A Predictive Algorithm for Discriminating Myeloid Malignancies and Leukemoid Reactions.

BACKGROUND: Adults presenting with a neutrophil-predominant leukocytosis (white cell count >50,000/µL) often necessitate urgent medical management. These patients are diagnosed with either acute presentations of chronic myeloid malignancies or leukemoid reactions, yet accurate models to distinguish between these entities do not exist. We used demographic and lab data to build a machine learning model capable of discriminating between these diagnoses. METHODS: The medical record at a tertiary care medical center was queried to identify adults with instances of white counts greater than 50,000/µL and >50% neutrophils from 2000 to 2021. For each patient, a full set of demographic and lab values were extracted at the time of their first presentation with a white count >50,000/µL. We generated a series of models in which the parameters most predictive of myeloid malignancies were identified, and a supervised machine learning approach was applied to the dataset. RESULTS: Our best model-using a support vector machine algorithm-produced a sensitivity of 96% and a specificity of 95.9% (area under the curve = 0.982) for identifying myeloid malignancies. We also identified a clinically meaningful and significant disparity in outcomes based on diagnosis-a 6-fold increase in 12-month mortality in those diagnosed with leukemoid reactions. CONCLUSIONS: These findings need to be validated but fill an unmet need for timely and accurate diagnosis in the setting of profound, neutrophil-predominant leukocytosis and support the use of predictive models as a means to improve patient outcomes.

Comparison of direct oral anticoagulants versus low-molecular-weight heparin in primary and metastatic brain cancers: a meta-analysis and systematic review.

BACKGROUND: The safety and efficacy of direct-acting oral anticoagulants (DOACs) for therapeutic anticoagulation in the setting of primary or metastatic brain cancer is not known. OBJECTIVES: To conduct a meta-analysis and systematic review of studies that compare the risk of intracranial hemorrhage (ICH) in patients with brain cancer treated with DOACs vs low-molecular-weight heparin (LMWH). METHODS: A literature search was conducted using PubMed, EMBASE, and Cochrane databases. Summary statistics were obtained by calculating the risk ratio (RR), and heterogeneity across studies was estimated using the I2 statistic. A total of 10 retrospective studies (n = 1638) met criteria for inclusion. The primary endpoint was the pooled RR for ICH in patients with brain tumors receiving anticoagulation with DOACs compared with those receiving LMWH. Secondary analyses included the risk of fatal ICH in each subgroup. RESULTS: The pooled RR for ICH in patients receiving DOACs vs those receiving LMWH was 0.65 (95% CI, 0.36-1.17; P = .15; I2 = 50%). In studies evaluating primary brain cancer, there was a reduction in risk of ICH with DOACs (RR, 0.35; 95% CI, 0.18-0.69; P = .003; I2 = 0%). In patients with metastatic brain cancer, there was no difference in the risk of ICH with the type of anticoagulation (RR, 1.05; 95% CI, 0.71-1.56; P = .80; I2 = 0%). The overall risk of fatal ICH was not different between anticoagulants. CONCLUSION: The risk of ICH in patients with brain cancer receiving therapeutic anticoagulation varies by anticoagulation agent and diagnosis of primary or metastatic disease.

Influence of thrombocytopenia on bleeding and vascular events in atrial fibrillation.

Whether thrombocytopenia substantively increases the risk of hemorrhage associated with anticoagulation in patients with atrial fibrillation (AF) is not established. The purpose of this study was to compare rates of bleeding in patients with AF and thrombocytopenia (platelet count < 100 000/µL) to patients with AF and normal platelet counts (>150 000/µL). We performed a propensity score-matched, retrospective cohort study of adults (n = 1070) with a new diagnosis of AF who received a prescription for an oral anticoagulant between 2015 and 2020. The thrombocytopenia cohort was defined as having at least 2 platelet counts <100 000/µL on separate days in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks after the initiation of anticoagulation. The primary end point was the 1-year cumulative incidence of major bleeding; secondary end points included clinically relevant bleeding, arterial and venous thrombotic events, and all-cause mortality. Patients with AF and thrombocytopenia experienced a higher 1-year cumulative incidence of major bleeding (13.3% vs 5.7%; P < .0001) and clinically relevant bleeding (24.5% vs 16.7%; P = .005) than the controls. Thrombocytopenia was identified as an independent risk factor for major bleeding (hazard ratio, 2.20; confidence interval, 1.36-3.58; P = .001), with increasing risk based on the severity of thrombocytopenia. The cumulative incidence of arterial thrombosis at 1 year was 3.6% in the group with thrombocytopenia and 1.5% in controls (Gray test, P = .08). These findings suggest that baseline platelet counts are an important biomarker for hemorrhagic outcomes in AF and that the degree of thrombocytopenia is an important factor in determining the level of risk.

Challenges in anticoagulation for patients with brain tumors.

Venous thromboembolism (VTE) is a common complication in patients with primary and metastatic brain cancer. Treatment of thrombosis in these patients must be balanced against the risk of intracranial hemorrhage (ICH). A number of cohort studies conducted over the last several years have assessed the risk of ICH in patients with primary or secondary brain tumors in the setting of anticoagulation. Anticoagulation with warfarin or low-molecular weight heparin significantly increases the risk of ICH in the setting of primary brain cancers. In contrast, therapeutic anticoagulation does not appear to alter the risk of ICH among patients with metastatic brain tumors. This review summarizes current data regarding anticoagulant and antiplatelet therapy in patients with brain tumors, including emerging data on direct-acting oral anticoagulants, and other related topics, such as the use of inferior vena cava filters and resumption of anticoagulation following ICH.

Patient-centered approach to managing factor XIII deficiency.

Factor XIII (FXIII) is a thrombin-activated protransglutaminase that plays a key role in blood clot formation. Congenital FXIII A-subunit deficiency represents a rare bleeding disorder that affects one in 2-3 million individuals worldwide and is treated with recombinant FXIII (rFXIII). However, due to the rarity of the disease, clinicians are often left to weigh individual variation in FXIII activity and/or symptoms to optimally guide dosing. Cases often become further complicated when patients experience refractory bleeding, which can be difficult to treat. This report describes an approach to rFXIII dosing in two patients who required deviation from standard protocols to maintain therapeutic FXIII troughs. We highlight limitations in our understanding of FXIII deficiency management, while also providing an example of the application of pharmacokinetic data to individualise therapy for improved outcomes. Finally, the case reminds us of the importance of patient-centered, cost-conscious care and multidisplinary teamwork in complex cases.

Diagnosis and management of a metastatic mixed gestational trophoblastic neoplasia with synchronous primary lung cancer.

Mixed gestational trophoblastic neoplasias (GTNs) are rare placental tumours that arise from abnormal fertilisation events. To date, only 34 patients with mixed GTNs have been reported in the literature. As such, the management of such cases remains challenging. This report presents a case of a mixed GTN that was further complicated by a synchronous primary lung adenocarcinoma. Our patient was initially treated with hysterectomy, with surveillance labwork showing persistence of her malignancy. She then began combination chemotherapy, at the end of which she appeared to be in remission clinically. Unfortunately, subsequent imaging showed the persistence of pulmonary nodules that were ultimately resected, demonstrating a new primary lung adenocarcinoma. At present, she remains free of both cancers 2 years after her initial diagnosis. The complexity of this case underscores the importance of patient-centred treatment for rare tumours and the role of a multidisciplinary team in the effort to provide holistic care.

Transcriptional changes during hepatic ischemia-reperfusion in the rat.

There are few effective targeted strategies to reduce hepatic ischemia-reperfusion (IR) injury, a contributor to poor outcomes in liver transplantation recipients. It has been proposed that IR injury is driven by the generation of reactive oxygen species (ROS). However, recent studies implicate other mediators of the injury response, including mitochondrial metabolic dysfunction. We examined changes in global gene expression after transient hepatic ischemia and at several early reperfusion times to identify potential targets that could be used to protect against IR injury. Male Wistar rats were subjected to 30 minutes of 70% partial warm ischemia followed by 0, 0.5, 2, or 6 hours of reperfusion. RNA was extracted from the reperfused and non-ischemic lobes at each time point for microarray analysis. Identification of differentially expressed genes and pathway analysis were used to characterize IR-induced changes in the hepatic transcriptome. Changes in the reperfused lobes were specific to the various reperfusion times. We made the unexpected observation that many of these changes were also present in tissue from the paired non-ischemic lobes. However, the earliest reperfusion time, 30 minutes, showed a marked increase in the expression of a set of immediate-early genes (c-Fos, c-Jun, Atf3, Egr1) that was exclusive to the reperfused lobe. We interpreted these results as indicating that this early response represented a tissue autonomous response to reperfusion. In contrast, the changes that occurred in both the reperfused and non-ischemic lobes were interpreted as indicating a non-autonomous response resulting from hemodynamic changes and/or circulating factors. These tissue autonomous and non-autonomous responses may serve as targets to ameliorate IR injury.

Mathematical Modeling and Analyses of Interspike-Intervals of Spontaneous Activity in Afferent Neurons of the Zebrafish Lateral Line.

Without stimuli, hair cells spontaneously release neurotransmitter leading to spontaneous generation of action potentials (spikes) in innervating afferent neurons. We analyzed spontaneous spike patterns recorded from the lateral line of zebrafish and found that distributions of interspike intervals (ISIs) either have an exponential shape or an "L" shape that is characterized by a sharp decay but wide tail. ISI data were fitted to renewal-process models that accounted for the neuron refractory periods and hair-cell synaptic release. Modeling the timing of synaptic release using a mixture of two exponential distributions yielded the best fit for our ISI data. Additionally, lateral line ISIs displayed positive serial correlation and appeared to exhibit switching between faster and slower modes of spike generation. This pattern contrasts with previous findings from the auditory system where ISIs tended to have negative serial correlation due to synaptic depletion. We propose that afferent neuron innervation with multiple and heterogenous hair-cells synapses, each influenced by changes in calcium domains, can serve as a mechanism for the random switching behavior. Overall, our analyses provide evidence of how physiological similarities and differences between synapses and innervation patterns in the auditory, vestibular, and lateral line systems can lead to variations in spontaneous activity.

Does Time-in-Range Matter? Perspectives From People With Diabetes on the Success of Current Therapies and the Drivers of Improved Outcomes.

IN BRIEF After assessing patient perspectives on the success of current diabetes therapies and the factors that have the greatest impact on daily life, we show that time-in-range is a crucial outcome for people with diabetes and that current therapies are falling short on this metric. We also show that patients feel significant stress and worry, and they believe they are falling short in diet, exercise, and weight maintenance. In addition, they believe diet and exercise and in-range blood glucose are the biggest drivers of improved diabetes management and mindset. Together, these findings support the need for therapies that improve outcomes including and beyond A1C.

Challenges in Diabetes Care: Can Digital Health Help Address Them?

In Brief There is great enthusiasm for the potential of digital health solutions in medicine and diabetes to address key care challenges: patient and provider burden, lack of data to inform therapeutic decision-making, poor access to care, and costs. However, the field is still in its nascent days; many patients and providers do not currently engage with digital health tools, and for those who do, the burden is still often high. Over time, digital health has excellent potential to collect data more seamlessly, make collected data more useful, and drive better outcomes at lower costs in less time. But there is still much to prove. This review offers key background information on the current state of digital health in diabetes, six of the most promising digital health technologies and services, and the challenges that remain.

Genome Sequences of Cluster G Mycobacteriophages Cambiare, FlagStaff, and MOOREtheMARYer.

Mycobacteriophages Cambiare, FlagStaff, and MOOREtheMARYer are newly isolated phages of Mycobacterium smegmatis mc(2) 155 recovered from soil samples in Pittsburgh, PA. All three genomes are closely related to cluster G mycobacteriophages but differ sufficiently in nucleotide sequence and gene content to warrant division of cluster G into several subclusters.

Genome Sequence of Mycobacteriophage Momo.

Momo is a newly discovered phage of Mycobacterium smegmatis mc(2)155. Momo has a double-stranded DNA genome 154,553 bp in length, with 233 predicted protein-encoding genes, 34 tRNA genes, and one transfer-messenger RNA (tmRNA) gene. Momo has a myoviral morphology and shares extensive nucleotide sequence similarity with subcluster C1 mycobacteriophages.