Estimating Cannabis Involvement in Fatal Crashes in Washington State Before and After the Legalization of Recreational Cannabis Consumption Using Multiple Imputation of Missing Values.

The government of Washington state legalized recreational cannabis consumption in December 2012. We used data on all drivers involved in fatal crashes in Washington in the years 2008-2019 (n = 8,282) to estimate prevalence in fatal crashes of drivers with ∆9-tetrahydrocannabinol (THC; the main psychoactive compound in cannabis) in their blood before and after legalization. However, nearly half of the drivers were not tested for drugs; we therefore used multiple imputation to estimate THC presence and concentration among them. We used logistic regression followed by marginal standardization to estimate the adjusted prevalence of THC-positive drivers after legalization relative to what would have been predicted without legalization. In the combined observed and imputed data, the proportion of drivers positive for THC was 9.3% before and 19.1% after legalization (adjusted prevalence ratio: 2.3, 95% confidence interval: 1.3, 4.1). The proportion of drivers with high THC concentrations increased substantially (adjusted prevalence ratio: 4.7, 95% confidence interval: 1.5, 15.1). Some of the increased prevalence of THC-positive drivers might have reflected cannabis use unassociated with driving; however, the increased prevalence of drivers with high THC concentrations suggests an increase in the prevalence of driving shortly after using cannabis. Other jurisdictions should compile quantitative data on drug test results of drivers to enable surveillance and evaluation.

Single Pass Diafiltration Integrated into a Fully Continuous mAb Purification Process.

The concept of continuous manufacturing has gained significant interest from the biopharmaceutical industry over the past several years. Benefits include increased manufacturing productivity, improved quality control, reduction in plant footprint, and more flexible management of facility capacity. There are several technologies currently available that enable continuous processing for chromatography and ultrafiltration. However, a single pass diafiltration design that meets the required small molecule clearance and has been integrated into a fully continuous monoclonal antibody purification process has not been previously published. Here, the theory and design of a 3-stage single pass diafiltration step is presented. Buffer exchange greater than 99.75% was experimentally demonstrated. Several critical design aspects were incorporated to minimize system complexity and reduce the buffer volume requirements. Lastly, single pass diafiltration was demonstrated in a pilot scale continuous process with uninterrupted flow from the bioreactor through the formulation step. This work illustrates the feasibility of incorporating a single pass diafiltration step into an end-to-end continuous protein purification process. This article is protected by copyright. All rights reserved.

Single pass diafiltration integrated into a fully continuous mAb purification process.

The concept of continuous manufacturing has gained significant interest from the biopharmaceutical industry over the past several years. Benefits include increased manufacturing productivity, improved quality control, reduction in plant footprint, and more flexible management of facility capacity. There are several technologies currently available that enable continuous processing for chromatography and ultrafiltration. However, a single pass diafiltration design that meets the required small molecule clearance and has been integrated into a fully continuous monoclonal antibody purification process has not been previously published. Here, the theory and design of a 3-stage single pass diafiltration step is presented. Buffer exchange greater than 99.75% was experimentally demonstrated. Several critical design aspects were incorporated to minimize system complexity and reduce the buffer volume requirements. Lastly, single pass diafiltration was demonstrated in a pilot scale continuous process with uninterrupted flow from the bioreactor through the formulation step. This work illustrates the feasibility of incorporating a single pass diafiltration step into an end-to-end continuous protein purification process.

GLYCEMIC OUTCOMES 3 YEARS AFTER IMPLEMENTATION OF A PERI-OPERATIVE GLYCEMIC CONTROL ALGORITHM IN AN ACADEMIC INSTITUTION.

OBJECTIVE: While hyperglycemia in the postoperative setting has been linked to an increase in surgical complications, limited data are available to inform the management of patients with diabetes in the operating room and the immediate peri-operative period. We describe the results of a peri-operative glycemic control program that standardized intravenous insulin with a target glucose (BG) range of 120 to 180 mg/dL for patients with diabetes presenting with a BG level >180 mg/dL and included transition to subcutaneous insulin. METHODS: Patients with known diabetes and a BG >180 mg/dL who underwent surgery were included. The control group included 260 patients from March 2, 2008 through December 31, 2008. The intervention group included 588 patients following protocol implementation from April 1, 2009 through December 31, 2012. Data included demographic information, hospital BG values, length of stay (LOS), mortality, and wound infections. RESULTS: The intervention group had significantly lower BG on arrival in the postoperative care unit (182.2 vs 194.9 mg/dL, P = .012). Mean BG during the first 24 hours after surgery was lower in the intervention group (182.1 vs. 190.5 mg/dL), and there were fewer BG values >200 mg/dL in the intervention group (P = .005). The percentage of BG values <70 mg/dL during the hospital stay was lower in the intervention group (1.94 vs. 2.43%, P<.01). There was no significant difference in mortality, LOS, or wound infections. CONCLUSION: Following implementation of a hospital-wide peri-operative glycemic control algorithm, we found a reduction in peri-operative BG levels and hypoglycemia rates. Ongoing research is needed to assess the impact on clinical outcomes. ABBREVIATIONS: BG = blood glucose CCI = Charlson comorbidity index EHR = electronic health record ICD-9 = International Classification of Disease-9 IV = intravenous LOS = length of stay OR = operating room PACU = postoperative care unit POC = point-of-care.

HYPOGLYCEMIA RATES AFTER RESTRICTION OF HIGH-DOSE GLARGINE IN HOSPITALIZED PATIENTS.

OBJECTIVE: Hypoglycemia remains one of the main challenges of insulin therapy. To reduce insulin-related hypoglycemia at our institution, we restricted inpatient ordering of high glargine doses (≥0.5 U/kg/day) to endocrine staff in May 2013. This retrospective cohort study assesses its effect on hypoglycemia and glycemic control within 48 hours of admission (ADM). METHODS: We identified 692 adult patients hospitalized at Boston Medical Center who received glargine upon ADM from November 1, 2012 through April 30, 2013 as the pre-intervention group, and 651 adult patients admitted between November 1, 2013 and April 30, 2014 as the postintervention group. Demographics, medical history, home insulin regimen, concurrent oral diabetes medications or glucocorticoid administration, ADM serum creatinine, all blood glucose levels (BG) ≤48 hours of ADM, and hemoglobin A1c values ≤3 months were assessed. Hypoglycemia was defined as BG ≤70 mg/dL, and hyperglycemia as BG ≥200 mg/dL. Multivariable regression models assessed potential associations between covariates and incidence of hypoglycemia and average BG ≤48 hours of ADM. RESULTS: Demographics were similar between groups. Significantly less patients received high-dose glargine in the post-intervention group (5.2% vs. 0.3%, P<.001). Incidences of hypoglycemia were significantly lower in the postintervention group (20.9% vs. 17.8%, P<.001 per ADM; 3.4% vs. 2.3%, P = .001 per BG measurements [BGM]). Mean BG levels ≤48 hours of ADM and incidence of hyperglycemia were not significantly different. The adjusted incident rate ratio of hypoglycemia was 0.63 per ADM and 0.74 per BGM in the postintervention group compared to the pre-intervention group (P = .001 and P = .063, respectively). CONCLUSION: We found that implementation of a restriction on high doses of glargine resulted in lower rates of hypoglycemia without worsening glycemic control. ABBREVIATIONS: ADM = admission BG = blood glucose BGM = blood glucose measurements BMC = Boston Medical Center BMI = body mass index EMR = electronic medical record HgbA1c = hemoglobin A1c IRR = incidence rate ratio NPH = neutral protamine Hagedorn TDD = total daily dose T2D = type 2 diabetes.

Novel thermo-responsive fucose binding ligands for glycoprotein purification by affinity precipitation.

Novel thermo-responsive affinity sugar binders were developed by fusing a bacterial fucose lectin with a thermo-responsive polypeptide. These designer affinity ligand fusions were produced using an Escherichia coli system capable of extracellular secretion of recombinant proteins and were isolated with a high recovery yield (95%) directly from growth medium by Inverse Temperature Cycling (ITC). With horse radish peroxidase (HRP) as a model protein, we demonstrate here that the designer thermo-responsive ligands are capable of interacting with glycans on a glycoprotein, a property that was used to develop a novel affinity precipitation method for glycoprotein purification. The method, requiring only simple process steps, affords full recovery of a target glycoprotein, and is effective at a target glycoprotein concentration as low as 1.4 pM in the presence of large amounts of contaminants. By developing other sugar binders in the similar fashion, the method should be highly useful for glycoprotein purification and detection.

Gender inequality in PGY1 residency leadership positions and conferral of health-system pharmacy professional awards.

PURPOSE: To address gender inequality, the American Society of Health-System Pharmacists (ASHP) created a steering committee that recommended the collection of baseline and ongoing metrics of pharmacy leadership. The purpose of this study was to quantify gender inequality in distributions of residency program director (RPD) and director of pharmacy (DOP) positions and to investigate gender distributions among recipients of ASHP professional leadership awards. METHODS: RPD and DOP information for postgraduate year 1 (PGY1) programs included in the online ASHP residency directory were collected in December of 2020. Publicly available records were used to collect information on recipients of the Harvey A.K. Whitney Award and John W. Webb Award during the periods 1950-2020 and 1985-2020, respectively. Gender information for RPDs, DOPs, and award recipients was collected from listed pronouns available in public records. A χ 2 test was used for analysis of the collected data. RESULTS: A total of 1,176 PGY1 residency programs were included. Of the RPD positions assessed, 66% (n = 775) were filled by women pharmacists (P < 0.0001), while the percentage of DOP leadership positions held by women was 42% (n = 496) (P < 0.0001). Evaluation of data on recipients of the Harvey A.K. Whitney Award and John W. Webb Award revealed the occurrence of female recipients is 19.7% (n = 14) and 16.7% (n = 6), respectively (P < 0.0001). CONCLUSION: RPD positions have a higher prevalence of being filled by women. DOP positions remain male-dominated and revealed gender inequality among senior-level leadership roles. Pharmacy leadership award analysis identified further gender inequality. The results from the study serve as a baseline of current gender metrics for pharmacy leaderships in hospital systems with PGY1 residency programs.

Fatal hit-and-run crashes: Factors associated with leaving the scene.

INTRODUCTION: Hit-and-run crashes are a criminal offense that leave the victim without prompt medical care or the ability to receive financial compensation. METHOD: The purpose of the current study was to quantify the factors associated with the probability that a driver leaves the scene of a fatal crash, using multiple imputation to incorporate information from drivers who were never apprehended and thus whose characteristics were unknown. RESULTS: The results of this study show that in addition to driver, vehicle, and environmental factors having significant impacts on the likelihood of a driver fleeing the scene, economic and demographic factors are important as well. Practical Applications: This analysis allows for a more holistic understanding of hit-and-run crashes and informs potential countermeasures and future research.

Sexual Harassment during Residency Training: A Cross-Sectional Analysis.

The reality of sexual harassment is unmasking in many fields, and medical trainees constitute a vulnerable and at-risk group. We report the prevalence of sexual harassment among GI, internal medicine, and pediatric residents, with a focus on identifying underlying reasons for lack of victim reporting. A modified previously validated Department of Defense survey on sexual harassment was e-mailed to 261 GI, 132 pediatric, and 271 internal medicine program directors. Three hundred eighty-one residents responded to the survey. Female trainees were more likely to be subject to sexual harassment (83% vs 44%, P <0 .0001). Offensive and/or suggestive jokes and comments were the most common type of harassment experienced. Most residents were unlikely to report the offender (87% females, 93% males). Although 77 per cent of residents believed they would be supported by their program if they reported a sexual harassment event, only 43 per cent were aware of institutional support in place for victims at their program. Although there is a persistently high incidence of harassment in training, the avenues in which to report it are largely unknown and underused. Further research should focus on evidence-based interventions to encourage reporting and to design institutional programs for victims of sexual harassment.

Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm.

The changing landscape of the biopharmaceutical market is driving a paradigm shift toward continuous manufacturing. To date, integrated continuous bioprocessing has not been realized as enabling technologies are nascent. In this work, a fully integrated continuous process is successfully demonstrated from pilot scale bioreactor to drug substance. Comparable product quality is observed between the continuous process and a 500 L fed-batch conventional process. The continuous process generated material at a rate of 1 kg of purified mAb every 4 days, achieving a 4.6-fold increase in productivity compared to the fed-batch process A plant throughput analysis using BioSolve software shows that a fed-batch facility with 4 × 12 500 L stainless steel bioreactors and purification train of the corresponding scale can be replaced by a continuous facility consisting of 5 × 2000 L single use bioreactors and smaller purification train, with a cost reduction of 15%.

An Integrated Approach to Aggregate Control for Therapeutic Bispecific Antibodies Using an Improved Three Column Mab Platform-Like Purification Process.

Single chain variable fragment-IgGs (scFv-IgG) are a class of bispecific antibodies consisting of two single chain variable fragments (scFv) that are fused to an intact IgG molecule. A common trend observed for expression of scFv-IgGs in mammalian cell culture is a higher level of aggregates (10%-30%) compared to mAbs, which results in lower purification yields in order to meet product quality targets. Furthermore, the high aggregate levels also pose robustness risks to a conventional mAb three column platform purification process which uses only the polishing steps (e.g., cation exchange chromatography [CEX]) for aggregate removal. Protein A chromatography with pH gradient elution, high performance tangential flow filtration (HP-TFF) and calcium phosphate precipitation were evaluated at the bench scale as means of introducing orthogonal aggregate removal capabilities into other aspects of the purification process. The two most promising process variants, namely Protein A pH gradient elution followed by calcium phosphate precipitation were evaluated at pilot scale, demonstrating comparable performance. Implementing Protein A chromatography with gradient elution and/or calcium phosphate precipitation removed a sufficient portion of the aggregate burden prior to the CEX polishing step, enabling CEX to be operated robustly under conditions favoring higher monomer yield. From starting aggregate levels ranging from 15% to 23% in the condition media, levels were reduced to between 2% and 3% at the end of the CEX step. The overall yield for the optimal process was 71%. Results of this work suggest an improved three-column mAb platform-like purification process for purification of high aggregate scFv-IgG bispecific antibodies is feasible. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2720, 2019.

Gastrointestinal and liver diseases and atrial fibrillation: a review of the literature.

Atrial fibrillation (AF) is the most common arrhythmia worldwide and is associated with significant morbidity and mortality. A number of risk factors have been associated with AF, though few studies have explored the association between gastrointestinal and liver diseases and AF. Additionally, AF and treatment for AF may predispose to gastrointestinal and liver diseases. We review the current literature on the bidirectional associations between gastrointestinal and liver diseases and AF. We highlight the gaps in knowledge and areas requiring future investigation.

Stop the Bleed: Is Mass Education the Best Approach?

The Stop the Bleed (STB) course teaches trainees prehospital hemorrhage control with a focus on mass education. Identifying populations most likely to benefit can help save on the significant cost and limited resources. In this study, we attempted to identify those populations and performed a cost analysis. Trainees underwent STB education and completed a survey on completion to assess demographics and prior experiences where STB skills could have been useful. Five hundred seventy-one trainees categorized as first responders (14%), students (56%), and the working public (30%) completed the survey. Most trainees found the lecture and simulation helpful, 96 per cent and 98 per cent, respectively. There were significant differences among groups who had previously been in situations where the STB course would have been helpful (88% first responders versus 40% students versus 43% public workers) (P < 0.001). Teaching a class of 10 students costs approximately $455; the cost can be as high as $1246 for a class of 50 students. Most STB trainees found the course helpful. First responders are most likely to be exposed to situations where course information could be helpful. Focusing on specific high-yield groups rather than mass education might be a more efficient approach to STB education.

Outcomes associated with vasoactive therapy in patients with acute decompensated heart failure.

STUDY OBJECTIVES: To describe the clinical management of acute decompensated heart failure (ADHF) in patients receiving intravenous treatment with dobutamine, milrinone, or nesiritide, and to evaluate differences, based on treatment received, in the in-hospital mortality rate, length of stay (LOS), total health care costs, and 30-day hospital readmission rate. DESIGN: Retrospective cohort analysis. DATA SOURCE: University HealthSystem Consortium (UHC) Clinical Database Pharmacy, a database with information from 32 academic hospitals. PATIENTS: Two thousand one hundred thirty patients with ADHF who received dobutamine (1311 patients), milrinone (433), or nesiritide (386). MEASUREMENTS AND MAIN RESULTS: Patients with ADHF were categorized according to the vasoactive therapy received. To evaluate baseline characteristics, chi(2) analysis was used; logistic regression was employed to assess the relationships between drug therapy and in-hospital mortality rates, and multivariate linear regression was used to assess whether drug therapy was related to LOS and total health care costs. All regression analyses controlled for age, sex, race, region of the United States where the hospital was located, primary payer for the hospital stay, UHC patient severity class, and chronic renal failure. In-hospital mortality rates were 10.2%, 7.9%, and 2.9% in the dobutamine, milrinone, and nesiritide groups, respectively. This resulted in an adjusted odds ratio for death of 3.5 (95% confidence interval [CI] 1.8-6.8) for dobutamine and 3.9 (95% CI 1.8-8.3) for milrinone (p<0.0001). Compared with inotropic therapy (dobutamine and milrinone), mean LOS in the hospital and the intensive care unit were lower with nesiritide (p<0.001). Total health care costs were lowest with nesiritide, but this reached statistical significance only when compared with milrinone (p<0.001). Thirty-day hospital readmission rates with dobutamine, milrinone, and nesiritide were 5.0%, 9.5%, and 3.9%, respectively (p=NS). CONCLUSION: Nesiritide therapy was associated with a lower in-hospital mortality rate and shorter LOS compared with dobutamine and milrinone. In addition, total health care costs with nesiritide were decreased compared with milrinone. These observations need to be validated by a randomized controlled trial.

Moxifloxacin and warfarin: additional evidence for a clinically relevant interaction.

Several case reports have been published regarding an interaction between fluoroquinolones and warfarin; however, the exact mechanism of the interaction has yet to be established. We describe three patients who were receiving warfarin and experienced increases in international normalized ratio (INR) when moxifloxacin was added. Two of the patients had stable anticoagulation regimens and then experienced persistent elevations in their INRs shortly after therapy with moxifloxacin was started. The third patient experienced a dramatic rise in INR after the first dose of moxifloxacin was administered. These cases strengthen the evidence that an interaction does exist despite manufacturer-generated statements to the contrary. Increased awareness of this potential interaction is necessary to ensure appropriate monitoring and improve therapeutic decision making.

The relationship between age and driving attitudes and behaviors among older Americans.

BACKGROUND: Due to a decreasing birth rate and longer life expectancy, the proportion of Americans over the age of 65 is expected to rise in coming years. Drivers over 65 drive two billion miles yearly, a number that will increase. For that reason, it is imperative to understand their attitudes and perceptions. It is also important to understand whether drivers over 65 can be treated as one cohesive group, or if there are differences among them. METHODS: A web-enabled survey was conducted among Americans in the years 2011-2013. Responses from 1793 persons over 65 regarding attitudes towards driving behaviors, support for safety interventions, and engagement in unsafe behaviors were analyzed. Respondents were stratified by age: 65-69, 70-74, and 75 and older. Age groups were compared using logistic regression. Other potential explanatory factors were analyzed and controlled for. RESULTS: The three groups were similar on many outcomes. However, statistically significant differences were found between them with regard to perceptions on speeding and the support for speed cameras, among other outcomes. In nearly all cases, those 75 and older were the most "pro-safety." However, when adjusted for demographic characteristics other than age, a larger proportion of respondents 75 and older reported engaging in red light running and drowsy driving in the last 30 days, and the difference was statistically significant. CONCLUSION: Older drivers are strongly "pro-traffic safety." However, the finding that those 65-69 are less so is concerning. This is especially true if it is the result of a cohort effect instead of an age effect. The increase in certain behaviors among those 75 and older is also concerning; drivers over this age are more prone to fatal injury when involved in a motor vehicle crashes. This poses a public health issue as the 75and older population expands.

Factors associated with hit-and-run pedestrian fatalities and driver identification.

As hit-and-run crashes account for a significant proportion of pedestrian fatalities, a better understanding of these crash types will assist efforts to reduce these fatalities. Of the more than 48,000 pedestrian deaths that were recorded in the United States between 1998 and 2007, 18.1% of them were caused by hit-and-run drivers. Using national data on single pedestrian-motor vehicle fatal crashes (1998-2007), logistic regression analyses were conducted to identify factors related to hit-and-run and to identify factors related to the identification of the hit-and-run driver. Results indicate an increased risk of hit-and-run in the early morning, poor light conditions, and on the weekend. There may also be an association between the type of victim and the likelihood of the driver leaving and being identified. Results also indicate that certain driver characteristics, behavior, and driving history are associated with hit-and-run. Alcohol use and invalid license were among the leading driver factor associated with an increased risk of hit-and-run. Prevention efforts that address such issues could substantially reduce pedestrian fatalities as a result of hit-and-run. However, more information about this driver population may be necessary.

Importance of direct patient care in advanced pharmacy practice experiences.

The Accreditation Council for Pharmacy Education issued revised standards (Standards 2007) for professional programs leading to the Doctor of Pharmacy degree in July 2007. The new standards require colleges and schools of pharmacy to provide pharmacy practice experiences that include direct interaction with diverse patient populations. These experiences are to take place in multiple practice environments (e.g., community, ambulatory care, acute care medicine, specialized practice areas) and must include face-to-face interactions between students and patients, and students and health care providers. In 2009, the American College of Clinical Pharmacy (ACCP) identified concerns among their members that training for some students during the fourth year of pharmacy curriculums are essentially observational experiences rather than encounters where students actively participate in direct patient care activities. These ACCP members also stated that there is a need to identify effective mechanisms for preceptors to balance patient care responsibilities with students' educational needs in order to fully prepare graduates for contemporary, patient-centered practice. The 2010 ACCP Educational Affairs Committee was charged to provide recommendations to more effectively foster the integration of pharmacy students into direct patient care activities during advanced pharmacy practice experiences (APPEs). In this commentary, the benefits to key stakeholders (pharmacy students, APPE preceptors, clerkship sites, health care institutions, academic pharmacy programs) of this approach are reviewed. Recommendations for implementation of direct patient care experiences are also provided, together with discussion of the practical issues associated with delivery of effective APPE. Examples of ambulatory care and acute care APPE models that successfully integrate pharmacy students into the delivery of direct patient care are described. Enabling students to engage in high-quality patient care experiences and to assume responsibility for drug therapy outcomes is achievable in a variety of practice settings. In our opinion, such an approach is mandatory if contemporary pharmacy education is to be successful in producing a skilled workforce capable of affecting drug therapy outcomes.