-2011. We estimated overall survival and applied logistic and Cox regression to evaluate the association between sociodemographic and selected clinical factors with early death and survival. Results There was a trend towards decline in early death from 9.7% in 1988-1995 to 7.1% in 2004-2011 (P=0.062). Survival improved substantially over time, but 5-year survival was still only 50% (95% CI 47%-53%) even in the most recent calendar period. Overall, the main factors associated with poor outcomes were older age at diagnosis, treatment at hospitals not affiliated with National Cancer Institute (NCI)-designated cancer centers, and black race/ethnicity. For patients diagnosed during 1996-2011, survival was lower for patients without health insurance and those who did not receive a hematopoietic stem cell transplant (HSCT). The association between survival and sociodemographic and clinical factors were stronger among patients aged 30-39 years. Conclusions Mortality after AML remained strikingly high and increased with age. To improve outcomes, strategies may include wider insurance coverage, treatment at hospitals affiliated with NCI-designated cancer centers and access to HSCT for high-risk patients. Collaborative clinical trials aimed to evaluate the efficacy and toxicity of novel agents for each subtype of disease are warranted. Disclosures No relevant conflicts of interest to declare.

BackgroundFindings from clinical trials and population-based studies have differed with regard to whether mortality within 30 days of diagnosis (early death) of acute promyelocytic leukemia (APL) has decreased in the era of all-trans retinoic acid and anthracycline-based chemotherapy.MethodsUsing data from the California Cancer Registry, the authors investigated 7-day and 30-day mortality and survival in 772 patients who were aged birth to 39 years when they were diagnosed with APL during 1988 to 2011. Logistic regression and Cox proportional models were used to examine the association of early death and survival, respectively, with sociodemographic and clinical factors.ResultsThe overall 30-day mortality decreased significantly over time, from 26% (1988-1995) to 14% (2004-2011) (P =.004). On multivariable analysis, the odds of 30-day mortality were 3 times as high during 1988 through 1995 than 2004 through 2011 (P =.001). However, 7-day mortality did not improve over time (P =.229). When patients who died within 7 days of diagnosis were excluded, the 30-day mortality during 1996 to 2011 was 3% to 8%, which is similar to levels reported in clinical trials. Higher early death and lower survival were associated with a lack of health insurance (1996-2011) (early death odds ratio, 2.67; P =.031) and Hispanic race/ethnicity (early death odds ratio, 2.13; P =.014). Early death was not found to be associated with age, sex, socioeconomic status, or hospital type. Black patients also experienced worse survival.ConclusionsThe findings of the current study revealed a decreased 30-day mortality during the all-trans retinoic acid era, but 7-day mortality remained high. Efforts to achieve equal outcomes in young patients with APL should focus on improving access to effective treatment, mainly among uninsured patients and those of Hispanic and black race/ethnicity.