Geriatric Assessment in Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous disease that affects mostly older adults with varying baseline health and functional status. Treatment options have expanded for older adults, ranging from less intensive chronic therapies to intensive induction strategies with curative intent. Despite this, outcomes remain poor with advancing age due to underlying disease biology and variability in treatment tolerance. Reliance on chronological age alone, however, increases risks of both over- and under-treatment. Strategies to better characterize fitness in the context of therapy are needed to optimize decision-making and enhance clinical trial design. SUMMARY: Geriatric assessment (GA) is a series of validated tools that evaluate multiple health and functional domains of an older adult including physical function, comorbidities, cognition, nutrition, psychological health, and social support. While studies of GA in AML remain limited, current evidence shows that it is feasible to perform GA among older adults starting therapy for AML. GA measures including those assessing physical function, cognition, and mood are associated with mortality and toxicity in both intensive and less intensive treatment settings. KEY MESSAGES: In this review, we discuss the existing evidence to support use of GA in AML and highlight implications for clinical practice and future research.

Highly sensitive in vivo detection of dynamic changes in enkephalins following acute stress.

Enkephalins are opioid peptides that modulate analgesia, reward, and stress. In vivo detection of enkephalins remains difficult due to transient and low endogenous concentrations and inherent sequence similarity. To begin to address this we previously developed a system combining in vivo optogenetics with microdialysis and a highly sensitive mass spectrometry-based assay to measure opioid peptide release in freely moving rodents (Al-Hasani, 2018, eLife). Here not only do we show improved detection resolution but also a critical discovery in the stabilization of enkephalin detection, which together allowed us to investigate enkephalin release during acute stress. We present an analytical method for Met- and Leu-Enkephalin (Met-Enk & Leu-Enk) detection in the mouse Nucleus Accumbens shell (NAcSh) after acute stress. We confirm that acute stress activates enkephalinergic neurons in the NAcSh using fiber photometry and that this leads to the release of Met- and Leu-Enk. We also demonstrate the dynamics of Met- and Leu-Enk release as well as how they correlate to one another in the ventral NAc shell, which was previously difficult due to the use of approaches that relied on mRNA transcript levels rather than post-translational products. This approach increases spatiotemporal resolution, optimizes the detection of Met-Enkephalin through methionine oxidation, and provides novel insight into the relationship between Met- and Leu-Enkephalin following stress.

Palliative Care's Role in Austere Medicine.

The integration of palliative care across multiple domains has increased in recent years, particularly in austere medical settings such as humanitarian crises and low- and middle-income countries. Providing relief from suffering through a multifaceted approach for patients in austere environments is both an ethical imperative and perfectly suited to palliative care's ethos. Practical resources have been developed that can guide many levels of medical practitioners in the administration of palliative care techniques in these settings. Further education and advocacy continue to be needed both for the promotion of primary palliative care and for access to certain classes of medications by which to deliver this care.

Phase Ib trial of lenalidomide as post-remission therapy for older adults with acute myeloid leukemia: Safety and longitudinal assessment of geriatric functional domains.

BACKGROUND AND OBJECTIVES: Novel, non-cytotoxic agents are driving a paradigm shift for treatment of older adults with acute myeloid leukemia (AML). Older patients who initially receive intensive cytotoxic induction may choose to not proceed with cytotoxic consolidation therapy. Lenalidomide is an orally-administered immunomodulatory small molecule with activity in AML and a favorable safety profile in older adults with active leukemia. We conducted a phase Ib study of lenalidomide as post-remission therapy in older adults and assessed its impact on geriatric functional domains. MATERIALS AND METHODS: Participants were patients with AML over age 60 years who had undergone induction therapy and were poor candidates for cytotoxic consolidation. Lenalidomide was administered for 28 days in three dose cohorts. A Bayesian dose-escalation method determined cohort assignment and maximum tolerated dose (MTD). Geriatric assessment (GA) was performed before and after the cycle of lenalidomide. RESULTS: Nineteen patients with median age 68 were treated with at least one 28-day course of lenalidomide. Dose-limiting toxicities were observed in three participants at 25 mg, zero participants at 35 mg, and one participant at 50 mg. MTD was 35 mg. Median relapse-free survival was 4.3 months. GA was completed before and after treatment in fifteen patients, demonstrating improved cognitive function and no changes in physical, psychological, or social function after lenalidomide. CONCLUSION: Lenalidomide can be safely administered to older adults with AML with preservation of functional domains important to older patients. Serial GA can be performed in a novel drug study as a tool to characterize treatment tolerability.

Does Irrigating While Drilling Decrease Bone Damage?

Background: Heat generated during bone drilling may be associated with thermal necrosis and direct damage, leading to complications after surgery. This preclinical study evaluates the in vivo effects of saline irrigation, drilling device type, and device sharpness on heat generation and bone damage in viable cortical bone. Methods: Bicortical drilling of each tibial diaphysis from anesthetized research dogs was performed to evaluate temperature and bone damage using five different devices with or without saline irrigation. Results: Saline irrigation and sharp drill bits were associated with smaller temperature increases and less acute osteonecrosis. Conventional trocar tip Kirschner wires were associated with the largest temperature increase and the most acute osteonecrosis changes. Conclusion: The use of saline irrigation during bone drilling reduces temperature change and osteonecrosis. Furthermore, we recommend that the use of dull drill bits or standard tip Kirschner wires be avoided. Lastly, drill bit design can directly contribute to bone damage during drilling. Clinical Relevance: This study provides in vivo data from a preclinical model to validate the benefits of saline irrigation and sharp drill bits during bone drilling to regulate increases in temperature and decrease associated osteonecrosis. Risk for early implant loosening and poor surgical outcome is influenced by thermal osteonecrosis of bone such that consistent use of saline irrigation, sharp drill bits, and optimized designs may have important clinical advantages. Level of Evidence: II.

Photon-counting MCP/Timepix detectors for soft X-ray imaging and spectroscopic applications.

Detectors with microchannel plates (MCPs) provide unique capabilities to detect single photons with high spatial (<10 µm) and timing (<25 ps) resolution. Although this detection technology was originally developed for applications with low event rates, recent progress in readout electronics has enabled their operation at substantially higher rates by simultaneous detection of multiple particles. In this study, the potential use of MCP detectors with Timepix readout for soft X-ray imaging and spectroscopic applications where the position and time of each photon needs to be recorded is investigated. The proof-of-principle experiments conducted at the Advanced Light Source demonstrate the capabilities of MCP/Timepix detectors to operate at relatively high input counting rates, paving the way for the application of these detectors in resonance inelastic X-ray scattering and X-ray photon correlation spectroscopy (XPCS) applications. Local count rate saturation was investigated for the MCP/Timepix detector, which requires optimization of acquisition parameters for a specific scattering pattern. A single photon cluster analysis algorithm was developed to eliminate the charge spreading effects in the detector and increase the spatial resolution to subpixel values. Results of these experiments will guide the ongoing development of future MCP devices optimized for soft X-ray photon-counting applications, which should enable XPCS dynamics measurements down to sub-microsecond timescales.

Switchable X-Ray Orbital Angular Momentum from an Artificial Spin Ice.

Artificial spin ices (ASI) have been widely investigated as magnetic metamaterials with exotic properties governed by their geometries. In parallel, interest in x-ray photon orbital angular momentum (OAM) has been rapidly growing. Here we show that a square ASI with a patterned topological defect, a double edge dislocation, imparts OAM to scattered x rays. Unlike single dislocations, a double dislocation does not introduce magnetic frustration, and the ASI equilibrates to its antiferromagnetic (AFM) ground state. The topological charge of the defect differs with respect to the structural and magnetic order; thus, x-ray diffraction from the ASI produces photons with even and odd OAM quantum numbers at the structural and AFM Bragg conditions, respectively. The magnetic transitions of the ASI allow the AFM OAM beams to be switched on and off by modest variations of temperature and applied magnetic field. These results demonstrate ASIs can serve as metasurfaces for reconfigurable x-ray optics that could enable selective probes of electronic and magnetic properties.

Atrio-esophageal Fistula Secondary to Atrial Fibrillation Ablation: A Case Report.

BACKGROUND: An atrio-esophageal fistula is an exceedingly rare but devastating complication of atrial fibrillation (AF) ablation procedures. Delays to diagnosis and definitive treatment herald a poor prognosis, with the development of catastrophic neurological injury or death secondary to cerebral air emboli. A high level of suspicion is essential to improve recognition of this rare but devastating condition. CASE REPORT: A 59-year-old man presented to the emergency department with an acute stroke and reduced consciousness. This presentation was preceded by an uncomplicated AF ablation 19 days prior and a subsequent emergency department attendance within a few days of his procedure, where he had presented with a history of new chest pain and reflux symptoms. Imaging revealed intra-cranial and intra-cardiac air, which was attributed to an uncontrolled atrio-esophageal fistula. Treatment options were limited by the patient's clinical instability and the patient was eventually palliated after developing catastrophic brain injury due to extensive cerebral air emboli. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients typically first present to the emergency department with new symptoms of either gastroesophageal reflux or chest pain, therefore, early recognition by emergency physicians is vital. Characteristic symptoms alongside a recent history of a cardiac ablation procedure should prompt additional diagnostic imaging to look for evidence of an atrio-esophageal fistula.

A biochemical basis for induction of retina regeneration by antioxidants.

The use of antioxidants in tissue regeneration has been studied, but their mechanism of action is not well understood. Here, we analyze the role of the antioxidant N-acetylcysteine (NAC) in retina regeneration. Embryonic chicks are able to regenerate their retina after its complete removal from retinal stem/progenitor cells present in the ciliary margin (CM) of the eye only if a source of exogenous factors, such as FGF2, is present. This study shows that NAC modifies the redox status of the CM, initiates self-renewal of the stem/progenitor cells, and induces regeneration in the absence of FGF2. NAC works as an antioxidant by scavenging free radicals either independently or through the synthesis of glutathione (GSH), and/or by reducing oxidized proteins through a thiol disulfide exchange activity. We dissected the mechanism used by NAC to induce regeneration through the use of inhibitors of GSH synthesis and the use of other antioxidants with different biochemical structures and modes of action, and found that NAC induces regeneration through its thiol disulfide exchange activity. Thus, our results provide, for the first time, a biochemical basis for induction of retina regeneration. Furthermore, NAC induction was independent of FGF receptor signaling, but dependent on the MAPK (pErk1/2) pathway.

Circulating microparticle levels are reduced in patients with ARDS.

BACKGROUND: It is unclear how to identify which patients at risk for acute respiratory distress syndrome (ARDS) will develop this condition during critical illness. Elevated microparticle (MP) concentrations in the airspace during ARDS are associated with activation of coagulation and in vitro studies have demonstrated that MPs contribute to acute lung injury, but the significance of MPs in the circulation during ARDS has not been well studied. The goal of the present study was to test the hypothesis that elevated levels of circulating MPs could prospectively identify critically ill patients who will develop ARDS and that elevated circulating MPs are associated with poor clinical outcomes. METHODS: A total of 280 patients with platelet-poor plasma samples from the prospective Validating Acute Lung Injury biomarkers for Diagnosis (VALID) cohort study were selected for this analysis. Demographics and clinical data were obtained by chart review. MP concentrations in plasma were measured at study enrollment on intensive care unit (ICU) day 2 and on ICU day 4 by MP capture assay. Activation of coagulation was measured by plasma recalcification (clot) times. RESULTS: ARDS developed in 90 of 280 patients (32%) in the study. Elevated plasma MP concentrations were associated with reduced risk of developing ARDS (odds ratio (OR) 0.70 per 10 µM increase in MP concentration, 95% CI 0.50-0.98, p = 0.042), but had no significant effect on hospital mortality. MP concentration was greatest in patients with sepsis, pneumonia, or aspiration as compared with those with trauma or receiving multiple blood transfusions. MP levels did not significantly change over time. The inverse association of MP levels with ARDS development was most striking in patients with sepsis. After controlling for age, presence of sepsis, and severity of illness, higher MP concentrations were independently associated with a reduced risk of developing ARDS (OR 0.69, 95% CI 0.49-0.98, p = 0.038). MP concentration was associated with reduced plasma recalcification time. CONCLUSIONS: Elevated levels of circulating MPs are independently associated with a reduced risk of ARDS in critically ill patients. Whether this is due to MP effects on systemic coagulation warrants further investigation.

Risk Factors for Early Readmission After Anatomical or Reverse Total Shoulder Arthroplasty.

Hospital readmissions are costly for patients and institutions. We conducted a study to evaluate rates of readmission within 30 days after anatomical total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA) and to determine independent risk factors for readmission. We queried the National Surgical Quality Improvement Program database for ATSAs and RTSAs performed between 2011 and 2013 and found a combined total of 3501 cases and an overall readmission rate of 2.7%. Of the readmissions, 67% were for medical complications, and 33% were for surgical complications. Of the medical complications, pneumonia was the most common (11.8%), followed by urinary tract infection (7.8%). Regarding surgical complications, surgical-site infection was the most common (13.7%), followed by prosthetic joint dislocation (9.8%). Hospital-acquired conditions, including surgical-site infection, urinary tract infection, deep vein thrombosis, and pulmonary embolism, accounted for 33% of all 30-day readmissions. Three independent risk factors for readmission were identified: revision surgery (odds ratio, 2.59), 3 or more comorbidities (odds ratio, 2.02), and extended length of stay (>4.3 days) during the index admission (odds ratio, 2.48). Other factors significantly (P < .05) associated with readmission were age over 75 years, dependent functional status, American Society of Anesthesiologists score of 4 or higher, cardiac comorbidity, 2 or more comorbidities, and urinary tract infection before discharge.

A retrospective analysis of benzodiazepine sedation vs. propofol anaesthesia in 252 patients undergoing endoscopic retrograde cholangiopancreatography.

BACKGROUND: Historically, hepatopancreatobiliary surgeons and gastroenterologists have undertaken endoscopic retrograde cholangiopancreatography (ERCP) using benzodiazepine sedation (BS). This is poorly tolerated by a substantial number of patients, which leads to its potential premature abandonment and subsequent additional investigations and therapeutics, and hence to the exposure of patients to avoidable risk and the health service to increased costs. Furthermore, concerns have been raised in the recent literature regarding safe sedation techniques. OBJECTIVES: The aim of this study was to compare the completion rates and safety profile of ERCP using BS vs. those of ERCP using light propofol anaesthesia (PA). METHODS: We carried out a retrospective, case-matched comparison analysis of consecutive patients who underwent ERCP with BS vs. PA, in the presence of an anaesthetist, over a 2-year period. Benzodiazepine sedation consisted of midazolam, fentanyl and buscopan. Propofol anaesthesia consisted of propofol, fentanyl and buscopan administered via a mouth guard in a non-intubated patient. Patient demographics, complications and completion rates were recorded. Procedural monitoring included pulse oximetry, non-invasive blood pressure, electrocardiography and end-tidal CO(2) . Statistical analyses used t-tests to compare continuous variables and chi-squared and Fisher's exact tests to compare categorical variables. A P-value of <0.05 was considered significant. RESULTS: Of 252 patients included in the study, 128 (50.8%) received BS and 124 (49.2%) received PA. Median ages in the BS and PA groups were 69 years (range: 20-99 years) and 65 years (range: 26-98 years), respectively (P= 0.07). Median hospital stays in the BS and PA groups were 1 day (range: day case to 61 days) and 1 day (range: day case to 38 days), respectively (P= 0.61). Incidences of mild anaesthesia-related complications in the BS and PA groups were 2.3% and 2.4%, respectively (P= 0.97). There were no severe anaesthesia-related complications. Incidences of mild procedural complications in the BS and PA groups were 2.3% and 1.6%, respectively (P= 0.68). One severe procedural complication occurred in the PA group. Incidences of incomplete ERCP procedures in the BS and PA groups were 10.9% (n= 14) and 4.0% (n= 5), respectively (odds ratio = 2.92, 95% confidence interval 1.02-8.38; chi-squared test, P= 0.04; Fisher's exact test, P= 0.03). CONCLUSIONS: Propofol anaesthesia for ERCP carried out in the presence of an anaesthetist is safe and may improve procedural completion rates.

Goal-directed therapy in high-risk surgical patients: a 15-year follow-up study.

PURPOSE: Goal-directed therapy in the perioperative setting has been shown to be associated with short-term improvements in outcome. This study assesses the longer-term survival of patients from a previous randomized controlled trial of goal-directed therapy in high-risk surgical patients. METHODS: All patients from a previous randomized controlled study were followed up for 15 years following randomization to ascertain their length of survival following surgery. Factors that may be associated with increased survival were evaluated to determine what influenced long-term outcomes. RESULTS: Data from 106 of the original 107 patients (99%) were available for analysis. At 15 years, 11 (20.7%) of the goal-directed therapy patients versus 4 (7.5%) of the control group were alive (p = 0.09). Median survival for the goal-directed group was increased by 1,107 days (1,781 vs. 674 days, p = 0.005). Long-term survival was associated with three independent factors: age [hazard ratio (HR) 1.04 (1.02-1.07), p < 0.0001], randomization to the goal-directed group of the study [HR 0.61 (0.4-0.92), p = 0.02], and avoidance of a significant postoperative cardiac complication [HR 3.78 (2.16-6.6), p = 0.007]. CONCLUSIONS: Long-term survival after major surgery is related to a number of factors, including patient age and avoidance of perioperative complications. Short-term goal-directed therapy in the perioperative period may improve long-term outcomes, in part due to its ability to reduce the number of perioperative complications.

Right ventricular dysfunction.

PURPOSE OF REVIEW: Until recently the right ventricle's role in myocardial dynamics has not been fully appreciated. This article provides an overview of the pathophysiology, imaging and management of right ventricular dysfunction. RECENT FINDINGS: That levosimendan may promote right ventricular function opens new avenues for treatment. In addition there are existing therapies such as phosphodiesterase inhibitors and nitric oxide, which offer yet further modalities to improve outcome in right ventricular failure. How these drugs are used, in combination or alone, in conjunction with ventilatory and cardiovascular strategies has not been evaluated in multicentred randomized controlled trials. SUMMARY: Acute right ventricular dysfunction is relatively common. There is a lack of convincing evidence in favour of any single treatment modality. Imaging methods now permit a more accurate evaluation of the right ventricle and its function. Combining treatments may offer significant advantages and the imaging and monitoring available allows real-time assessment of the response to intervention. This article illustrates how incomplete our knowledge of this condition and its management within the critical care setting is and reinforces previous calls for suitably designed trials to evaluate and develop guidelines for existing strategies and therapeutic agents.