Intrathecal Central Nervous System Prophylaxis in Patients With Diffuse Large B-cell Lymphoma at an Academic Healthcare System

Introduction

Intrathecal chemoprophylaxis is often administered to patients with diffuse large B-cell lymphoma (DLBCL) to lower the rates of central nervous system (CNS) relapse, although its benefit has not been well-described. Prognostic models, including the CNS-International Prognostic Index (IPI), have been developed to aid in identifying patients at highest risk for CNS relapse.

Ascertaining Design Requirements for Postoperative Care Transition Interventions

Background  Handoffs or care transitions from the operating room (OR) to intensive care unit (ICU) are fragmented and vulnerable to communication errors. Although protocols and checklists for standardization help reduce errors, such interventions suffer from limited sustainability. An unexplored aspect is the potential role of developing personalized postoperative transition interventions using artificial intelligence (AI)-generated risks. Objectives  This study was aimed to (1) identify factors affecting sustainability of handoff standardization, (2) utilize a human-centered approach to develop design ideas and prototyping requirements for a sustainable handoff intervention, and (3) explore the potential role for AI risk assessment during handoffs. Methods  We conducted four design workshops with 24 participants representing OR and ICU teams at a large medical academic center. Data collection phases were (1) open-ended questions, (2) closed card sorting of handoff information elements, and (3) scenario-based design ideation and prototyping for a handoff intervention. Data were analyzed using thematic analysis. Card sorts were further tallied to characterize handoff information elements as core, flexible, or unnecessary. Results  Limited protocol awareness among clinicians and lack of an interdisciplinary electronic health record (EHR)-integrated handoff intervention prevented long-term sustainability of handoff standardization. Clinicians argued for a handoff intervention comprised of core elements (included for all patients) and flexible elements (tailored by patient condition and risks). They also identified unnecessary elements that could be omitted during handoffs. Similarities and differences in handoff intervention requirements among physicians and nurses were noted; in particular, clinicians expressed divergent views on the role of AI-generated postoperative risks. Conclusion  Current postoperative handoff interventions focus largely on standardization of information transfer and handoff processes. Our design approach allowed us to visualize accurate models of user expectations for effective interdisciplinary communication. Insights from this study point toward EHR-integrated, “flexibly standardized” care transition interventions that can automatically generate a patient-centered summary and risk-based report. Keyword: continuity of care, care transition, requirements analysis and design, handoffs, surgery, anesthesia, intensive and critical care, machine learning     

Proximal External Aortic Compression for Life-Threatening Abdominal-Pelvic and Junctional Hemorrhage: An Ultrasonographic Study in Adult Volunteers

Introduction: Following life-threatening junctional trauma, the goal is to limit blood loss while expediting transfer to operative rescue. Unfortunately, life-threatening abdominal-pelvic or junctional hemorrhage is often not amenable to direct compression and few temporizing strategies are available beyond hemostatic dressings, hypotensive resuscitation, and balanced transfusion. Objectives: In this study, we evaluated proximal external aortic compression to arrest blood flow in healthy adult men. Methods: This was a simulation trial of proximal external aortic compression, for life-threatening abdominal-pelvic and junctional hemorrhage, in a convenience sample of healthy adult male volunteers. The primary end points were cessation of femoral blood flow as assessed by pulse wave Doppler ultrasound at the right femoral artery, caudal to the inguinal ligament. Secondary end points were discomfort and negative sequelae. Results: Aortic blood flow was arrested in 12 volunteers. Median time to blood flow cessation was 12.5?seconds. Median reported discomfort was 5 out of 10. No complications or negative sequelae were reported. Conclusion: This trial suggests that it may be reasonable to attempt temporization of major abdominal-pelvic and junctional hemorrhage using bimanual proximal external aortic compression. In the absence of immediate alternatives for this dangerous and vexing injury pattern, there appear to be few downsides to prehospital proximal external aortic compression while concomitantly expediting definite care.     

Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice

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Climate change and cancer: converging policies

Intervening on risk factors for noncommunicable diseases (including cancer) in industrialized countries could achieve a reduction of between 30% and 40% of premature deaths. In the meantime, the need to intervene against the threat of climate change has become obvious. CO₂ emissions must be reduced by 45% by the year 2030 and to zero by 2050 according to recent agreements. We propose an approach in which interventions are designed to prevent diseases and jointly mitigate climate change, the so‐called cobenefits. The present article describes some examples of how climate change mitigation and cancer prevention could go hand in hand: tobacco control, food production, and transportation (air pollution). Many others can be identified. The advantage of the proposed approach is that both long‐term (climate) and short‐term (health) benefits can be accrued with appropriate intersectoral policies.

Abbreviations

GHG

greenhouse gases

IARC

International Agency for Research on Cancer

LMICs

low‐ and middle‐income countries

NCD

noncommunicable disease

PMI

Philip Morris International

SDGs

Sustainable Development Goals

UPF

ultraprocessed food

     

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen

By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite 1 lacking structural and binding similarity to known FTase inhibitors. Although multiple lines of evidence established the binding interaction, these ligands exhibited minimal inhibitory activity in a cell-free biochemical FTase inhibition assay. Subsequent modification of the biochemical assay by increasing anion concentration demonstrated FTase inhibitory activity in this novel class. We propose 1 binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed.     

Comparison of the Clinical Manifestations between Acute Vogt-Koyanagi-Harada Disease and Acute Bilateral Central Serous Chorioretinopathy

PurposeTo compare clinical, angiographic, and optical coherence tomographic characteristics between eyes with acute Vogt-Koyanagi-Harada (VKH) disease and eyes with acute bilateral central serous chorioretinopathy (CSC), and to demonstrate distinguishing features between the two diseases in confusing cases.MethodsThe medical records of 35 patients with VKH disease and 25 patients with bilateral CSC were retrospectively reviewed. Characteristics according to slit-lamp biomicroscopy, ophthalmoscopy, fundus photography, fluorescein angiography, indocyanine green angiography, and spectral-domain optical coherence tomography were compared between the two diseases.ResultsFive of 35 patients (10 of 70 eyes, 14.3%) with VKH disease were initially misdiagnosed as CSC patients, and six of 25 patients (12 of 50 eyes, 24%) with bilateral CSC were initially misdiagnosed as patients with VKH disease. Pigment epithelial detachment in CSC and optic disc hyperemia in VKH disease show the highest positive predictive values of 100% for each disease.ConclusionsOptic disc hyperemia in VKH disease and pigment epithelial detachment in bilateral CSC are the most specific clinical manifestations of each disease at initial patient presentation.     

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.