Advancing Equity in Graduate Medical Education Recruitment Through a Diversity Equity and Inclusion (DEI) Toolkit for Program Directors.

Objectives: To increase diversity and inclusion in graduate medical education (GME), the Accreditation Council for Graduate Medical Education (ACGME) issued new diversity standards requiring programs to engage in practices that focus on systematic recruitment and retention of a diverse workforce of trainees and faculty. The literature on how program directors (PDs) can incorporate and prepare for this standard is limited. Methods: We developed a diversity, equity, and inclusion (DEI) toolkit for PDs as an example of an institutional GME-led effort to promote inclusive recruitment and DEI awareness among residency and fellowship programs at a large academic center. Results: A survey was sent to 80 PDs before the launch of the toolkit and 6 months afterwards with response rates of 27% (22/80) and 97% (78/80), respectively. At baseline, 45% (10/22) anticipated that the DEI toolkit might provide better resources than those currently available to them and 41% (9/22) perceived that the toolkit might improve recruitment outcomes. At 6 months, 63% (49/78) found the toolkit helpful in the 2021-2022 recruitment season. By contrast, 2% (2/78) of PDs did not find the toolkit helpful, and 33% (26/78) said they did not access the toolkit. When asked if a PD changed their program's recruitment practices because of the toolkit, 31% (24/78) responded yes. Programs that changed recruitment practices started to require unconscious bias training for all faculty and residents involved in the residency interviews and ranking. Others worked on creating a standardized scoring rubric for interviews focused on four main domains: Experiences, Attributes, Competencies, and Academic Metrics. Conclusion: There is a need to support PDs in their DEI journey and their work to recruit a diverse workforce in medicine. Utilizing a DEI toolkit is one option to increase DEI knowledge, skills, awareness, and self-efficacy among PDs and can be adopted by other institutions and leaders in academic medicine.

Serving on a Graduate Medical Education Diversity, Equity, Inclusion, and Justice Committee: Lessons Learned From a Journey of Growth and Healing.

Efforts toward achieving diversity, equity, inclusion, and justice (DEIJ) within graduate medical education (GME) often begin with the formation of a DEIJ committee that steers the work. Little is known about the experiences and the challenges faced by those serving on such committees. We sought to describe the experiences of members of our institutional GME DEIJ committee to gain knowledge that would propel this work forward. An open-ended survey was electronically administered to members of our institutional GME DEIJ committee. Responses were analyzed using a rapid qualitative analytical approach. Eighteen members (58%) responded. Of these, (67%) were women and five (28%) were Black. Six domains emerged: "motivation," "challenges," "emotional response," "highs," "facilitators," and "advice." Black respondents more often cited the need to increase diversity as a motivator to join this work. Women and Black respondents more often identified time constraints as a challenge to participation. Some members found the work emotionally draining; others described it as uplifting. Two themes emerged as high points of participation-pride and achievement around the work completed and the personal benefits of building a community with a shared purpose. Three themes emerged as facilitators: effective leadership, support, and establishing psychological safety during the meetings. Many arrived at the realization that change would take time and advocated for patience and perseverance. Protected time and DEIJ expertise were identified as integral to successful committee work. Our findings provide novel insights into the experience of serving on a GME DEIJ committee and highlights infrastructural and institutional prerequisites for success.

Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents.

Tobacco use is associated with lethal diseases in an estimated 440,000 persons in the United States each year (Centers for Disease Control and Prevention, 2005). Successful smoking quit-rates are estimated at 5%-8%, even though a quarter of those attempts included use of smoking-cessation aids (Messer et al., 2008; Henningfield et al., 2009). Current projections are that 16% of the U.S. population-35 million people-will still smoke in 2025, thus more effective smoking-cessation aids are urgently needed (Pollock et al., 2009). The minor tobacco alkaloids may be promising candidates, but further research is necessary (Hoffman & Evans, 2013). Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine.

Anatabine supplementation decreases thyroglobulin antibodies in patients with chronic lymphocytic autoimmune (Hashimoto's) thyroiditis: a randomized controlled clinical trial.

CONTEXT: Hashimoto's thyroiditis is less prevalent in tobacco smokers. Anatabine, an alkaloid found in Solanaceae plants including tobacco, has been reported to ameliorate a mouse model of Hashimoto's thyroiditis. OBJECTIVE: The effects of anatabine in patients with Hashimoto's thyroiditis were studied. DESIGN, SETTING, PATIENTS, AND INTERVENTION: This was a double-blind, randomized, placebo-controlled multisite study. A total of 146 patients (70 treated with anatabine and 76 with placebo) completed the study. Approximately 50% of patients in each group were taking levothyroxine. Anatabine lozenges (9-24 mg/d) or placebo, each containing vitamins A and D3, were administered orally 3 times a day for 3 months. MAIN OUTCOME MEASURES: Serum thyroperoxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels were assessed. Safety was assessed through adverse events, clinical laboratory evaluations, and vital sign measurements. RESULTS: Anatabine-treated patients had a significant reduction in absolute serum TgAb levels from baseline by study end relative to those receiving placebo (P=.027); however, there were no significant changes or differences in treatment group means for TPOAb or TgAb levels. Mean±SD TgAb values decreased by 46.2±101.1 and 3.9±83.9 World Health Organization units for the anatabine and placebo groups, respectively. Significantly more patients had a >20% drop in TgAb levels in the anatabine than placebo group (P=.023). Overall, the anatabine supplement was safe and well tolerated, although significantly (P<.05) more patients in the anatabine group reported adverse events. CONCLUSIONS: These results demonstrate an immunological effect of anatabine on TgAb levels. Further studies are warranted to determine the longer-term effects and possible actions of anatabine on the course of Hashimoto's thyroiditis.

Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPßCD-diclofenac (Dyloject) compared with other diclofenac formulations.

STUDY OBJECTIVE: To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN: Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING: Clinical research center. SUBJECTS: Healthy adult volunteers. INTERVENTION: Study 1: Subjects received HPßCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPßCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS: Study 1: IV HPßCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPßCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPßCD-diclofenac (IV) to HPßCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPßCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPßCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). CONCLUSIONS: Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPßCD-diclofenac compared with Voltarol and after IM administration of HPßCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPßCD-diclofenac was equivalent to IV administration of HPßCD-diclofenac and IV administration of Voltarol. Study 2: HPßCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPßCD-diclofenac. HPßCD-diclofenac was safe and well tolerated following IV and IM administration.

Effects of injectable HPßCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo.

BACKGROUND: Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. OBJECTIVE: This study evaluated the proarrhythmic potential of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD), on ventricular electrical conduction in preclinical and clinical models. METHODS: We assessed the effects of diclofenac, HPßCD, and HPßCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPßCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). RESULTS: In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPßCD or HPßCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPßCD in this in vitro model. In vivo, neither HPßCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPßCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS: The findings from the present study suggest that HPßCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: a randomized, single dose, crossover study in healthy male volunteers.

STUDY OBJECTIVE: To assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg. DESIGN: Open-label, randomized, single-dose, 4-treatment crossover study. SETTING: Clinical research unit. PATIENTS: 30 healthy, ASA physical status I adult men. INTERVENTIONS: Subjects were randomized to one of 6 treatment sequences that included 4 single-dose treatments. Study drug administration occurred on Days 1, 3, 5, and 7. MEASUREMENTS: Platelet count, closure time as measured by platelet function analyzer (PFA-100), prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma concentrations of the study drugs were obtained over 24 hours after each treatment. The primary endpoint was the area under the curve for PFA collagen-epinephrine (CEPI) closure time difference from 0-6 hours post-drug administration (AUC(0-6h)). Secondary endpoints included the maximum change from baseline in PFA CEPI closure time. MAIN RESULTS: AUC(0-6h) (mean ± SD) for CEPI closure time difference was significantly smaller after IV diclofenac 37.5 mg (249 ± 216 sec.hrs) than after ketorolac [and ASA (950 ± 287 sec.hrs and 834 ± 237 sec.hrs, respectively); P ≤ 0.0001 for both] but not after the oral diclofenac control (286 ± 265 sec.hrs; P = 0.40). Similarly, the maximum change from baseline in PFA CEPI closure time was lower after IV diclofenac than after ketorolac or ASA across all time intervals examined. There were no significant changes in PT or aPTT at any time point with any treatment. There was a low frequency of adverse events. CONCLUSIONS: Acetylsalicylic acid and ketorolac both substantially disrupted platelet function in contrast to IV diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than nonsteroidal antiinflammatory drugs (NSAIDs) such as ketorolac and ASA, which predominantly inhibit COX-1.

Risk evaluation and mitigation strategies for drugs with abuse liability: public interest, special interest, conflicts of interest, and the industry perspective.

Risk evaluation and mitigation strategies (REMS) formerly known as Risk Minimization Action Plans (RiskMAPs) are a regulatory technique for dealing with anticipated risks of new medications and are especially important for new drugs with abuse potential. This paper describes the origin and history of risk-management plans for drugs that might be abused, the proper use of these plans in minimizing the risk to the public, and the special difficulties inherent in managing risks for drugs with abuse potential. Drugs with abuse liability are distinctive since the risks inherent in manufacture and distribution include not only risks to patients prescribed the medications, but also risks to the general public including subgroups in the population not intended to get the drug and who receive no medical benefit from the medication. The crafting of risk-management plans intended to protect nonpatient populations is unique for these products. The content, extent, and level of intensity of these plans affect areas of medical ethics, civil liability, and criminal prosecution. The need for risk-management plans for drugs with abuse liability can potentially act as a deterrent to investment and is a factor in decisions concerning the development of new medications for the treatments of pain, ADHD, anxiety disorders, and addictions. This paper provides a framework for moving the process of REMS development forward and criteria for evaluating the probity and adequacy of such programs.

Analgesic efficacy and safety of morphine-chitosan nasal solution in patients with moderate to severe pain following orthopedic surgery.

INTRODUCTION: Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. METHODS: In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a dose-response assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. RESULTS: A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. CONCLUSIONS: By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.

Risk identification, risk assessment, and risk management of abusable drug formulations.

There is a demand for pharmaceutical products with reduced abuse liability. These products must meet three tests to be successful. They must be safe for patients, be less likely to injure the abuser, and be less desirable for abuse by established drug abusers relative to existing products on a dose for dose (milligram-equivalent) basis. There is a need for standardization of the evaluation of abusable pharmaceuticals in the various stages of drug development from preclinical animal studies to postmarketing surveillance. Formulations with reduced abuse liability must: (1) be tested using standard animal, benchtop, and human pharmacokinetic methods that allow interpretation, (2) sufficiently reduce the recovery of abusable drug substance, or contain another ingredient to deter abuse, (3) not alter drug activity for patients in an undesirable or risky way, and (4) have an accurate pre-approval estimation of their reduced abuse liability, which is validated by adequate epidemiologic post-approval surveillance.

Association between non-medical and prescriptive usage of opioids.

Understanding and managing prescription opioid abuse is one of the major challenges in pain management worldwide. The relationships between prescriptive usage of opioids and reported morbidity at the national level, using data from the Drug Abuse Warning Network (DAWN), were examined. When the major prescription opioids were evaluated, the association between prescriptive medical use in kilograms and reported morbidity, as measured by a ratio between the two, was similar for the intermediate-potency opioids (hydrocodone, methadone, oxycodone, and morphine). This rate was much lower for low-potency opioids (codeine, meperidine, pentazocine, and propoxyphene) and much greater for high-potency opioids (hydromorphone and fentanyl). When the drugs were adjusted by potency (relative to morphine), the rates of reported morbidity per kilogram of morphine equivalent opioid in prescriptive usage were similar among the opioids. Using the potency-adjusted total kilograms of opioid in prescriptive use for all the opioids evaluated, there was a statistically significant association (r(2)=0.9791) with the reported morbidity for prescription analgesics as a class, as measured in the DAWN system. These data suggest that non-medical use of opioids is predictable based on potency and extent of prescriptive use.

Hyperalgesia in outpatients with dermal injury: quantitative sensory testing versus a novel simple technique.

OBJECTIVE: Dermal inflammation from many causes may produce a reversible period of hyperalgesia (increased sensitivity to pain perception) or allodynia (pain from innocuous stimuli). Hyperalgesia and allodynia have received relatively little attention in clinical trials of acute pain. We sought to quantitate tactile allodynia and thermal hyperalgesia in outpatients presenting with acute dermal injuries. DESIGN: We performed a randomized clinical trial to compare standard methodology for the assessment of hyperalgesia with two novel simple quantitative techniques. PATIENTS: After Institutional Review Board approval, 40 patients presenting with acute chemical, thermal, mechanical, or infectious skin injury were subjected to a series of tests at the site of injury, an intact mirror site, and a noninjured ipsilateral control site. OUTCOME MEASURES: Quantitative thermal sensory testing (Medoc sensory analyzer) was followed by a 5-second application, in random order, of copper rods preheated in water to 40 degrees C, 43 degrees C, 46 degrees C, and 49 degrees C. Pressure testing was conducted with a 1.25-inch diameter commercially available pressure transducer gauge. RESULTS: The observed pattern of responses was remarkably consistent among testing methods. All challenges with the four different temperatures elicited pain scores on a visual analog scale markedly greater at the injured than at the mirror or control site (P < 0.001 vs control). Pressure discomfort thresholds followed a similar pattern. CONCLUSIONS: We conclude that hyperalgesia is a prominent contributor to discomfort in acute dermal injury and hence is a legitimate therapeutic target. Quantitation of the contribution of thermal hyperalgesia and tactile allodynia and assessment of their management is feasible using simple, rugged, low-cost methods. This inexpensive methodology may be useful in everyday clinical practice as well as in clinical research evaluating pharmacological agents to manage hyperalgesia.

Assessment of patients' perceptions of bowel preparation quality at colonoscopy.

AIMS: There is little published literature evaluating the accuracy of patients' perceptions of the quality of their own bowel preparation for colonoscopy. The aim of this article was to compare patients' perceptions of the adequacy of their bowel preparation with the endoscopists' rating at colonoscopy. METHODS: Outpatients undergoing elective colonoscopy completed surveys assessing bowel preparation. Patient responses regarding quality of bowel preparation were compared with endoscopists' assessment of colonic preparation. A residual stool score was also calculated for each subject based on the amount of stool, consistency of residual stool, and percentage of bowel visualized. RESULTS: A total of 474 patients were enrolled. Patients' perceptions of the quality of their bowel preparation were inaccurate when compared to the endoscopists' rating (sensitivity, 75%; specificity, 34%; accuracy, 50%). Overall correlation with endoscopists' rating was low, r = 0.08. Young patient age (<61 yr) was an independent predictor of both adequate bowel preparation ( p= 0.009) and agreement of patient/endoscopist ratings ( p= 0.003). CONCLUSIONS: Patients are unreliable judges of the quality of their own bowel preparation, tending to overestimate the cleanliness of their colon. Conversely, a patient's fear that their preparation is suboptimal is also inaccurate. A colonoscopy should not be canceled on the basis of a patient's perception that the quality of their preparation is poor.

Impact on patient outcomes of experience in the performance of endoscopic pancreatic fluid collection drainage.

BACKGROUND: Much attention has been focused on the competence to perform endoscopic procedures. The aim of this study was to determine the impact of procedure experience on patient outcomes after endoscopic pancreatic fluid collection drainage. METHODS: Outcomes for consecutive patients with symptoms from pancreatic fluid collections who were referred for endoscopic transmural and/or transpapillary drainage were analyzed retrospectively. Collections were classified as acute pseudocyst, chronic pseudocyst, and pancreatic necrosis. To assess the impact of endoscopist experience, outcomes for patients who underwent the first 20 procedures were compared with those for patients who had subsequent procedures. RESULTS: In total, 175 patients underwent pancreatic fluid collection drainage; 40 (23%) acute pseudocyst, 78 (44%) chronic pseudocyst, and 57 (33%) pancreatic necrosis. Procedure complication rates, collection recurrence rates, and patient outcomes after acute pseudocyst drainage were independent of endoscopist experience. There was a dramatic improvement in chronic pseudocyst resolution rates after the first 20 procedures versus subsequent procedures (45% vs. 93%; p = 0.0002) and a reduction in days to resolution (50 days, initial 20 procedures vs. 33.5 days, subsequent procedures; p = 0.05). In patients with pancreatic necrosis, there was a decrease in median hospital stay with greater experience (23 days to 15 days; p = 0.04). CONCLUSIONS: Resolution of chronic pseudocyst after endoscopic drainage improves markedly with increasing endoscopist experience. Future prospective studies assessing skill acquisition are required to define the minimum number of collection drainage procedures at which competence can be achieved.

Current concepts in abuse liability testing for pharmaceuticals July 2002: new lessons for a new century.

New pharmaceuticals, new pharmaceutical delivery systems and old pharmaceuticals used in new ways may have to be tested for abuse liability. Needless testing wastes valuable resources and talent, and adds delay and expense to the development of new medications. Failing to conduct appropriate abuse liability testing can cost lives and create needless suffering. Selecting which tests are to be conducted is an expert decision to be individualized in each case, and should be directed by the pharmacology of the drug, the therapeutic indication being sought, the characteristics of the delivery system or dosage form, the population intended for treatment and specific knowledge of historic, current and emerging patterns and trends in drug abuse.