Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia.

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.

Patient experiences with requests for medical assistance in dying: Perspectives of those with complex chronic conditions.

OBJECTIVE: To explore experiences of patients who have complex chronic conditions (CCCs), such as fibromyalgia and chronic fatigue syndrome, when they request medical assistance in dying (MAID) in Canada. DESIGN: Qualitative study using semistructured interviews. SETTING: Canada. PARTICIPANTS: Individuals with CCCs who had contacted any 1 of 4 advocacy organizations between January 21, 2021, and December 20, 2022, about requesting MAID for suffering related to CCCs or who had applied and been assessed for MAID. METHODS: Interviews were conducted virtually (by video or audio) and recordings were transcribed. Thematic analysis was conducted in an iterative manner with abductive analysis. As interviews were completed, transcripts were reviewed and emerging themes were discussed at regular intervals. MAIN FINDINGS: Sixteen individuals were interviewed. All spoke of long-lasting suffering that was unresponsive to an array of medical treatments. Although some participants had hoped to receive MAID immediately following the 90-day assessment period, many mentioned that approval would provide or had provided validation of their illness and a sense of control, especially should their illness become unbearable. Participants sharply distinguished between MAID and suicide, saying they preferred MAID because it offered greater certainty and caused less emotional pain to others. Many said that participating in this research was beneficial because they believed the interviewers truly listened to them. CONCLUSION: Participants described experiences with CCCs and requests for MAID. This information may provide family doctors with new insight to inform interactions with patients with CCCs.

The Impact of Chronic Ozone and Particulate Air Pollution on Mortality in Patients With Sepsis Across the United States.

OBJECTIVE: The impact of chronic exposure to air pollution on mortality in patients with sepsis is unknown. We attempted to quantify the relationship between air pollution, notably excess ozone, and particulate matter (PM), with in-hospital mortality in patients with sepsis nationwide. METHODS: The 2011 Nationwide Inpatient Sample (NIS) was linked with ambient air pollution data from the Environmental Protection Agency for both 8-hour ozone exposure and annual mean 2.5-micron PM (PM2.5) pollution levels. A validated severity of illness model for sepsis using administrative data was used to control for sepsis severity. RESULTS: The records of 8 023 590 hospital admissions from the 2011 NIS sample were analyzed. Of these, there were 444 928 patients who met the Angus definition of sepsis, treated in hospitals for which air pollution data were available. The cohort had an overall mortality of 11.2%. After adjustment for severity of sepsis, increasing exposure to ozone pollution was associated with increased risk of mortality (odds ratio [OR]: 1.04 for each 0.01 ppm increase, 95% confidence interval [CI]: 1.03-1.05; P < .01). Particulate matter was not associated with mortality (OR: 0.99 for each 5 µg/m3 increase, 95% CI: 0.97-1.01; P = .28). When stratified by sepsis source, ozone pollution had a higher impact on patients with pneumonia (OR: 1.06, 95% CI: 1.04-1.08; P < .01) compared to those patients without pneumonia (OR: 1.02, 95% CI: 1.01-1.03; P < .01). CONCLUSION: Exposure to increased levels of ozone but not particulate air pollution was associated with higher risk of mortality in patients with sepsis. This association was strongest in patients with pneumonia but persisted in all sources of sepsis. Further work is needed to understand the relationship between ambient ozone air pollution and sepsis outcomes.

Association between seizures and mortality in patients with aneurysmal subarachnoid hemorrhage: A nationwide retrospective cohort analysis.

PURPOSE: The impact of seizures on outcomes in patients with subarachnoid hemorrhage (SAH) is not well understood, with conflicting results published in the literature. METHOD: For this retrospective cohort analysis, data from the Nationwide Inpatient Samples (NIS) for 2006-2011 were utilized. All patients aged ≥18 years with a primary admitting diagnosis of subarachnoid hemorrhage were included. Patients with a diagnosis of seizure were segregated from the initial cohort. Multivariable logistic regression modeled the risk of death while adjusting for severity of SAH as well as co-morbidities. The primary outcome of this analysis was in-hospital mortality. RESULTS: 12,647 patients met inclusion criteria for the study, of which 1336 had a diagnosis of seizures. The unadjusted in-hospital mortality was higher for patients with seizures compared to those without (16.2% vs 11.6%, p<0.01). Compared to patients without seizures, patients with seizures were younger (52.4 years SD 13.9 vs 54.8 years, SD 13.6; p<0.01), more likely to be male (35.6% vs 31.0%, p<0.01) and had longer hospital stays (18.3 days, IQR 12.0-27.5 vs 14.8 days, IQR 10.0-21.9; p<0.01). After adjusting for the severity of SAH, seizures were found to be associated with increased mortality (OR 1.57, 95% CI 1.32-1.87, p<0.01). CONCLUSION: In this large nationwide analysis, the presence of seizures in patients with SAH was associated with higher in-hospital mortality. This finding has potentially important implications for goals of care decision-making and prognostication, but further study in the area is needed.