bluuebunny/crossref_metadata_2025 huggingface dataset:
Frontline treatment options for higher-risk MDS: can we move past azacitidine?
Authors: Sallman David A. , Xie Zhuoer
Published: December 2023

Although remarkable international efforts have been ongoing for over 17 years to improve upon azacitidine, representing the standard of care therapy for higher-risk myelodysplastic neoplasms (MDS), there still has not been a positive randomized trial in comparison to azacitidine. Real-world data from numerous trials have shown similar results with a median overall survival of 14-18 months, a 40%-50% overall response rate, and a complete remission rate close to 20%. Despite these outcomes, 6 randomized controlled trials have failed to improve outcomes in this patient population, although relevant issues in some of these studies included improper dose adjustments of the hypomethylating agent, lack of placebo- controlled studies, and lack of overall survival (OS) as a primary endpoint, among others. Critical updates in MDS management include the development of molecular prognostication models (eg, the molecular international prognostic scoring system), updates in classification systems highlighting significant overlap in patients with MDS-increased blasts and acute myeloid leukemia (most relevant to TP53 mutations), and refinement of response criteria. Although these paradigm-shifting studies have had great impact in MDS management, the current ongoing randomized phase 3 trials were initiated prior, and prognostic stratification remains via the revised international prognostic scoring system) and with bone marrow blast counts of <20%. Notably, azacitidine + venetoclax, azacitidine + sabatolimab, and azacitidine + magrolimab have shown exciting results in large, single-arm studies and have completed accrual in placebo-controlled, double-blind studies with OS as a primary endpoint. We all eagerly await the results of these studies.
Novel approaches to acute graft-versus-host disease prevention
Authors: Watkins Benjamin , Qayed Muna
Published: December 2023

The field of graft-versus-host disease (GvHD) has experienced significant growth, with increased number of clinical trials and the approval of several agents by the US Food and Drug Administration for both acute and chronic GvHD treatment. In addition, the development of prognostic biomarker algorithms has enabled risk stratification in acute GvHD. However, prevention remains the cornerstone of GvHD management. Notable recent changes include the expansion of donor options with the increased use of haploidentical donor and unrelated donor transplantation, the development of ex vivo selective T-cell depletion strategies, recent approval by the Food and Drug Administration of abatacept for GvHD prevention, and the application of posttransplant cyclophosphamide in matched and mismatched donor settings. In this article, we review the results of recent clinical trials in GvHD prophylaxis and discuss the changes in clinical practice and promising emerging strategies driving the field forward.
Acute leukemias and complicated lymphomas: pearls to optimize management when patients stay local
Authors: Patel-Donnelly Dipti , Gandhi Mitul
Published: December 2023

Hematologic malignancies often present acutely with a constellation of infectious complications, pancytopenia, tumor lysis, and renal dysfunction. Acute leukemias and aggressive lymphomas often require hospitalization for rapid diagnostic evaluation, urgent management of complicating presentations, and timely management of intensive systemic therapies. There is an emerging paradigm whereby complex cancer care can be safely and effectively provided in the community, where the majority of cancer is treated. A substantive and effective network between local oncologists and their academic counterparts will enhance care for the patient, advance research, and help bring complicated therapies to local centers, thereby improving access. Here we present several cases that highlight a collaborative approach to complicated hematologic malignancies in the community.
Selection of bispecific antibody therapies or CAR-T cell therapy in relapsed lymphomas
Authors: Major Ajay , Kamdar Manali
Published: December 2023

Patients with relapsed and refractory (R/R) aggressive B-cell non-Hodgkin lymphomas have historically poor survival outcomes, with chimeric antigen receptor T-cell (CAR-T) therapy now presenting a curative option for a subset of those patients. However, with the approval of several novel bispecific monoclonal antibody (BsAb) therapies with considerable activity in R/R aggressive large B-cell lymphomas (LBCL), patients and oncologists will be faced with decisions regarding how to sequence CAR-T and BsAb therapies based on patient- and disease-related factors. In this review, we compare CAR-T and BsAb therapies for R/R LBCL, highlighting data on the efficacy and toxicity of each treatment paradigm, and provide a roadmap for sequencing these highly effective therapies.
Considerations for next therapy after anti-CD38 monoclonal antibodies used as first line
Authors: Hartley-Brown Monique , Zinkeng Ateh
Published: December 2023

In the current treatment paradigm, the use of anti-CD38 monoclonal antibodies (mAbs) in frontline has notably increased, for both transplant-ineligible and transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) patients. As a result, patients with multiple myeloma (MM) are frequently exposed to or develop resistance to anti-CD38 mAb therapy during the initial stages of treatment. Here, we review second-line (first relapse) and some third-line (second relapse) therapies for patients with MM with disease progression after exposure to anti-CD38 mAb-based therapy. We discuss therapies including B-cell maturation antigen (BCMA)–targeted and non-BCMA-targeted therapeutic options in the setting of prior anti-CD38 mAb exposure/refractoriness.
Accelerated-phase CML: de novo and transformed
Authors: Shanmuganathan Naranie , Hughes Timothy P.
Published: December 2023

Despite the dramatic improvements in outcomes for the majority of chronic myeloid leukemia (CML) patients over the past 2 decades, a similar improvement has not been observed in the more advanced stages of the disease. Blast phase CML (BP-CML), although infrequent, remains poorly understood and inadequately treated. Consequently, the key initial goal of therapy in a newly diagnosed patient with chronic phase CML continues to be prevention of disease progression. Advances in genomic investigation in CML, specifically related to BP-CML, clearly demonstrate we have only scratched the surface in our understanding of the disease biology, a prerequisite to devising more targeted and effective therapeutic approaches to prevention and treatment. Importantly, the introduction of the concept of “CML-like” acute lymphoblastic leukemia (ALL) has the potential to simplify the differentiation between BCR::ABL1-positive ALL from de novo lymphoid BP-CML, optimizing monitoring and therapeutics. The development of novel treatment strategies such as the MATCHPOINT approach for BP-CML, utilizing combination chemotherapy with fludarabine, cytarabine, and idarubicin in addition to dose-modified ponatinib, may also be an important step in improving treatment outcomes. However, identifying patients who are high risk of transformation remains a challenge, and the recent 2022 updates to the international guidelines may add further confusion to this area. Further work is required to clarify the identification and treatment strategy for the patients who require a more aggressive approach than standard chronic phase CML management.
Resistance mutations in CML and how we approach them
Authors: Soverini Simona
Published: December 2023

Among the variety of resistance mechanisms that may underlie a non-optimal response to tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia patients, secondary point mutations in the BCR::ABL1 kinase domain (KD) represent the only actionable one. Each of the 5 ATP-competitive inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) has a well-defined spectrum of resistance mutations. Growing clinical experience will soon allow to also elucidate the full spectrum of mutations conferring resistance to asciminib (that appear not to be confined to the myristate binding pocket). Regular molecular response (MR) monitoring is fundamental for evaluating treatment efficacy, catching early signs of relapse, and intervening promptly in case of confirmed failure. Whenever MR is not deemed satisfactory according to the European LeukemiaNet or the National Comprehensive Cancer Network definitions, BCR::ABL1 KD mutations testing should be performed. When needed, prompt and informed TKI switch can improve response and outcome and prevent the accumulation of mutations, including highly challenging compound mutations. Novel technologies like next-generation sequencing and digital polymerase chain reaction have recently been explored for BCR::ABL1 KD mutation testing; they have both advantages and disadvantages that are discussed in this article. This review also provides suggestions for interpretation and clinical translation of mutation testing results, which may not always be straightforward, particularly in cases of low-level or unknown mutations.
Evolving landscape of JAK inhibition in myelofibrosis: monotherapy and combinations
Authors: Gill Harinder , Leung Garret M. K. , Kwong Yok-Lam
Published: December 2023

Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post–polycythemia vera MF, and post–essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor–based combinations.
Are transplant indications changing for myelofibrosis?
Authors: Palmer Jeanne
Published: December 2023

Myelofibrosis is a devastating myeloid malignancy characterized by dysregulation of the JAK-STAT pathway, resulting in splenomegaly, constitutional symptoms, anemia, thrombocytopenia, leukocytosis, and an increased likelihood of progression to acute leukemia. The only curative option is allogeneic stem cell transplantation. The numbers of transplants have been increasing every year, and although there have been improvements in survival, there remain many unanswered questions. In this review, we will evaluate patient selection and appropriate timing for transplantation. We will cover the current prognostic scoring systems, which can aid in the decision of when to move forward with transplant. We will also review the different donor options, as well as the conditioning regimens. The peritransplant management of splenomegaly will be reviewed. We will discuss management of posttransplant complications such as loss of donor chimerism or disease relapse. Finally, we will review what is known about the outlook of patients who have undergone allogeneic stem cell transplant with regards to quality of life and long-term survival.
Understanding differential technologies for detection of MRD and how to incorporate into clinical practice
Authors: Cloos Jacqueline , Ngai Lok Lam , Heuser Michael
Published: December 2023

Patient- and leukemia-specific factors assessed at diagnosis classify patients with acute myeloid leukemia (AML) in risk categories that are prognostic for outcome. The induction phase with intensive chemotherapy in fit patients aims to reach a complete remission (CR) of less than 5% blasts in bone marrow by morphology. To deepen and sustain the response, induction is followed by consolidation treatment. This postremission treatment of patients with AML is graduated in intensity based on this favorable, intermediate, or adverse risk group classification as defined in the European Leukemia Network (ELN) 2022 recommendations. The increment of evidence that measurable residual disease (MRD) after induction can be superimposed on risk group at diagnosis is instrumental in tailoring further treatment accordingly. Several techniques are applied to detect MRD such as multiparameter flow cytometry (MFC), quantitative (digital) polymerase chain reaction (PCR), and next-generation sequencing. The clinical implementation of MRD and the technique used differ among institutes, leading to the accumulation of a wide range of data, and therefore harmonization is warranted. Currently, evidence for MRD guidance is limited to the time point after induction using MFC or quantitative PCR for NPM1 and core binding factor abnormalities in intermediate-risk patients. The role of MRD in targeted or nonintensive therapies needs to be clarified, although some data show improved survival in patients achieving CR-MRD negativity. Potential application of MRD for selection of conditioning before stem cell transplantation, monitoring after consolidation, and use as an intermediate end point in clinical trials need further evaluation.
Diagnosis and laboratory monitoring of acquired hemophilia A
Authors: Platton Sean , Sivapalaratnam Suthesh , Raheja Priyanka
Published: December 2023

Acquired hemophilia A (AHA) is a rare disorder in which autoantibodies against factor VIII (FVIII) lead to a bleeding phenotype that varies from life-threatening to no bleeding at all. Prolonged activated partial thromboplastin times (APTT) in patients with a bleeding phenotype should be investigated to rule out AHA and should never be ignored in a preprocedure patient. Most inhibitors in AHA are heat and time dependent, so mixing studies performed only on an immediate mix are not useful: both lupus anticoagulants and treatment with direct oral anticoagulants can coexist with AHA and confound the diagnosis. Assays for intrinsic coagulation factors and von Willebrand factor should always be performed, regardless of the results of mixing studies. A Bethesda or modified Bethesda assay should be performed to quantify any inhibitor, and if susoctocog alfa (rpFVIII) is available, then an assay for cross-reacting antibodies should also be performed. At diagnosis and until complete remission, if the FVIII in the patient sample is >5 IU/dL, heat inactivation should be performed before the inhibitor assays are performed. While there are no conventional tests available to measure the effects of FVIII bypassing therapies, newer therapies may require monitoring, or their effects may need to be considered when choosing appropriate assays. Measurement of rpFVIII requires a 1-stage clotting assay, and measurement of patient FVIII while on emicizumab requires a chromogenic assay that does not contain human FX. Close communication is required between the treating clinicians and the laboratory to ensure that the correct tests are performed while patients are receiving treatments.
Clonal evolution in inherited marrow failure syndromes predicts disease progression
Authors: Schratz Kristen E.
Published: December 2023

Progression to myelodysplastic syndromes (MDS) and acute myeloid leukemia is one of the most serious complications of the inherited bone marrow failure and MDS-predisposition syndromes. Given the lack of predictive markers, this risk can also be a source of great uncertainty and anxiety to patients and their providers alike. Recent data show that some acquired mutations may provide a window into this risk. While maladaptive mechanisms, such as monosomy 7, are associated with a high risk of leukemogenesis, mutations that offset the inherited defect (known as somatic genetic rescue) may attenuate this risk. Somatic mutations that are shared with age-acquired clonal hematopoiesis mutations also show syndrome-specific patterns that may provide additional data as to disease risk. This review focuses on recent progress in this area with an emphasis on the biological underpinnings and interpretation of these patterns for patient care decisions.
Management of pregnant women who have bleeding disorders
Authors: James Andra H. , Pacheco Luis D. , Konkle Barbara A.
Published: December 2023

Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta. Bleeding occurs during pregnancy when there is an interruption of the normal utero-placental interface, during miscarriage, during an ectopic pregnancy, or at the time of placental separation at the conclusion of pregnancy. Although mild platelet defects may be more prevalent, the most commonly diagnosed bleeding disorder among women is VWD. Other bleeding disorders are less common, but hemophilia carriers are unique in that they are at risk of bleeding themselves and of giving birth to an affected male infant. General guidance for maternal management of a woman who is moderately or severely affected includes obtaining coagulation factor levels at a minimum in the third trimester; planning for delivery at a center with hemostasis expertise; and anticipating the need for hemostatic agents. General guidance for fetal management includes pre-pregnancy counseling; the option of preimplantation genetic testing for hemophilia; delivery at a tertiary care center with pediatric hematology and newborn intensive care; consideration of cesarean delivery of a potentially severely affected infant; and avoidance of invasive procedures such as scalp electrodes and operative vaginal delivery in any potentially affected infant.
Prevention, diagnosis, and management of PE and DVT in pregnant women
Authors: Kevane Barry , Áinle Fionnuala Ní
Published: December 2023

Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality worldwide. Despite the impact of VTE on pregnant and postpartum people and on society, guidelines addressing prevention, diagnosis, and management of VTE in pregnant and postpartum people frequently are based on recommendations from expert opinion and are extrapolated from data in nonpregnant populations. Pregnant individuals are frequently excluded from clinical trials, which is a barrier to providing safe, effective care. Anchoring to a case discussion, this review provides an update on recently published and ongoing randomized clinical trials (RCTs), prospective clinical management studies, and other research in this area. It highlights, in particular, the results of the Highlow RCT, which addresses optimal prevention of recurrence during pregnancy in people with prior VTE. Finally, we raise awareness of the impact of national and international clinical trial networks on the conduct of RCTs in pregnancy. We conclude, based on these data, that academic VTE clinical trials in pregnant women can and must be done.
MSM and blood donation: shifting to individualized risk assessment
Authors: Goldman Mindy
Published: December 2023

Deferring donors at higher risk for transfusion transmissible infections is an important part of ensuring blood safety. The deferral for gay, bisexual, and other men who have sex with men (gbMSM) was implemented in the 1980s in many countries, since they were identified as a high-risk group for AIDS/HIV. With the introduction of increasingly sensitive HIV antibody testing, augmented by nucleic acid testing, the window period for HIV infection—when a donor may be infectious but have negative test results—has shrunk dramatically. In Canada, this has led to progressively shorter deferral periods for gbMSM, decreasing from a permanent deferral for sex with another male since 1977 to a 5-year, 12-month, and eventually 3-month deferral period. These time-based deferrals maintained safety; however, they are seen as stigmatizing by many and still result in the deferral of sexually active gbMSM. More recently, several countries have moved to a donor screening approach based on assessing sexual risk behaviors in all donors. This article outlines research supporting changes in policy, current eligibility screening policies in several countries, and preliminary results postimplementation of new eligibility policies in Canada in September 2022.
IV iron formulations and use in adults
Authors: Van Doren Layla , Auerbach Michael
Published: December 2023

Intravenous iron has become a major component of the therapeutic armamentarium for iron deficiency and iron deficiency anemia. The earliest formulations were associated with unacceptable toxicity. Newer formulations, with complex carbohydrate cores that bind elemental iron more tightly, allow the administration of full therapeutic doses in 15 to 60 minutes. Nonetheless, a folklore of danger, fueled by earlier formulations no longer available, continues to foment caution. Complement-mediated minor infusion reactions, referred to as complement activation-related pseudo-allergy, resolve without therapy. Inappropriate intervention with vasopressors and H1 blockers converts these minor reactions into hemodynamically significant adverse events. Four new formulations, low-molecular-weight iron dextran, ferumoxytol, ferric carboxymaltose, and ferric derisomaltose, all approved for the treatment of iron deficiency in a host of conditions, are now widely used with an excellent safety profile. Herein, the administration, safety, indications, and management of infusion reactions are discussed. Treatment-emergent hypophosphatemia, a newly recognized side effect for some formulations, is also reviewed. Based on the preponderance of published evidence, intravenous iron should be moved up-front for the treatment of iron deficiency and iron deficiency anemia in those conditions in which oral iron is suboptimal.
Medical consult: aHUS, TTP? How to distinguish and what to do
Authors: Story Charlotte M. , Gerber Gloria F , Chaturvedi Shruti
Published: December 2023

Immune thrombotic thrombocytopenic purpura (iTTP) caused by an autoantibody-mediated deficiency of ADAMTS13 and atypical hemolytic syndrome (aHUS) caused by alternative complement dysregulation are the most common primary thrombotic microangiopathies (TMAs). The evaluation of a patient with TMA is a medical emergency since it is critical to quickly distinguish iTTP and aHUS from other causes of TMA. Untreated iTTP is rapidly fatal, and delays in initiating complement inhibition in aHUS increase the risk of irreversible renal failure. An ADAMTS13 activity level of less than 10% is diagnostic of iTTP in the appropriate clinical setting. In settings where rapid-turnaround ADAMTS13 testing is not available, clinical features and clinical prediction tools are useful to identify patients who should receive emergent plasma exchange. We present an evidence-based approach to the initial (first 24 hours) diagnosis and management of iTTP and review the clinical and laboratory features that can be used to identify patients with aHUS who will benefit from early C5 blockade. We also discuss the potential use of complement blockade to improve outcomes in selected patients with secondary TMA.
Improving long-term outcomes with intensive induction chemotherapy for patients with AML
Authors: Röllig Christoph
Published: December 2023

Intensive chemotherapy in combination with allogeneic hematopoietic cell transplantation and supportive care can induce long-term remissions in around 50% of acute myeloid leukemia patients eligible for intensive treatment. Several treatment optimization trials helped to refine schedule and dosing of the historic “7 + 3” combination. Together with the addition of novel agents, increased efficacy and tolerability led to improved long-term outcomes. Unsatisfactory outcomes in fit elderly patients and unfavorable genetic subgroups have raised the question of whether less-intensive venetoclax-based approaches may be beneficial as an alternative. Although tempting and worth exploring, this issue will remain controversial until the results of randomized comparisons appear. To date, intensive chemotherapy remains the only evident curative treatment option for long-term disease eradication in a fixed treatment time. With the advent of more novel agents and advances in minimal residual disease (MRD) detection and maintenance approaches, the face of intensive treatment could change in many ways. Several are being explored in clinical trials, such as (1) combinations of more than 1 novel agent with the intensive backbone, (2) head-to-head comparisons of novel agents, (3) replacement or dose reduction of cytotoxic components such as anthracyclines, and (4) MRD-guided escalation and de-escalation strategies. The combination of intensive treatment with individualized tailored innovative strategies will most certainly reduce treatment-related toxicities and increase the chances for long-term remission in the future.
Acute lymphoblastic leukemia in young adults: which up-front treatment?
Authors: Molina John C. , Rotz Seth
Published: December 2023

Significant improvements have occurred for adolescent and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients following the widespread adoption of “pediatric-inspired” treatment regimens for AYA patients cared for in adult oncology settings. However, for AYA patients, aged 15 to 39, an outcomes gap remains in B-ALL, necessitating the incorporation of novel therapies into up-front treatment regimens. As a result, clinical trial enrollment remains the current standard of care for AYA B-ALL across disease subtypes when available and accessible. Currently, several up-front trials are looking to incorporate the use of inotuzumab, blinatumomab, and chimeric antigen receptor T-cell therapy into existing chemotherapy backbones for AYA patients, as well as tyrosine kinase inhibitors for both Philadelphia-positive (Ph+) and Ph-like B-ALL. In addition to ongoing attempts to improve up-front treatments by incorporating immunotherapy and targeted approaches, the increased use of next generation sequencing for measurable residual disease evaluation has led to superior risk-stratification and a decreased need to pursue consolidative hematopoietic stem cell transplantation during the first complete remission for many patients.
Checkpoint inhibitors
Authors: Kroll Michael H.
Published: December 2023

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. These medications commonly cause immune-related adverse effects due to activated adaptive and innate immune cells, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses. Management is challenging because one must attend to the hematologic toxicity while simultaneously attending to the malignancy, with the imperative that therapeutic effects be maintained or minimally interrupted when possible.
Compromised trigemino-coerulean coupling in migraine sensitization can be prevented by blocking beta-receptors in the locus coeruleus
Authors: Signoret-Genest Jérémy , Barnet Maxime , Gabrielli François , Aissouni Youssef , Artola Alain , Dallel Radhouane , Antri Myriam , Tovote Philip , Monconduit Lénaïc
Published: December 2023

Background

Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors.

Methods

We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol.

Results

We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions’ interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity.

Conclusions

Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol’s prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.
Phenotypic and genotypic characterization of colistin-resistant Escherichia Coli with mcr-4, mcr-5, mcr-6, and mcr-9 genes from broiler chicken and farm environment
Authors: Lemlem Mulu , Aklilu Erkihun , Mohamed Maizan , Kamaruzzaman Nor Fadhilah , Zakaria Zunita , Harun Azian , Devan Susmita Seenu , Kamaruzaman Intan Noor Aina , Reduan Mohd Farhan Hanif , Saravanan Muthupandian
Published: December 2023

Background

Colistin is an antibiotic used as a last-resort to treat multidrug-resistant Gram-negative bacterial infections. Colistin had been used for a long time in veterinary medicine for disease control and as a growth promoter in food-producing animals. This excessive use of colistin in food animals causes an increase in colistin resistance. This study aimed to determine molecular characteristics of colistin-resistantEscherichia coliin broiler chicken and chicken farm environments.

Results

Four hundred fifty-three cloacal and farm environment samples were collected from six different commercial chicken farms in Kelantan, Malaysia.E. coliwas isolated using standard bacteriological methods, and the isolates were tested for antimicrobial susceptibility using disc diffusion and colistin minimum inhibitory concentration (MIC) by broth microdilution. Multiplex PCR was used to detectmcrgenes, and DNA sequencing was used to confirm the resistance genes. Virulence gene detection, phylogroup, and multilocus sequence typing (MLST) were done to further characterize theE. coliisolates. Out of the 425 (94%; 425/453)E. coliisolated from the chicken and farm environment samples, 10.8% (48/425) isolates were carrying one or more colistin-resistance encoding genes. Of the 48 colistin-resistant isolates, 54.2% (26/48) of themcrpositive isolates were genotypically and phenotypically resistant to colistin with MIC of colistin ≥ 4 μg/ml. The most prominentmcrgene detected wasmcr-1(47.9%; 23/48), followed bymcr-8(18.8%; 9/48), mcr-7 (14.5%; 7/48),mcr-6(12.5%; 6/48),mcr-4(2.1%; 1/48),mcr-5(2.1%; 1/48), andmcr-9(2.1%; 1/48) genes. OneE. coliisolate originating from the fecal sample was found to harbor bothmcr-4andmcr-6genes and another isolate from the drinking water sample was carryingmcr-1andmcr-8genes. The majority of themcrpositive isolates were categorized under phylogroup A followed by phylogroup B1. The most prevalent sequence typing (ST) was ST1771 (n = 4) followed by ST206 (n = 3). 100% of themcrpositiveE. coliisolates were multidrug resistant. The most frequently detected virulence genes amongmcrpositiveE. coliisolates were ast (38%; 18/48) followed byiss(23%; 11/48). This is the first research to report the prevalence ofmcr-4, mcr-5, mcr-6, mcr-7,andmcr-8genes inE. colifrom broiler chickens and farm environments in Malaysia.

Conclusion

Our findings suggest that broiler chickens and broiler farm environments could be reservoirs of colistin-resistantE. coli, posing a risk to public health and food safety.
Symptomatic intracranial hemorrhage mediates the association between eosinophils and 90-day outcomes after mechanical thrombectomy for acute ischemic stroke
Authors: Yu Shuhong , Wang Xiaocui , Huang Hao , Luo Yi , Guo Zhiliang
Published: December 2023

Background

Decreased eosinophil level is associated with poor outcomes after mechanical thrombectomy in patients with acute ischemic stroke (AIS), but the underlying mechanism of this association is elusive. We aimed to assess the mediation effect of symptomatic intracranial hemorrhage (sICH) on the aforementioned association.

Methods

A total of 328 consecutive AIS patients undergoing mechanical thrombectomy between May 2017 and March 2021 were analyzed. SICH was defined as any evidence of brain hemorrhage on CT scan with neurological deterioration. Regression analysis was used to assess the effect of eosinophils on sICH, and its effect on poor outcome. Mediation analysis was performed to assess the proportion of total effect by sICH on the association between eosinophils and poor outcome.

Results

Multivariate analysis revealed an independent association between eosinophil count and sICH after adjusting for potential confounders (odds ratio, 0.00; 95% CI, 0.00–0.01; P = 0.0141), which is consistent with the result of eosinophil count (dichotomous) as a categorical variable (odds ratio, 0.22; 95% CI, 0.11–0.46; P < 0.0001). Eosinophil count was negatively associated with poor outcome (odds ratio, 0.00; 95% CI, 0.00–0.02; P = 0.0021). Mediation analysis revealed that sICH partially mediated the negative relationship between eosinophil count and poor outcome (indirect effect=-0.1896; 95%CI: -0.3654 – -0.03, P < 0.001).

Conclusion

This study showed an important effect of sICH on the association between eosinophils and poor outcome.
Genome-wide expansion and reorganization during grass evolution: from 30 Mb chromosomes in rice and Brachypodium to 550 Mb in Avena
Authors: Liu Qing , Ye Lyuhan , Li Mingzhi , Wang Ziwei , Xiong Gui , Ye Yushi , Tu Tieyao , Schwarzacher Trude , Heslop-Harrison John Seymour
Published: December 2023

Background

The BOP (Bambusoideae, Oryzoideae, and Pooideae) clade of the Poaceae has a common ancestor, with similarities to the genomes of rice, Oryza sativa (2n = 24; genome size 389 Mb) and Brachypodium, Brachypodium distachyon (2n = 10; 271 Mb). We exploit chromosome-scale genome assemblies to show the nature of genomic expansion, structural variation, and chromosomal rearrangements from rice and Brachypodium, to diploids in the tribe Aveneae (e.g., Avena longiglumis, 2n = 2x = 14; 3,961 Mb assembled to 3,850 Mb in chromosomes).

Results

Most of the Avena chromosome arms show relatively uniform expansion over the 10-fold to 15-fold genome-size increase. Apart from non-coding sequence diversification and accumulation around the centromeres, blocks of genes are not interspersed with blocks of repeats, even in subterminal regions. As in the tribe Triticeae, blocks of conserved synteny are seen between the analyzed species with chromosome fusion, fission, and nesting (insertion) events showing deep evolutionary conservation of chromosome structure during genomic expansion. Unexpectedly, the terminal gene-rich chromosomal segments (representing about 50 Mb) show translocations between chromosomes during speciation, with homogenization of genome-specific repetitive elements within the tribe Aveneae. Newly-formed intergenomic translocations of similar extent are found in the hexaploid A. sativa.

Conclusions

The study provides insight into evolutionary mechanisms and speciation in the BOP clade, which is valuable for measurement of biodiversity, development of a clade-wide pangenome, and exploitation of genomic diversity through breeding programs in Poaceae.
Genome-wide analysis of the SCAMPs gene family of soybean and functional identification of GmSCAMP5 in salt tolerance
Authors: Wang Min , He Chuanrong , Shi Guangcheng , Yin Qiukai , Zhang Hanyue , Yang Wanmin , Yue Aiqin , Wang Lixiang , Du Weijun
Published: December 2023

The effect of salt damage on plants is mainly caused by the toxic effect of Na+. Studies showed that the secretory carrier membrane proteins were associated with the Na+ transport. However, the salt tolerance mechanism of secretory carrier protein (SCAMP) in soybean was yet to be defined. In this study, ten potential SCAMP genes distributed in seven soybean chromosomes were identified in the soybean genome. The phylogenetic tree of SCAMP domain sequences of several plants can divide SCAMPs into two groups. Most GmSCAMPs genes contained multiple Box4, MYB and MYC cis-elements indicated they may respond to abiotic stresses. We found that GmSCAMP1, GmSCAMP2 and GmSCAMP4 expressed in several tissues and GmSCAMP5 was significantly induced by salt stress. GmSCAMP5 showed the same expression patterns under NaCl treatment in salt-tolerant and salt-sensitive soybean varieties, but the induced time of GmSCAMP5 in salt-tolerant variety was earlier than that of salt-sensitive variety. To further study the effect of GmSCAMP5 on the salt tolerance of soybean plants, compared to GmSCAMP5-RNAi and EV-Control plants, GmSCAMP5-OE had less wilted leave and higher SPAD value. Compared to empty vector control, less trypan blue staining was observed in GmSCAMP5-OE leaves while more staining in GmSCAMP5-RNAi leaves. The Na+ of GmSCAMP5-RNAi plants leaves under NaCl stress were significantly higher than that in EV-Control plants, while significantly lower Na+ in GmSCAMP5-OE plants than in that EV-Control plants. The contents of leaves K+ of GmSCAMP5-RNAi, EV-Control, and GmSCAMP5-OE plants under NaCl stress were opposite to that of leaves Na+ content. Finally, salt stress-related genes NHX1, CLC1, TIP1, SOD1, and SOS1 in transformed hairy root changed significantly compared with the empty control. The research will provide novel information for study the molecular regulation mechanism of soybean salt tolerance.
How should preoperative examinations be chosen for infants with a ventricular septal defect: transthoracic echocardiography, cardiac CTA, or a combination of these two technologies?
Authors: Lin Wei-Hua , Luo Fu-Rong , Cai Yi-Yong , Xiao Hui-Jun , Huang Qing-Wen
Published: December 2023

Objective

To evaluate the accuracy of transthoracic echocardiography (TTE) and cardiac computed tomography angiography (CTA) in detecting the size and location of ventricular septal defects (VSD) in infants.

Methods

Data from 258 infants diagnosed with VSD between January 2020 and December 2022 were retrospectively analyzed. All infants underwent both TTE and cardiac CTA. The accuracy of these imaging modalities was assessed by comparing their findings with intraoperative observations of VSD size and location.

Results

Intraoperatively, the average VSD size was 6.1 ± 2.5 mm. The defects were classified as committed VSD (Type 1) in 45 patients, noncommitted VSD (Type 2) in 198 patients, inlet VSD (Type 3) in 12 patients, and muscular VSD (Type 4) in 3 patients. Echocardiography estimated the average VSD size at 5.6 ± 2.7 mm, with 42 patients identified as Type 1, 203 as Type 2, 10 as Type 3, and 3 as Type 4. Cardiac CTA estimated the average size at 5.9 ± 3.2 mm, with 48 patients identified as Type 1, 196 as Type 2, 11 as Type 3, and 3 as Type 4. The accuracy rates of TTE and cardiac CTA in diagnosing VSD location were 98.1% and 98.8%, respectively. A survey of surgeons indicated that 80% believe both TTE and cardiac CTA are essential preoperative evaluations.

Conclusions

TTE accurately diagnoses the size and location of VSD, while cardiac CTA serves as a valuable complementary method to TTE. Most surgeons advocate for the combined use of these examinations for preoperative assessment.
What are the correlates of intention to be physically active in Brazilian adolescents? A network analysis
Authors: Lima Cayo Vinnycius Pereira , Ywgne José , Thuany Mabliny , Araujo Raphael H. O. , Silva Ellen C. M. , Melo João C. N. , Bandeira Paulo Felipe R , Luz Leonardo G. O. , Silva Danilo R.
Published: December 2023

Objective

The current study aimed to explore the association of individual characteristics, social and environmental factors - school and region - in the intention to be physically active in Brazilian adolescents.

Methods

This is a cross sectional study based on the third edition of the National School Health Survey. The study included a total of 53,937 adolescents. To assess the intention to be physically active, only who engaged in less than 300 min of physical activity per week were included. Participants were asked: “If you had the opportunity to practice physical activity most days of the week, what would your attitude be?” Individual characteristics, physical activity domains, social factors, school, and regional environments were used as exposures. Network analysis was utilized to evaluate the associations.

Results

We observed that boys had higher intentions to be physically active compared to their peers, as did adolescents who perceived themselves as fat. In addition, students from private schools show a higher intention to regularly engage in physical activities, and in general, private schools offer more extracurricular physical activities.

Conclusion

In conclusion, individual factors such as sex and body image perception, and environmental factors such as school administrative dependency and availability of extracurricular activities had a significant contribution to the intention to be physically active among Brazilian adolescents.
The safety and efficacy of tislelizumab, alone or in combination with chemotherapy, for the treatment of non-small cell lung cancer: a systematic review of clinical trials
Authors: Daei Sorkhabi Amin , ZareDini Mahta , Fazlollahi Asra , Sarkesh Aila , Naseri Amirreza , Mousavi Seyed Ehsan , Nejadghaderi Seyed Aria , Sullman Mark J M , Kolahi Ali-Asghar , Safiri Saeid
Published: December 2023

Background

Tislelizumab is an anti-programmed death-1 (PD-1) monoclonal antibody with a construction that enables it to have a higher affinity to its target. We aimed to evaluate tislelizumab’s safety and efficacy for treating non-small cell lung cancer (NSCLC).

Methods

Embase, Scopus, PubMed, Web of Science, and Google Scholar were searched up to December 20, 2022. The review only included randomized controlled trials (RCTs) that evaluated the safety or efficacy of tislelizumab for treating patients with lung cancer. The revised Cochrane risk-of-bias tool (RoB2) was utilized to evaluate study quality.

Results

There were four RCTs identified, which included 1565 patients with confirmed locally advanced or metastatic squamous and/or non-squamous types of NSCLC. Treatment with tislelizumab was associated with better progression-free survival (PFS) and objective response rate (ORR), particularly when used in combination with chemotherapy. Almost all patients in both arms reported at least one treatment-emergent adverse event (TEAE). Decreased hematologic indexes accounted for more than 20% of the grade ≥ 3 TEAEs in the tislelizumab plus chemotherapy group. The proportion of TEAE that led to death in the tislelizumab plus chemotherapy arms ranged from 3.2 to 4.2%. Hypothyroidism, pneumonitis, and hyperglycemia were the most frequently noted immune-mediated adverse events in the tislelizumab group.

Conclusions

Tislelizumab, whether used alone or in combination with chemotherapy, seems to demonstrate both a safety and efficacy as a treatment for NSCLC.
Combined utility of Ki-67 index and tumor grade to stratify patients with pancreatic ductal adenocarcinoma who underwent upfront surgery
Authors: Li Bo , Yin Xiaoyi , Ding Xiuwen , Zhang Guoxiao , Jiang Hui , Chen Cuimin , Guo Shiwei , Jin Gang
Published: December 2023

Objective

To investigate the prognostic prediction of a new indicator, combined by tumor grade and Ki-67, in patients with resected pancreatic ductal adenocarcinoma (PDAC).

Methods

Data were retrospectively collected from consecutive patients who underwent primary resection of pancreas from December 2012 to December 2017. Tumor grade and Ki-67 were reviewed from routine pathological reports. G-Ki67 was classified as three categories as I (G1/2 and Ki-67 < 40%), II (G1/2 and Ki-67 ≥ 40%), and III(G3/4 and all Ki-67).

Results

Cox regression analyses revealed that tumor stage (II vs. I: hazard ratio (HR), 3.781; 95% confidence index (CI), 2.844–5.025; P < 0.001; III vs. I: HR, 7.476; 95% CI, 5.481–10.20; P < 0.001) and G-Ki67 (II vs. I: HR, 1.299; 95% CI, 1.038–1.624; P = 0.022; III vs. I: HR, 1.942; 95% CI, 1.477–2.554; P < 0.001) were independent prognostic factors in the developing cohort. The result was rectified in the validation cohort. In subgroups analysis, G-Ki67 (II vs. I: HR, 1.866 ; 95% CI, 1.045–3.334; P = 0.035; III vs. I: HR, 2.333 ; 95% CI, 1.156–4.705; P = 0.018) also had a high differentiation for survival prediction.

Conclusion

Our findings indicate that three-categories of G-Ki67 in resectable PDAC according to the routine pathological descriptions provided additional prognostic information complementary to the TNM staging system.
A nomogram to predict conversion of laparoscopic surgery to laparotomy for Choledocholithiasis
Authors: Zheng Yitao , Lv Haoyang , Lin Zhuoqun , Shi Hongqi , Huang Xiaming
Published: December 2023

Background

Laparoscopic surgery is effective for treating common bile duct (CBD) stones. However, it has high requirements for surgeons and the risk of conversion to laparotomy cannot be ignored. However, when conditions during surgery are not favorable, persisting with laparoscopic procedures blindly can lead to serious complications. Our study aimed to establish a nomogram model for predicting conversion of laparoscopic to laparotomy for choledocholithiasis.

Materials and methods

A total of 867 patients who were diagnosed with choledocholithiasis and underwent laparoscopic surgery were randomly divided into a training group (70%, n = 607) and a validation group (30%, n = 260). A nomogram was constructed based on the results of logistic regression analysis. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram.

Results

Previous upper abdominal surgery, maximum diameter of stone ≥12 mm, medial wall of the duodenum stone, thickening of the gallbladder wall, thickening of CBD wall, stone size/CBD size ≥0.75, and simultaneous laparoscopic hepatectomy were included in the nomogram. The AUC values were 0.813 (95% CI: 0.766–0.861) and 0.804 (95% CI: 0.737–0.871) in the training and validation groups, respectively. The calibration curve showed excellent consistency between the nomogram predictions and actual observations. DCA showed a positive net benefit for the nomogram.

Conclusions

We constructed a nomogram with a good ability to predict conversion to open surgery in laparoscopic surgery for choledocholithiasis, which can help surgeons to make a reasonable operation plan before surgery and timely convert to laparotomy during operation to reduce potential harm to the patient.