The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239.

Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.

Amoeba species colonizing the gills of rainbow trout (Oncorhynchus mykiss) in Swiss aquaculture.

Nodular gill disease (NGD) is an infectious condition characterized by proliferative gill lesions leading to respiratory problems, oxygen deficiency and mortality in fish. Globally, NGD primarily impacts freshwater salmonids in intensive aquaculture systems. In recent years, numerous outbreaks of severe gill disease have affected more than half of the larger rainbow trout (Oncorhynchus mykiss) farms in Switzerland, mainly during spring and early summer. Mortality has reached up to 50% in cases where no treatment was administered. Freshwater amoeba are the presumed aetiologic agent of NGD. The gross gill score (GS) categorising severity of gill pathology is a valuable first-line diagnostic tool aiding fish farmers in identifying and quantifying amoebic gill disease (AGD) in farmed marine salmonids. In this study, the GS was adapted to the NGD outbreak in farmed trout in Switzerland. In addition to scoring disease severity, gill swabs from NGD-affected rainbow trout were sampled and amoeba were cultured from these swabs. Morphologic and molecular methods identified six amoeba strains: Cochliopodium sp., Naegleria sp., Vannella sp., Ripella sp., Saccamoeba sp. and Mycamoeba sp. However, the importance of the different amoeba species for the onset and progression of NGD still has to be evaluated. This paper presents the first description of NGD with associated amoeba infection in farmed rainbow trout in Switzerland.

The Relationship between Plastic Surgery Residency Instagram Characteristics and Doximity Rank.

Social media provides unique insight into the facilities, personnel, and culture of plastic surgery residency programs. Applicants can gain a more holistic view of programs based on their social media accounts. This study aims to evaluate the relationship between the popularity of a program's Instagram account and the program's Doximity ranking and to investigate the factors which contribute to greater viewership, with a special focus on diversity. Methods: Using Doximity's 2021-2022 Residency Navigator, a list of all integrated plastic surgery residency programs was obtained, and their social media accounts were documented. Instagram accounts were analyzed for metrics, post content, and website links. A 15-month period of posts was analyzed, then grouped into eight categories. Diversity was assessed using average Fitzpatrick skin type for each post containing photographs of people. Results: Of the 88 programs, 85 (96.6%) had an Instagram account at the time of analysis. Analysis of Instagram post content found that personnel and social function posts had significantly more likes than other categories. Posts with average Fitzpatrick type greater than or equal to III also had significantly more likes. Linear regression demonstrated a positive relationship between higher Doximity rank and number of followers; however, there was no clear relationship between rank and posts per week or engagement score. Conclusions: Plastic surgery social media accounts may make a positive impact on followers. It is important to understand the factors that can increase engagement and broaden viewership. Tailoring posts based on content popularity and highlighting diversity may help to accomplish these goals.

Allicin-Loaded Hydroxyapatite: Enhanced Release, Cytocompatibility, and Antibacterial Properties for Bone Tissue Engineering Applications.

Allicin, the active compound of garlic extract, is a naturally sourced biomolecule, which promotes a vast range of health benefits. However, the limited stability of allicin restricts its applications in tissue engineering. Additionally, the detailed effects of allicin in bone health are yet to be explored. Our work reports on the fabrication of a novel allicin-loaded hydroxyapatite drug delivery system with enhanced biological properties. The fabricated system shows excellent antibacterial efficiency against S. aureus after 36 h of bacterial interaction with a sample. The allicin release kinetics are enhanced with polycaprolactone (PCL). The obtained results after 20 days of drug release study indicate that PCL coating leads to an increase in cumulative allicin release from ~ 35% to 70% at a physiological pH of 7.4. These scaffolds maintain stability during the whole period of drug release. Cytocompatibility of tested compositions with osteoblasts indicates enhanced cell viability and good filopodial attachment on the sample surface at day 7. These allicin-loaded antibacterial and cytocompatible scaffolds can find applications as localized delivery vehicles for bone tissue engineering.

Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist: In Vitro, Preclinical, and Clinical Data.

ACT-1004-1239 is a potent, selective, first-in-class CXCR7 antagonist, which shows a favorable preclinical and clinical profile. Here we report the metabolites and the metabolic pathways of ACT-1004-1239 identified using results from in vitro and in vivo studies. Two complementary in vitro studies (incubation with human liver microsomes in the absence/presence of cytochrome P450- [CYP] specific chemical inhibitors and incubation with recombinant CYPs) were conducted to identify CYPs involved in ACT-1004-1239 metabolism. For the in vivo investigations, a microtracer approach was integrated in the first-in-human study to assess mass balance and absorption, distribution, metabolism, and excretion (ADME) characteristics of ACT-1004-1239. Six healthy male subjects received orally 100 mg non-radioactive ACT-1004-1239 together with 1 µCi 14C-ACT-1004-1239. Plasma, urine, and feces samples were collected up to 240 h post-dose and 14C-drug-related material was measured with accelerator mass spectrometry. This technique was also used to construct radiochromatograms of pooled human samples. Metabolite structure elucidation of human-relevant metabolites was performed using high performance liquid chromatography coupled with high resolution mass spectrometry and facilitated by the use of rat samples. CYP3A4 was identified as the major CYP catalyzing the formation of M1 in vitro. In humans, the cumulative recovery from urine and feces was 84.1% of the dose with the majority being eliminated via the feces (69.6%) and the rest via the urine (14.5%). In human plasma, two major circulating metabolites were identified, i.e., M1 and M23. Elimination via M1 was the only elimination pathway that contributed to ≥25% of ACT-1004-1239 elimination. M1 was identified as a secondary amine metabolite following oxidative N-dealkylation of the parent. M23 was identified as a difluorophenyl isoxazole carboxylic acid metabolite following central amide bond hydrolysis of the parent. Other metabolites observed in humans were A1, A2, and A3. Metabolite A1 was identified as an analog of M1 after oxidative defluorination, whereas both, A2 and A3, were identified as a reduced analog of M1 and parent, respectively, after addition of two hydrogen atoms at the isoxazole ring. In conclusion, CYP3A4 contributes to a relevant extent to ACT-1004-1239 disposition and two major circulating metabolites were observed in humans. Clinical Trial Registration: (https://clinicaltrials.gov/ct2/show/NCT03869320) ClinicalTrials.gov Identifier NCT03869320.

Evaluation of an Electronic Health Record Alert to Improve Screening and Management of Cardiovascular Disease and Stroke Factors in a High-Risk Population.

OBJECTIVES: Cardiovascular disease and stroke risk factor screening and management by primary care providers (PCPs) have a significant impact on their patients' health. The objective of this study was to investigate the effectiveness of an electronic health record (EHR) cardiovascular disease and stroke risk alert in improving the ability of PCPs to manage risk factors among women and men aged 45 years and older. METHODS: PCPs at a tertiary care hospital were randomized. The intervention group received an EHR alert, which calculated the individual patient risk and provided an order set incorporating the American Heart Association and American Stroke Association guidelines, whereas the control group used the EHR in the usual manner. Multilevel analysis compared the rate of prescriptions between the intervention and control groups. RESULTS: A total of 23 PCPs were randomized: 12 in the intervention group and 11 in the control group, attending to 7190 patients between September 2016 and January 2017. None of the providers in the intervention group used the programmed order set. Intervention group providers were significantly more likely to prescribe smoking cessation medication to women than to the control group (adjusted odds ratio 2.37, 95% confidence interval 1.23-4.57). There were no statistically significant differences between the intervention and control groups in the rate of other medication prescriptions. CONCLUSIONS: As measured by prescriptions for medications, other than those for smoking cessation, the EHR alert was not shown to be successful in increasing the management of high-risk patients. Physicians receiving numerous messages in the EHR may experience alert desensitization.

Hospital admission medication reconciliation in high-risk prescription opioid users.

BACKGROUND: No studies have assessed the clinical significance of medication reconciliation in surgical patients using high-risk extended-release/long-acting (ER/LA) opioid medications. OBJECTIVES: We assessed differences in the perioperative use of opioid analgesics in patients who underwent medication reconciliation upon hospital admission compared to patients who did not and identified predictors of perioperative use of opioids. METHODS: Retrospective observational quasi-experimental study including adult non-cancer patients who underwent elective surgery at UCSF Medical Center in the period January 2017 through December 2019 and received at least one opioid analgesic during surgical hospitalization. The primary study outcome was perioperative use of opioids measured in daily oral morphine equivalents (OME). Secondary outcomes were predictors of perioperative use of opioids after adjusting for baseline differences between groups. RESULTS: We identified 402 patients. Of them, 59.5% were female. The mean patient age was 58.5 years. Most patients underwent neurological or orthopedic surgery (each 40.8%). Over 94.3% of our patients underwent medication reconciliation upon hospital admission, with 78.4% completed by a pharmacy staff. Medication reconciliation evidenced that 5.5% patients were not taking the ER/LA opioids on their medication history list. Inactive ER/LA opioids were discontinued during hospitalization. None of the patients with inactive ER/LA opioids had those opioids restarted at hospital discharge. In addition, patients (26.9%) were successfully converted from ER/LA to SA opioids. After adjusting for patients' demographic and clinical characteristics, surgical procedure type and post-operative pain, opioid formulation conversion was the main predictor of perioperative use of opioids per hospitalization day. Switching patients from ER/LA to SA opioids reduced the mean daily use of OME by 66.03 units (p < 0.02) without adversely impacting postoperative pain. CONCLUSIONS: Medication reconciliation upon hospital admission reduced unnecessary exposure to opioids in hospitalized surgical patients.

Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans.

Antagonism of the chemokine receptor CXCR7 has shown promising effects in diverse disease areas through modulation of its ligands, CXCL11 and CXCL12. Preclinical data of the first-in-class CXCR7 antagonist, ACT-1004-1239, showed efficacy in animal models of multiple sclerosis and acute lung injury. In healthy humans, single-dose administration of ACT-1004-1239 revealed a favorable clinical profile. Here, we report the target engagement of ACT-1004-1239 in healthy mice and humans after multiple doses using CXCL11 and CXCL12 as biomarkers. In addition, safety/tolerability, concentration-QTc relationship, and pharmacokinetics (PK) were assessed in a randomized, double-blind, placebo-controlled Phase 1 clinical study. Multiple-dose ACT-1004-1239 dose-dependently increased CXCL12 plasma concentration across the investigated dose range in mice and humans (mice: 1-100 mg/kg b.i.d.; humans: 30-200 mg o.d.) when compared to vehicle/placebo demonstrating target engagement. Mouse and human PK/PD models predicted that CXCL12 concentration approached a plateau within these dose ranges. In humans, ACT-1004-1239 was rapidly absorbed (tmax: 1.75-3.01 h) and the terminal t1/2 was approximately 19 h. Steady-state conditions were reached by Day 3 with an accumulation index of 1.2. Female subjects had overall higher exposure compared to males. Multiple-dose ACT-1004-1239 was well tolerated up to 200 mg once daily in humans. There was no evidence of ACT-1004-1239-mediated QTc interval prolongation. Overall, multiple oral doses of ACT-1004-1239 showed target engagement with CXCR7 in healthy mice and humans, therefore, assessment of CXCL12 as translational tool for further investigations in patients is warranted. Favorable safety/tolerability and PK profiles allow for further clinical development.

Ontario dentists' ease to discuss sensitive health issues with their patients: A cross-sectional study.

OBJECTIVES: With consistent calls for a more integrated approach to improve the healthcare system's effectiveness, the scope of practice for dentists has expanded; dentists are now seen to positively intervene to address several sensitive health issues among their patients. However, it is not clear how comfortable dentists feel in doing so. This study endeavored to assess self-perceived ease of dentists to discuss various sensitive health issues and if their socio-demographics influence their ease. METHODS: A self-administered online survey was sent to Ontario dentists (n = 9975) to assess their self-perceived ease in discussing five sensitive health issues with their patients: eating disorders, substance abuse, sexually transmitted infections (STIs), sexual behaviors, and physical abuse. Ordinal logistic regressions were performed along with descriptive analyses. RESULTS: The response rate was 9.3%. Over 50% of participants indicated difficulty discussing STIs, sexual behaviors and physical abuse. Younger dentists, female practitioners, dentists practicing in private settings, and those practicing in rural areas perceived more difficulty to discuss all five health issues. Place of training was also a significant predictor: internationally trained dentists perceived it easier to discuss eating disorders, substance abuse, and physical abuse while Canadian trained were more at ease to discuss STIs and sexual behaviors. CONCLUSION: This exploratory study identified that a large proportion of dentists are not comfortable discussing sensitive health issue with their patients. There are numerous opportunities for intervention in Canadian dental curriculums, continuing education programs, and communication practices to support dentists' discussions with patients about these important health concerns.

The Trypanosoma brucei subpellicular microtubule array is organized into functionally discrete subdomains defined by microtubule associated proteins.

Microtubules are inherently dynamic cytoskeletal polymers whose length and organization can be altered to perform essential functions in eukaryotic cells, such as providing tracks for intracellular trafficking and forming the mitotic spindle. Microtubules can be bundled to create more stable structures that collectively propagate force, such as in the flagellar axoneme, which provides motility. The subpellicular microtubule array of the protist parasite Trypanosoma brucei, the causative agent of African sleeping sickness, is a remarkable example of a highly specialized microtubule bundle. It is comprised of a single layer of microtubules that are crosslinked to each other and to the overlying plasma membrane. The array microtubules appear to be highly stable and remain intact throughout the cell cycle, but very little is known about the pathways that tune microtubule properties in trypanosomatids. Here, we show that the subpellicular microtubule array is organized into subdomains that consist of differentially localized array-associated proteins at the array posterior, middle, and anterior. The array-associated protein PAVE1 stabilizes array microtubules at the cell posterior and is essential for maintaining its tapered shape. PAVE1 and the newly identified protein PAVE2 form a complex that binds directly to the microtubule lattice, demonstrating that they are a true kinetoplastid-specific MAP. TbAIR9, which localizes to the entirety of the subpellicular array, is necessary for maintaining the localization of array-associated proteins within their respective subdomains of the array. The arrangement of proteins within the array likely tunes the local properties of array microtubules and creates the asymmetric shape of the cell, which is essential for parasite viability.

Insulin and glucose responses to hypoxia in male and female neonatal rats: Effects of the androgen receptor antagonist flutamide.

Hypoxia is common with preterm birth and may lead to long-term effects on adult pancreatic endocrine function and insulin sensitivity. This phenomenon may be sexually dimorphic due to the hypoxia-induced augmentation of the neonatal androgen surge in male newborns. We evaluated this phenomenon by pretreating neonatal rats on postnatal days (PD) 1, 6, 13, or 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to either acute normoxic or hypoxic separation (fasting) for 90 min, and blood was sampled for the measurement of insulin and glucose and the calculation of HOMA-IR as an index of insulin resistance. During normoxic and hypoxic separation (fasting), flutamide increased insulin secretion in PD2, PD7, and PD14 pups, high dose flutamide attenuated insulin secretion, and high dose flutamide attenuated the increase in HOMA-IR due to hypoxia. Our studies suggest a unique role of the androgen receptor in the control of neonatal pancreatic function, possibly by blocking a direct effect of neonatal testosterone or in response to indirect regulatory effects of androgens on insulin sensitivity.

A Multipurpose First-in-Human Study With the Novel CXCR7 Antagonist ACT-1004-1239 Using CXCL12 Plasma Concentrations as Target Engagement Biomarker.

The C-X-C chemokine receptor 7 (CXCR7) has evolved as a promising, druggable target mainly in the immunology and oncology fields modulating plasma concentrations of its ligands CXCL11 and CXCL12 through receptor-mediated internalization. This "scavenging" activity creates concentration gradients of these ligands between blood vessels and tissues that drive directional cell migration. This randomized, double-blind, placebo-controlled first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a first-in-class drug candidate small-molecule CXCR7 antagonist. Food effect and absolute bioavailability assessments were also integrated in this multipurpose study. Healthy male subjects received single ascending oral doses of ACT-1004-1239 (n = 36) or placebo (n = 12). At each of six dose levels (1-200 mg), repeated blood sampling was done over 144 hours for pharmacokinetic/pharmacodynamic assessments using CXCL11 and CXCL12 as biomarkers of target engagement. ACT-1004-1239 was safe and well tolerated up to the highest tested dose of 200 mg. CXCL12 plasma concentrations dose-dependently increased and more than doubled compared with baseline, indicating target engagement, whereas CXCL11 concentrations remained unchanged. An indirect-response pharmacokinetic/pharmacodynamic model well described the relationship between ACT-1004-1239 and CXCL12 concentrations across the full dose range, supporting once-daily dosing for future clinical studies. At doses ≥ 10 mg, time to reach maximum plasma concentration ranged from 1.3 to 3.0 hours and terminal elimination half-life from 17.8 to 23.6 hours. The exposure increase across the dose range was essentially dose-proportional and no relevant food effect on pharmacokinetics was determined. The absolute bioavailability was 53.0% based on radioactivity data after oral vs. intravenous 14 C-radiolabeled microtracer administration of ACT-1004-1239. Overall, these comprehensive data support further clinical development of ACT-1004-1239.

Weight Gain After Thyroidectomy: A Systematic Review and Meta-Analysis.

CONTEXT: Weight gain is a major driver of dissatisfaction and decreased quality of life in patients with hypothyroidism. Data on the changes in body weight following thyroidectomy are conflicting. OBJECTIVE: To perform a systematic review of the literature and a meta-analysis of weight changes following total thyroidectomy. DATA SOURCES: Literature search on PubMed. STUDY SELECTION: Studies in English published between September 1998 and May 2018 reporting post-thyroidectomy weight changes. DATA EXTRACTION: Data were reviewed and compared by 3 investigators; discrepancies were resolved by consensus. Meta-analyses were performed using fixed and random effect models. Univariable and multivariable meta-regression models for weight change were implemented against study follow-up, gender, and age. Exploratory subgroup analyses were performed for indication for surgery. DATA SYNTHESIS: Seventeen studies (3164 patients) with 23.8 ± 23.6 months follow-up were included. Severe heterogeneity across studies was observed. Using a random effect model, the estimated overall weight change was a gain of 2.13 kg, 95% confidence interval (CI; 0.95, 3.30). Age was negatively associated with weight change (ß = -0.238, P < 0.001). In subgroup analyses, weight gain was more evident in patients undergoing thyroidectomy for hyperthyroidism: 5.19 kg, 95% CI (3.21, 7.17) vs goiter or malignancy 1.55 kg, 95% CI (0.82, 2.27) and 1.30 kg, 95% CI (0.45, 2.15), respectively. CONCLUSIONS: Patients undergoing thyroidectomy experience possible mild weight gain, particularly younger individuals and those with hyperthyroidism as the indication for surgery. Prospective studies directed to assess the pathophysiology of weight gain post-thyroidectomy, and to test novel treatment modalities, are needed to better characterize post-thyroidectomy weight changes.

Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions.

The impact of the C-X-C receptor (CXCR) 7 and its close co-player CXCR4 in different physiological and pathophysiological processes has been extensively investigated within the last decades. Following activation by their shared ligand C-X-C ligand (CXCL) 12, both chemokine receptors can induce various routes of cell signaling and/or scavenge CXCL12 from the extracellular environment. This contributes to organ development and maintenance of homeostasis. Alterations of the CXCR4/CXCR7-CXCL12 axis have been detected in diseases such as cancer, central nervous system and cardiac disorders, and autoimmune diseases. These alterations include changes of the expression pattern, distribution, or downstream effects. The progression of the diseases can be regulated in preclinical models by the use of various modulators suggesting that this axis serves as a promising therapeutic target. It is therefore of great interest to investigate CXCR4/CXCR7/CXCL12 modulators in clinical development, with several CXCR4 and CXCL12 modulators such as plerixafor, ulocuplumab, balixafortide, and olaptesed pegol having already reached this stage. An overview is presented of the most important diseases whose outcomes can be positively or negatively regulated by the CXCR4/CXCR7-CXCL12 axis and summarizes preclinical and clinical data of modulators of that axis. Contrary to CXCR4 and CXCL12 modulators, CXCR7 modulators have, thus far, not been extensively studied. Therefore, more (pre)clinical investigations are needed.

Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects.

The P2Y12 receptor antagonist selatogrel which exhibits rapid inhibition of platelet aggregation following subcutaneous administration is in development for the treatment of acute myocardial infarction.This human ADME study was performed in six healthy male subjects to determine the routes of elimination and to identify/quantify the metabolites of selatogrel at a therapeutically relevant dose of 16 mg [14C]-radiolabelled selatogrel.The median tmax and t1/2 of selatogrel was 0.75 h and 4.7 h, respectively. It was safe and well tolerated based on adverse event, ECG, vital sign and laboratory data.Geometric mean total recovery of [14C]-radioactivity was 94.9% of which 92.5% was recovered in faeces and 2.4% in urine.Selatogrel was the most abundant entity in each matrix. In plasma, no major metabolite was identified. In excreta, the glucuronide M21 (14.7% of radioactivity) and the mono-oxidized A1 (6.2%) were the most abundant metabolites in urine and faeces, respectively.Overall, none of the metabolic pathways contributed to a relevant extent to the overall elimination of selatogrel, i.e. by more than 25% as defined per regulatory guidance. Hence, no pharmacokinetic interaction studies with inhibitors or inducers of drug-metabolizing enzymes are warranted for clinical development of selatogrel.

The effects of flutamide on the neonatal rat hypothalamic-pituitary-adrenal and gonadal axes in response to hypoxia.

Hypoxia is common with preterm birth and may lead to long-term effects on the adult hypothalamic-pituitary-adrenal (HPA) axis that are sexually dimorphic due to neonatal androgens. Although the adult rat adrenal does not express appreciable CYP17 activity, the neonatal rat adrenal may synthesize androgens that could be a critical local factor in the development of adrenal function. We evaluated these phenomena by pretreating the neonatal rats on postnatal days (PD) 1, 6, 13, 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 mg/kg or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to acute hypoxia and blood was sampled. We found that (a) in PD2 pups, flutamide augmented corticosterone responses in a sexually dimorphic pattern and without an increase in ACTH, (b) PD7 and PD14 pups had the smallest corticosterone response to hypoxia (c) PD21 pups had an adult-like corticosterone response to hypoxia that was sexually dimorphic, (d) flutamide attenuated ACTH responses in PD7 hypoxic pups, and (e) high-dose flutamide suppressed the HPA axis, FSH, and estradiol. Flutamide demonstrated mixed antagonist and agonist effects that changed during the first three weeks of neonatal life. We conclude that the use of flutamide in neonatal rats to evaluate androgen-induced programming of subsequent adult behavior is not optimal. However, our studies suggest neonatal androgens play a role in regulation of adrenal function that is sexually dimorphic and changes during early development.

Change implementation: the association of adaptive reserve and burnout among inpatient medicine physicians and nurses.

Adaptive Reserve (AR) is positively associated with implementing change in ambulatory settings. Deficits in AR may lead to change fatigue or burnout. We studied the association of self-reported AR and burnout among providers to hospitalized medicine patients in an academic medical center. An electronic survey containing a 23-item Adaptive Reserve scale, burnout inventory, and demographic questions was sent to a convenience sample of nurses, house staff team members, and hospitalists. A total of 119 self-administered, online surveys collected from June 2014 to March 2015 were analyzed. Ordinal regression analyses were used to examine the association between AR and burnout. Eighty percent of participants reported either level 1 or 2 burnout. Additionally, 10.9% of participants responded level 0% and 7.6% of participants reported level 3. Participants reporting higher burnout were about three times more likely to report lower AR levels. AR is strongly associated with self-reported burnout by physicians and nurses providing inpatient care at this academic medical center. Growing evidence supports the positive association of AR to successful change implementation in ambulatory settings. Similar studies are needed to determine whether certain levels of AR can predict successful change in hospital settings.

Interprofessional education in a primary care teaching clinic: findings from a study involving pharmacy and medical students.

Interprofessional education (IPE) can be hindered by the lack of infrastructure required to support it. We developed a clinical IPE experience for medical and pharmacy students built upon an existing infrastructure. We created tools to orient students to IPE and had students participate in pharmacist-led and physician-led IPE clinics. Results from the surveys indicated that after participating in the IPE experience, there were no significant changes in attitudes toward interprofessional teamwork or attitudes toward different members of the healthcare team. Students found less value in tools outlining roles and responsibilities of team members, on-line modules about the other profession, and IPE group discussion. They placed more value on the actual clinical experience. Themes derived from analysis of open-ended survey questions reflected the value that students placed on interprofessional interaction in the setting of direct patient care.

Preparation, confidence, and attitudes about chronic noncancer pain in graduate medical education.

BACKGROUND: Physicians report they feel ill-prepared to manage chronic noncancer pain (CNCP), in part because of inadequate training. Published studies and clinical observation demonstrate that trainees lack confidence and reflect negative attitudes about CNCP. Overall, there is minimal published guidance on specific specialty roles and responsibilities in CNCP management. OBJECTIVE: The purpose of this study was to assess resident preparation, confidence, and attitudes about CNCP across graduate medical education programs and to assess resident perception of roles and responsibilities in CNCP management. METHODS: In 2006 we surveyed residents from 13 graduate medical education programs in 3 institutions about CNCP and report quantitative and qualitative analyses of survey responses from 246 respondents. RESULTS: A total of 59% of respondents rated their medical school preparation and 36% rated their residency preparation as "fair" or "poor"; only 17% reported being "confident" or "very confident" in assessing patients with CNCP; and 30% used negative or derogatory terms (eg, manipulative, irritable, needy) to describe patients with CNCP. Respondents from postgraduate years 3-6 were more than twice as likely as postgraduate year 1 or postgraduate year 2 respondents (44% versus 21% and 20%, respectively) to use negative or derogatory terms (P  =  .0007). Respondents were significantly more likely to report that pain specialists are "good" or "excellent" in managing CNCP compared with generalists (73% versus 6%; P < .0001). CONCLUSION: Education in pain management should begin in medical school and continue through graduate medical education, regardless of specialty. Early and sustained training interventions are needed to foster empathy in caring for patients with pain. Residency and fellowhip training should impart a clear understanding of each specialty's role and responsibilities in pain management to better foster patient-centered pain care.