Assessment of cellular and molecular changes in the rat brain after gamma radiation and radioprotection by anisomycin.

The objective of the study was to describe cellular and molecular markers of radioprotection by anisomycin, focusing on the changes in rat brain tissue. Two-month-old Wistar rats were exposed to a 60Co radiation source at a dose of 6 Gy, with or without radioprotection with anisomycin (150 mg/kg) administered subcutaneously 30 min before or 3 or 6 h after irradiation. Survivors were analyzed 30 days after treatment. Astroglial and microglial responses were investigated based on the expression of glial markers assessed with immunohistochemistry, and quantitative changes in brain biomolecules were investigated by Raman microspectroscopy. In addition, blood plasma levels of pro-inflammatory (interleukin 6 and tumor necrosis factor α) and anti-inflammatory (interleukin 10) cytokines were assessed. We found that application of anisomycin either before or after irradiation significantly decreased the expression of the microglial marker Iba-1. We also found an increased intensity of Raman spectral bands related to nucleic acids, as well as an increased level of cytokines when anisomycin was applied after irradiation. This suggests that the radioprotective effects of anisomycin are by decreasing Iba-1 expression and stabilizing genetic material by increasing the level of nucleic acids.

Premedication prior to PEG-asparaginase is cost-effective in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions. PROCEDURES: This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty. RESULTS: In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios. CONCLUSION: Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.

Longitudinal assessment of preoperative dexamethasone administration on cognitive function after cardiac surgery: a 4-year follow-up of a randomized controlled trial.

BACKGROUND: The pathogenesis of postoperative cognitive decline (POCD) is still poorly understood; however, the inflammatory response to surgical procedures seems likely to be involved. In addition, our recent randomized controlled trial showed that perioperative corticosteroid treatment may ameliorate early POCD after cardiac surgery. To assess the long-term effect of dexamethasone administration on cognitive function, we conducted a 4-year follow-up. METHODS: The patients were randomized to receive a single intravenous bolus of 0.1 mg kg- 1 dexamethasone or placebo 10 h before elective cardiac surgery. The endpoint in both groups was POCD incidence on the 6th day and four years postoperatively. RESULTS: Of the 161 patients analyzed previously, the current follow-up included 116 patients. Compared to the 62 patients in the placebo group, the 54 patients in the dexamethasone group showed a lower incidence of POCD on the 6th day (relative risk (RR), 0.510; 95 % confidence interval (CI), 0.241 to 1.079; p = 0.067, time interval also analyzed previously) and four years (RR, 0.459; 95 % CI, 0.192 to 1.100; p = 0.068) after cardiac surgery. The change in cognitive status between the two postoperative measurements was not significant (p = 0.010) among the patients in the dexamethasone group, in contrast to patients in the placebo group (p = 0.673). CONCLUSIONS: Although statistical significance was not reached in the current study, the prophylactic administration of dexamethasone seems to be useful to prevent POCD development following cardiac surgery. However, further large multicenter research is needed to confirm these directions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02767713 (10/05/2016).

Preventing complications in dermatologic surgery: Presurgical concerns.

Cutaneous surgery has become critical to comprehensive dermatologic care, and dermatologists must therefore be equipped to manage the risks associated with surgical procedures. Complications may occur at any point along the continuum of care, and therefore assessing, managing, and preventing risk from beginning to end becomes essential. This review focuses on preventing surgical complications pre- and postoperatively as well as during the surgical procedure.

Rates and reasons for safety incident reporting in the medical imaging department of a large academic health sciences centre.

BACKGROUND: Safety incident reporting is essential in medical imaging (MI) departments due to the fast-paced environment and high patient volume. However, there is an evident knowledge gap in the identification and investigation of contributing factors to incidents reports in MI departments. The objective of this study was to investigate the following rates of incident reporting in a MI department at a large academic health sciences centre: departmental incident rate, incident rates per imaging modality, and incident rates per incident type. Characteristics associated with the most frequently occurring incident types were examined to identify opportunities for quality improvement. METHODS: This observational, retrospective study collected approximately 665 MI incident reports submitted by staff between July 2018 and July 2019. Individual incident reports were categorized according to imaging modality and incident type. Subcategories of the top four incident types were also created to identify possible contributory factors based on the staff member's safety incident report submission. RESULTS: The safety incident rate for the entire medical imaging department was 0.263%. The safety incident reporting rate was calculated (# of incidents reported per modality total/ # of completed exams in that modality x 100%) for each modality and varied from 0.113 to 1.26%. The four highest safety incident rates were from adverse drug reaction (ADR) (21.5%), followed by delay in care/treatment (18.9%), identification/documentation/order (18.5%) and extravasation (11.4%). Possible contributory factors involved transfer of accountability (TOA)/communication barriers, and incorrect ordering information. Further analysis was also completed to assess whether patients that experienced an ADR or extravasation incident followed the correct protocols. DISCUSSION: This study demonstrated the importance of how analysis of incident report data can be used to uncover opportunities for quality improvement in the medical imaging department. However, more information must be collected at the time of safety incident report submission to allow for quality improvement. Investigators hope that by future standardization of safety incident reporting, with the increased use of drop-down menus to capture more open-ended responses, corrective strategies can be implemented to address safety concerns in MI departments. In comparison to incident reporting rates published in similar studies, there may be a significant underrepresentation of safety incident reports filed from underreporting. Reducing barriers to reporting is essential in improving the effectiveness of the current safety incident reporting system.

Lessons Learned: Using the Caprini Risk Assessment Model to Provide Safe and Efficacious Thromboprophylaxis Following Hip and Knee Arthroplasty.

Two of the more common potential complications after arthroplasty are venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolus (PE), and excess bleeding. Appropriate chemoprophylaxis choices are essential to prevent some of these adverse events and from exacerbating others. Risk stratification to prescribe safe and effective medications in the prevention of postoperative VTE has shown benefit in this regard. The Department of Orthopaedic Surgery at Syosset Hospital/Northwell Health, which performs over 1200 arthroplasties annually, has validated and is using the 2013 version of the Caprini Risk Assessment Model (RAM) to stratify each patient for risk of postoperative VTE. This tool results in a culling of information, past and present, personal and familial, that provides a truly thorough evaluation of the patient's risk for postoperative VTE. The Caprini score then guides the medication choices for thromboprophylaxis. The Caprini score is only valuable if the data is properly collected, and we have learned numerous lessons after applying it for 18 months. Risk stratification requires practice and experience to achieve expertise in perioperative patient evaluation. Having access to pertinent patient information, while gaining proficiency in completing the Caprini RAM, is vital to its efficacy. Ongoing, real time analyses of patient outcomes, with subsequent change in process, is key to improving patient care.

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies.

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.

Call to Action to Prevent Venous Thromboembolism in Hospitalized Patients: A Policy Statement From the American Heart Association.

Venous thromboembolism (VTE) is a major preventable disease that affects hospitalized inpatients. Risk stratification and prophylactic measures have good evidence supporting their use, but multiple reasons exist that prevent full adoption, compliance, and efficacy that may underlie the persistence of VTE over the past several decades. This policy statement provides a focused review of VTE, risk scoring systems, prophylaxis, and tracking methods. From this summary, 5 major areas of policy guidance are presented that the American Heart Association believes will lead to better implementation, tracking, and prevention of VTE events. They include performing VTE risk assessment and reporting the level of VTE risk in all hospitalized patients, integrating preventable VTE as a benchmark for hospital comparison and pay-for-performance programs, supporting appropriations to improve public awareness of VTE, tracking VTE nationwide with the use of standardized definitions, and developing a centralized data steward for data tracking on VTE risk assessment, prophylaxis, and rates.

Association of pre-operative medication use with unplanned 30-day hospital readmission after surgery in oncology patients receiving comprehensive geriatric assessment.

BACKGROUND: This study aimed to determine whether pre-operative medication use is associated with unplanned 30-day readmission in elderly people undergoing cancer surgery. METHODS: Patients aged 65 years or older who were scheduled for cancer surgery and presented for comprehensive geriatric assessment were included. Comparisons of variables between patients with readmission and those without readmission were performed by univariate and multivariate analyses. RESULTS: A total of 473 patients were included. Multivariate analysis showed that pre-operative discontinuation-requiring medications (PDRMs) and gastrointestinal/hepato-pancreato-biliary (GI/HPB) cancer were significant factors for 30-day readmission. PDRM increased the risk of readmission by about 2.2-fold. Attributable risk of PDRM to readmission was around 55%. The adjusted odds ratio and attributable risk for GI/HPB surgery was 3.4 (95% CI 1.0-11.5) and 70.8%, respectively. CONCLUSIONS: Medication use has an impact on unplanned 30-day readmission in geriatric oncology patients, further highlighting the importance of medication optimization for elderly patients with cancer surgery.

Incidence and Management of Olaratumab Infusion-Related Reactions.

PURPOSE: Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports. METHODS: Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti-galactose-α-1,3-galactose (anti-α-Gal) antibodies. RESULTS: In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti-α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti-α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials. CONCLUSION: Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.

Adultification of Black Children in Pediatric Anesthesia.

BACKGROUND: Unconscious racial bias in anesthesia care has been shown to exist. We hypothesized that black children may undergo inhalation induction less often, receive less support from child life, have fewer opportunities to have a family member present for induction, and receive premedication with oral midazolam less often. METHODS: We retrospectively collected data on those <18 years of age from January 1, 2012 to January 1, 2018 including age, sex, race, height, weight, American Society of Anesthesiologists (ASA) physical status, surgical service, and deidentified anesthesiology attending physician. Outcome data included mask versus intravenous induction, midazolam premedication, child life consultation, and family member presence. Racial differences between all outcomes were assessed in the cohort using a multivariable logistic regression model. RESULTS: A total of 33,717 Caucasian and 3901 black children were eligible for the study. For the primary outcome, black children 10-14 years were 1.3 times more likely than Caucasian children to receive mask induction (adjusted odds ratio [AOR], 1.3; 95% confidence interval [CI], 1.1-1.6; P = .001). Child life consultation was poorly documented (<0.5%) and not analyzed. Black children <15 years of age were at least 31% less likely than Caucasians to have a family member present for induction (AOR range, 0.4-0.6; 95% CI range, 0.31-0.84; P < .010). Black children <5 years of age were 13% less likely than Caucasians to have midazolam given preoperatively (AOR, 0.9; 95% CI, 0.8-0.9; P = .012). CONCLUSIONS: This study suggests that disparities in strategies for mitigating anxiety in the peri-induction period exist and adultification may be 1 cause for this bias. Black children 10 to 14 years of age are 1.3 times as likely as their Caucasian peers to be offered inhalation induction to reduce anxiety. However, black children are less likely to receive premedication with midazolam in the perioperative period or to have family members present at induction. The cause of this difference is unclear, and further prospective studies are needed to fully understand this difference.

Update on the Use of C1-Esterase Inhibitor Replacement Therapy in the Acute and Prophylactic Treatment of Hereditary Angioedema.

In the vast majority of patients with hereditary angioedema (HAE), angioedema attacks are due to the quantitative or functional deficiency of C1-esterase inhibitor (C1-INH), which leads to increased vascular permeability and unregulated release of bradykinin. Exogenous administration of C1-INH is a rational way to restore the concentration and functional activity of this protein, regulate the release of bradykinin, and attenuate or prevent subcutaneous and submucosal edema associated with HAE. Recent international guidelines for the management of HAE include C1-INH as an option for acute treatment of HAE. In addition, these guidelines recommend C1-INH as first-line treatment for long-term prophylaxis and as the therapy of choice for short-term/preprocedural prophylaxis. Several C1-INH products are available, with approved indications varying across regions. For the acute treatment of HAE, both plasma-derived and recombinant C1-INH formulations have been shown to be effective and well tolerated in adolescents and adults with HAE, with onset of relief within 30 min to a few hours. Plasma-derived C1-INH is approved for use in children, and recombinant C1-INH is being evaluated in this population. Intravenous (IV) and subcutaneous (SC) formulations of C1-INH have been approved for routine prophylaxis to prevent HAE attacks in adolescents and adults. Both formulations when administered twice weekly have been shown to reduce the frequency and severity of HAE attacks. The SC formulation of C1-INH obviates the need for repeated venous access and may facilitate self-administration of HAE prophylaxis at home, as recommended in HAE treatment guidelines. As with most rare diseases, the costs of HAE treatment are high; however, the development of additional acute and prophylactic medications for HAE may result in competitive pricing and help drive down the costs of HAE treatment.

A decade-long clinical experience on the prophylactic use of activated prothrombin complex concentrate in acquired haemophilia A: a case series from a tertiary care centre.

: In acquired haemophilia A (AHA), risk for recurrent bleeding exists until the inhibitor is detectable. Thus, patients with persisting inhibitor may benefit from prophylaxis with activated prothrombin complex concentrate (aPCC). Potential thromboembolic complications and cost are also factors to consider. Today, no high level evidence or clear recommendations are available on aPCC prophylaxis in AHA. Recently, a small prospective study demonstrated a favourable outcome with short-term, daily administered aPCC infusion. Here we report a retrospective case series of 19 patients with AHA to demonstrate our practice on aPCC prophylaxis. In our practice, clinical bleeding tendency guided our decision on the initiation of aPCC prophylaxis. In patients with serious bleeding tendency, aPCC infusion was prolonged beyond bleeding resolution in a twice-weekly or thrice-weekly regimen. Serious bleeding phenotype included a single episode of life-threatening bleeding or recurrent, severe haemorrhages. Patients who did not present such events were treated on-demand. The preventive dose of aPCC was equal with the lowest effective therapeutic dose. Prophylaxis was continued until the inhibitor disappeared. Eleven patients received aPCC prophylaxis. In nine cases, prophylaxis lasted beyond two months. No severe bleeding developed spontaneously and no thromboembolic complication occurred in the median 16 weeks (interquartile range 9-34) duration of prophylaxis. Eight patients of the nonprophylaxis group did not present any severe haemorrhage. According to our experience, we consider prophylaxis with aPCC effective and well tolerated for patients with AHA and serious bleeding tendency, until the acquired inhibitor persists.

Validation of a Patient-Completed Caprini Risk Assessment Tool for Spanish, Arabic, and Polish Speakers.

Targeted prophylaxis for venous thromboembolism (VTE) using the Caprini risk score (CRS) is effective reducing postoperative VTE. Despite its availability as preventive strategy, risk scoring remains underutilized. Critics to the CRS contend the time it takes to complete, and its limitation to English language. Aim is to create and validate patient-completed CRS tools for Spanish, Arabic, and Polish speakers. We translated the first patient-completed CRS to Spanish, Arabic, and Polish. We conducted a pilot study followed by the validation study. Using PASS version 11, we determined that a sample size of 37 achieved a power of 80%, to detect a difference of 0.1 between the null hypothesis correlation of 0.5 and the alternative hypothesis correlation of 0.7 using a 2-sided hypothesis test, significance level of .05. We tabulated and categorized scores using SPSS version 23 to estimate κ, linear correlation, and Bland Altman test. κ value >0.8 was defined as "almost perfect agreement." From 129 recruited patients, 50 (39%) spoke Spanish, 40 (31%) spoke Arabic, and 39 (30%) spoke Polish; average age 51 (16.69) years, 58 (45%) were men, with less than college education (67%). Mean (standard deviation) CRS was 5 (3.90), the majority (63%) above moderate VTE risk. We report excellent agreement comparing physician and patient results (κ = 0.93) and high correlation 0.97 ( P < .01) for the overall score. Bland Altman did not show trend for extreme values. We created and validated the first Spanish, Arabic, and Polish versions of the patient-completed CRS, with excellent correlation and agreement when compared to CRS-trained physician-completed form. Based on these results, the physician needs to calculate the body mass index. Completing the form was not time-consuming.

Assessment of Antihistamines and Corticosteroids as Premedication in Rapid Drug Desensitization to Paclitaxel: Outcomes in 155 Procedures.

BACKGROUND: In early clinical trials, infusion reactions during the administration of taxanes were managed using systematic premedication with antihistamines and corticosteroids before standard infusions. Consequently, these premedications are also administered before rapid drug desensitization (RDD) with taxanes. However, their role in RDD has not been studied. OBJECTIVE: To assess the need for premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions in RDD to paclitaxel. METHODS: Over a 4-year period, we selected patients with confirmed hypersensitivity to paclitaxel (positive skin testing and/or drug provocation testing results) who had received paclitaxel through RDD. These patients were assigned to 2 prospective noninception cohorts: one cohort premedicated with antihistamine and corticosteroids and another cohort that was not. RESULTS: We assessed 66 paclitaxel-reactive patients, of whom 22 met the inclusion criteria. A total of 155 RDDs to paclitaxel were performed. There were no significant differences in tolerance to RDD between the cohorts. CONCLUSIONS: Administering systematic premedication with corticosteroids and antihistamines had no significant effect on the effectiveness or safety of RDD in patients with confirmed hypersensitivity to paclitaxel in the study population. Moreover, these premedications can mask early signs of hypersensitivity and delay treatment. We believe that systematic premedication with these drugs for patients undergoing RDD should be carefully and individually assessed if their only purpose is to prevent breakthrough reactions during RDD.

UK consensus statement on the use of plerixafor to facilitate autologous peripheral blood stem cell collection to support high-dose chemoradiotherapy for patients with malignancy.

Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte-colony stimulating factor [G-CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re-mobilization after a failed mobilization attempt with G-CSF, and rescue or pre-emptive mobilization in patients in whom mobilization with G-CSF is likely to fail. Pre-emptive use has the advantage that it avoids the need to re-schedule the transplant procedure, with its attendant inconvenience, quality-of-life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre-emptive plerixafor is associated with an incremental drug cost of less than £2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 µl-1 at the time of recovery after chemomobilization or after four days of G-CSF treatment, or an apheresis yield of <1 × 106 CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre-emptive plerixafor.

A cost-utility analysis of dabigatran, enoxaparin, and usual care for venous thromboprophylaxis after hip or knee replacement surgery in Thailand.

To analyze the cost-utility of oral dabigatran etexilate, enoxaparin sodium injection, and no intervention for venous thromboembolism (VTE) prophylaxis after total hip or knee replacement (THR/TKR) surgery among Thai patients. A cost-utility analysis using a decision tree model was conducted using societal and healthcare payers' perspectives to simulate relevant costs and health outcomes covering a 3-month time horizon. Costs were adjusted to year 2014. The willingness-to-pay threshold of THB 160,000 (USD 4926) was used. One-way sensitivity and probabilistic sensitivity analyses using a Monte Carlo simulation were performed. Compared with no VTE prophylaxis, dabigatran and enoxaparin after THR and TKR surgery incurred higher costs and increased quality adjusted life years (QALYs). However, their incremental cost-effectiveness ratios were high above the willingness to pay. Compared with enoxaparin, dabigatran for THR/TKR lowered VTE complications but increased bleeding cases; dabigatran was cost-saving by reducing the costs [by THB 3809.96 (USD 117.30) for THR] and producing more QALYs gained (by 0.00013 for THR). Dabigatran (vs. enoxaparin) had a 98 % likelihood of being cost effective. Dabigatran is cost-saving compared to enoxaparin for VTE prophylaxis after THR or TKR under the Thai context. However, both medications are not cost-effective compared to no thromboprophylaxis.