Hypomethylating agents are associated with high rates of hematologic toxicity in patients with secondary myeloid neoplasms developing after acquired aplastic anemia.

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RAD21 mutations in acute myeloid leukemia.

The cohesin complex is a ring-shaped protein structure involved in DNA repair and chromosomal segregation. Studies have showed that genomic alterations in the cohesin complex members are among the initial occurrences in the development of acute myeloid leukemia (AML). STAG2 is the most commonly mutated and best-studied member of the cohesin complex in AML and mutations in this gene have been associated with adverse outcomes and are diagnostically relevant. However, the exact role of mutations in other members of the cohesin complex in the development of myeloid neoplasia is controversial. In this single institution study, we retrospectively reviewed data from the molecular profiles of 1,381 AML patients and identified 14 patients with mutations in RAD21, another member of the cohesin complex. We evaluated the frequency, mutational profile, clinico-pathologic features, and prognostic impact of RAD21 in this cohort. This study showed that RAD21-mutated AML often associates with monocytic differentiation, CD7 expression, co-existing mutations in epigenetic regulators, a normal karyotype, and poor prognosis. Our findings provide additional insights into the morphologic, immunophenotypic, and genomic profile of RAD21 mutation-positive AML and suggest that RAD21 mutations should be evaluated for independent prognostic significance in AML.

Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.

Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Real-world effectiveness of intensive chemotherapy with 7&3 versus venetoclax and hypomethylating agent in acute myeloid leukemia.

Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)-derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60-75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40-0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53-0.94). A sub-group of patients with equipoise, likelihood at least 30%-70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75-1.6). Regarding safety outcomes, 60-day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real-word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome.

Competition and co-association, but not phosphorous availability, shape the benefits of phosphate-solubilizing root bacteria for maize (Zea mays).

Predicting the conditions under which rhizobacteria benefit plant growth remains challenging. Here we tested the hypothesis that benefits from inoculation with phosphate-solubilizing rhizobacteria will depend upon two environmental conditions: phosphate availability and competition between bacteria. We used maize-associated rhizobacteria with varying phosphate solubilization ability in experiments in soil, sterilized soil and gnotobiotic microcosms under conditions of varying orthophosphate availability, while we manipulated the intensity of competition by varying the number of isolates in plant inocula. Growth promotion by microbes did not depend on phosphate availability but was affected by interactions between inoculants: the beneficial effects of one Serratia isolate were only detectable when plants were inoculated with a single strain and the beneficial effects of a competition-sensitive Rhizobium was only detectable in sterilized soil or in microcosms inoculated with single strains. Moreover, microcosm experiments suggested that facilitation of a parasitic isolate, not competitive interactions between bacteria, prevented plants from gaining benefits from a potential mutualist. Competition and facilitation affected colonization of plants in microcosms but growth promotion by Serratia was more affected by inoculation treatment than culturable densities on roots. Experimental manipulation of seed inocula can reveal whether plant growth stimulation is robust with respect to competition, as well as the ecological strategies of different rhizobacteria. From an applied perspective, phosphate solubilization may not provide the mechanism for bacterial growth promotion but may indicate mutualistic potential due to phylogenetic associations. Importantly, benefits to plants are vulnerable to interactions between rhizobacteria and may not persist in mixed inoculations.

Optimizing outcomes in secondary AML.

Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.

Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia.

After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to targeting mutations in isocitrate dehydrogenase, FMS-like tyrosine kinase 3 (FLT3), B-cell lymphoma 2 and hedgehog pathways. Yet outcomes remain variable; especially in defined molecular and genetic subgroups such as NPM1 (Nucleophosmin 1) mutations, 11q23/KMT2A rearranged and TP53 mutations. Emerging therapies seek to address these unmet needs, and all three of these subgroups have promising new therapeutic approaches. Here, we will discuss the normal biological roles of menin in acute leukemia, notably in KMT2A translocations and NPM1 mutation, as well as current drug development. We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall.

Real-world effectiveness of CPX-351 vs venetoclax and azacitidine in acute myeloid leukemia.

CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

Overexpression of UDP-glucuronosyltransferase and cytochrome P450 enzymes confers resistance to sulfoxaflor in field populations of the aphid, Myzus persicae.

The green peach aphid, Myzus persicae, is a highly damaging, globally distributed crop pest that has evolved multiple resistance to numerous insecticides. It is thus imperative that insecticides that are not strongly compromised by pre-existing resistance are carefully managed to maximise their effective life span. Sulfoxaflor is a sulfoximine insecticide that retains efficacy against M. persicae clones that exhibit resistance to older insecticides. In the current study we monitored the efficacy of sulfoxaflor against M. persicae populations collected in Western Australia, following reports of control failures in this region. We identified clones with low (4-23-fold across multiple independent bioassay experiments), but significant, levels of resistance to sulfoxaflor compared with a reference susceptible clone. Furthermore, we demonstrate that sulfoxaflor resistance can persist after many months of culturing in the laboratory in the absence of insecticide exposure. Resistance was not conferred by known mechanisms of resistance to neonicotinoid insecticides, that act on the same target-site as sulfoxaflor, i.e. the R81T mutation or overexpresssion of the P450 gene CYP6CY3. Rather, transcriptome profiling of multiple resistant and susceptible clones identified the P450 CYP380C40 and the UDP-glucuronosyltransferase UGT344P2 as highly overexpressed (21-76-fold and 6-33-fold respectively) in the resistant clones. Transgenic expression of these genes demonstrated that they confer, low, but significant, levels of resistance to sulfoxaflor in vivo. Taken together, our data reveal the presence of low-level resistance to sulfoxaflor in M. persicae populations in Australia and uncover two novel mechanisms conferring resistance to this compound. The findings and tools generated in this study provide a platform for the development of strategies that aim to slow, prevent or overcome the evolution of more potent resistance to sulfoxaflor.

Increased copy number couples the evolution of plasmid horizontal transmission and plasmid-encoded antibiotic resistance.

Conjugative plasmids are mobile elements that spread horizontally between bacterial hosts and often confer adaptive phenotypes, including antimicrobial resistance (AMR). Theory suggests that opportunities for horizontal transmission favor plasmids with higher transfer rates, whereas selection for plasmid carriage favors less-mobile plasmids. However, little is known about the mechanisms leading to variation in transmission rates in natural plasmids or the resultant effects on their bacterial host. We investigated the evolution of AMR plasmids confronted with different immigration rates of susceptible hosts. Plasmid RP4 did not evolve in response to the manipulations, but plasmid R1 rapidly evolved up to 1,000-fold increased transfer rates in the presence of susceptible hosts. Most evolved plasmids also conferred on their hosts the ability to grow at high concentrations of antibiotics. This was because plasmids evolved greater copy numbers as a function of mutations in the copA gene controlling plasmid replication, causing both higher transfer rates and AMR. Reciprocally, plasmids with increased conjugation rates also evolved when selecting for high levels of AMR, despite the absence of susceptible hosts. Such correlated selection between plasmid transfer and AMR could increase the spread of AMR within populations and communities.

Function is a better predictor of plant rhizosphere community membership than 16S phylogeny.

Rhizobacterial communities are important for plant health but we still have limited understanding of how they are constructed or how they can be manipulated. High-throughput 16S rRNA sequencing provides good information on taxonomic composition but remains an unreliable proxy for phenotypes. In this study, we tested the hypothesis that experimentally observed functional traits would be better predictors of community membership than phylogenetic origin. To test this hypothesis, we sampled communities on four plant species grown in two soil types and characterized 593 bacterial isolates in terms of antibiotic susceptibility, carbon metabolism, resource use and plant growth-promoting traits. In support of our hypothesis we found that three of the four plant species had phylogenetically diverse, but functionally constrained communities. Notably, communities did not grow best on complex media mimicking their host of origin but were distinguished by variation in overall growth characteristics (copiotrophy/oligotrophy) and antibiotic susceptibility. These data, combined with variation in phylogenetic structure, suggest that different classes of traits (antagonistic competition or resource-based) are more important in different communities. This culture-based approach supports and complements the findings of a previous high-throughput 16S rRNA analysis of this experiment and provides functional insights into the patterns observed with culture-independent methods.

Bleeding risk by intensity of anticoagulation in critically ill patients with COVID-19: A retrospective cohort study.

BACKGROUND: Studies report hypercoagulability in coronavirus disease 2019 (COVID-19), leading many institutions to escalate anticoagulation intensity for thrombosis prophylaxis. OBJECTIVE: To determine the bleeding risk with various intensities of anticoagulation in critically ill patients with COVID-19 compared with other respiratory viral illnesses (ORVI). PATIENTS/METHODS: This retrospective cohort study compared the incidence of major bleeding in patients admitted to an intensive care unit (ICU) within a single health system with COVID-19 versus ORVI. In the COVID-19 cohort, we assessed the effect of anticoagulation intensity received on ICU admission on bleeding risk. We performed a secondary analysis with anticoagulation intensity as a time-varying covariate to reflect dose changes after ICU admission. RESULTS: Four hundred and forty-three and 387 patients were included in the COVID-19 and ORVI cohorts, respectively. The hazard ratio of major bleeding for the COVID-19 cohort relative to the ORVI cohort was 1.26 (95% confidence interval [CI]: 0.86-1.86). In COVID-19 patients, an inverse-probability treatment weighted model found therapeutic-intensity anticoagulation on ICU admission had an adjusted hazard ratio of bleeding of 1.55 (95% CI: 0.88-2.73) compared with standard prophylactic-intensity anticoagulation. However, when anticoagulation was assessed as a time-varying covariate and adjusted for other risk factors for bleeding, the adjusted hazard ratio for bleeding on therapeutic-intensity anticoagulation compared with standard thromboprophylaxis was 2.59 (95% CI: 1.20-5.57). CONCLUSIONS: Critically ill patients with COVID-19 had a similar bleeding risk as ORVI patients. When accounting for changes in anticoagulation that occurred in COVID-19 patients, therapeutic-intensity anticoagulation was associated with a greater risk of major bleeding compared with standard thromboprophylaxis.

Mistaken Identity: Frequency and Effects of Gender-Based Professional Misidentification of Resident Physicians.

PURPOSE: Evaluation of the medical profession at all levels has exposed episodes of gender-based role misidentification whereby women physicians are disproportionately misidentified as nonphysicians. The authors of this study investigate this phenomenon and its repercussions, quantifying the frequency with which resident physicians experience role misidentification and the effect this has on their experience and behavior. METHOD: In 2018, the authors conducted a cross-sectional survey study of internal medicine, surgical, and emergency medicine residents at a single, large, urban, tertiary academic medical center. The survey tool captured both the self-reported frequency and effect of professional misidentification. The authors used a t test and linear multivariate regression to analyze the results. RESULTS: Of the 260 residents who received the survey, 186 (72%) responded, and the authors analyzed the responses of 182. All 85 of the women respondents (100%) reported being misidentified as nonphysicians at least once in their professional experience by patients or staff members, compared with 49% of the 97 men respondents. Of those 182 residents, 35% of women were misidentified more than 8 times per month by patients compared with 1% of men. Of the 85 women physicians responding to the survey, 38% felt angry and 36% felt less satisfied with their jobs as a result of misidentification compared with, respectively, 7% and 9% of men. In response to role misidentification, 51% of women changed their manner of attire and 81% changed their manner of introduction, compared with, respectively, 7% and 37% of men. CONCLUSIONS: These survey results demonstrate that women physicians are more likely than men physicians to be misidentified as nonphysicians and that role misidentification provokes gender-polarized psychological and behavioral responses that have potentially important professional ramifications.

Receiving Real-Time Clinical Feedback: A Workshop and OSTE Assessment for Medical Students.

BACKGROUND: Many programs designed to improve feedback to students focus on faculty's ability to provide a safe learning environment, and specific, actionable suggestions for improvement. Little attention has been paid to improving students' attitudes and skills in accepting and responding to feedback effectively. Effective "real-time" feedback in the clinical setting is dependent on both the skill of the teacher and the learner's ability to receive the feedback. Medical students entering their clinical clerkships are not formally trained in receiving feedback, despite the significant amount of feedback received during this time. METHODS: We developed and implemented a one-hour workshop to teach medical students strategies for effectively receiving and responding to "real-time" (formative) feedback in the clinical environment. Subjective confidence and skill in receiving real-time feedback were assessed in pre- and post-workshop surveys. Objective performance of receiving feedback was evaluated before and after the workshop using a simulated feedback encounter designed to re-create common clinical and cognitive pitfalls for medical students, called an objective structured teaching exercise (OSTE). RESULTS: After a single workshop, students self-reported increased confidence (mean 6.0 to 7.4 out of 10, P<0.01) and skill (mean 6.0 to 7.0 out of 10, P=0.10). Compared to pre-workshop OSTE scores, post-workshop OSTE scores objectively measuring skill in receiving feedback were also significantly higher (mean 28.8 to 34.5 out of 40, P=0.0131). CONCLUSION: A one-hour workshop dedicated to strategies in receiving real-time feedback may improve effective feedback reception as well as self-perceived skill and confidence in receiving feedback. Providing strategies to trainees to improve their ability to effectively receive feedback may be a high-yield approach to both strengthen the power of feedback in the clinical environment and enrich the clinical experience of the medical student.

COVID-19: The need for an Australian economic pandemic response plan.

OBJECTIVES: Pandemics pressure national governments to respond swiftly. Mitigation efforts created an imbalance between population health, capacity of the healthcare system and economic prosperity. Each pandemic arising from a new virus is unknown territory for policy makers, and there is considerable uncertainty of the appropriateness of responses and outcomes. METHODS: A qualitative approach was used to review mixed sources of data including Australian reports, official government publications, and COVID-19 data to discern robust future responses. Publicly available epidemiological and economic data were utilised to provide insight into the impact of the pandemic on Australia's healthcare system and economy. RESULTS: Policies implemented by the Australian Government to mitigate the spread of COVID-19 impacted the healthcare sector and economy. This paper incorporates lessons learned to inform optimal economic preparedness. The rationale for an economic response plan concomitant with the health pandemic plan is explored to guide Australian Government policy makers in ensuring holistic and robust solutions for future pandemics. CONCLUSIONS: In future, an Australian Economic Pandemic Response Plan will aid in health and economic system preparedness, whilst a strong Australian economy and strategic planning will ensure resilience to future pandemics.

Strong Environment-Genotype Interactions Determine the Fitness Costs of Antibiotic Resistance In Vitro and in an Insect Model of Infection.

The acquisition of antibiotic resistance commonly imposes fitness costs, a reduction in the fitness of bacteria in the absence of drugs. These costs have been quantified primarily using in vitro experiments and a small number of in vivo studies in mice, and it is commonly assumed that these diverse methods are consistent. Here, we used an insect model of infection to compare the fitness costs of antibiotic resistance in vivo to those in vitro Experiments explored diverse mechanisms of resistance in a Gram-positive pathogen, Bacillus thuringiensis, and a Gram-negative intestinal symbiont, Enterobacter cloacae Rifampin resistance in B. thuringiensis showed fitness costs that were typically elevated in vivo, although these were modulated by genotype-environment interactions. In contrast, resistance to cefotaxime via derepression of AmpC ß-lactamase in E. cloacae resulted in no detectable costs in vivo or in vitro, while spontaneous resistance to nalidixic acid, and carriage of the IncP plasmid RP4, imposed costs that increased in vivo Overall, fitness costs in vitro were a poor predictor of fitness costs in vivo because of strong genotype-environment interactions throughout this study. Insect infections provide a cheap and accessible means of assessing the fitness consequences of resistance mutations, data that are important for understanding the evolution and spread of resistance. This study emphasizes that the fitness costs imposed by particular mutations or different modes of resistance are extremely variable and that only a subset of these mutations is likely to be prevalent outside the laboratory.

Accuracy checking of dispensed medications by a pharmacy technician: a hospital case study.

Medication order accuracy checking is an integral and time-consuming component of the current Australian pharmacist's role. However, the pharmacy profession internationally has moved towards separating the checking task into two parts: a clinical check performed by the registered pharmacist and a technical accuracy check delegated to an appropriately trained pharmacy technician. This case study demonstrates that in an Australian hospital pharmacy context, appropriately trained pharmacy technicians have the potential to be more proficient and time efficient than pharmacists when undertaking accuracy checking of dispensed medications.