Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy

4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value.     

Promoting head CT exams in the emergency department triage using a machine learning model

Neuroradiology - In this study, we aimed to develop a novel prediction model to identify patients in need of a non-contrast head CT exam during emergency department (ED) triage. We collected data...     

Can laboratory evaluation differentiate between coronavirus disease-2019, influenza,and respiratory syncytial virus infections? A retrospective cohort study

AimTo identify clinical and laboratory parameters that can assist in the differential diagnosis of coronavirus disease 2019 (COVID-19), influenza, and respiratory syncytial virus (RSV) infections.MethodsIn this retrospective cohort study, we obtained basic demographics and laboratory data from all 685 hospitalized patients confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza virus, or RSV from 2018 to 2020. A multiple logistic regression was employed to investigate the relationship between COVID-19 and laboratory parameters.ResultsSARS-CoV-2 patients were significantly younger than RSV (P = 0.001) and influenza virus (P = 0.022) patients. SARS-CoV-2 patients also displayed a significant male predominance over influenza virus patients (P = 0.047). They also had significantly lower white blood cell count (median 6.3 × 10⁶ cells/μ) compared with influenza virus (P < 0.001) and RSV (P = 0.001) patients. Differences were also observed in other laboratory values but were insignificant in a multivariate analysis.ConclusionsMale sex, younger age, and low white blood cell count can assist in the diagnosis of COVID-19 over other viral infections. However, the differences between the groups were not substantial enough and would probably not suffice to distinguish between the viral illnesses in the emergency department.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus causing coronavirus disease 2019 (COVID-19). First identified in the Chinese province of Hubei in late 2019, COVID-19 was declared a global pandemic by the World Health Organization in March 2020 (1).As of July 2021, there were more than 180 million confirmed COVID-19 cases and more than four million patients who died due to the disease complications (2). Moreover, the disease caused a substantial economic and social burden (3), and affected health care quality (4-7).The diagnosis of COVID-19 is currently determined primarily by molecular methods and antigen tests (8,9). Radiographic diagnosis is possible as well (10,11). This practice often consumes valuable time and expensive equipment (12). There is a growing need to accelerate the diagnostic process by enabling point-of care diagnosis in various ambulatory settings, while keeping it accurate to ensure the necessary precautionary measures (13).The clinical presentation of SARS-CoV-2 infection resembles that of other respiratory viruses, with predominant symptoms of fever, cough, fatigue, and dyspnea (14-17). Hematological abnormalities, including leukopenia, lymphopenia, and thrombocytopenia, are common among COVID-19 patients, as well as elevated levels of C-reactive protein (CRP), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and ferritin (14,15,18-21). Some of these inflammatory markers correlated with disease severity and mortality (22,23).The influenza season of 2021 in the Northern hemisphere was relatively weak in contrast with predictions. Low to zero rates of influenza were detected in several countries. This was attributed to social distancing, masks wearing, and a reduced number of air travelers (24). Despite a growing number of vaccinated individuals (25), the emergence of new SARS-CoV-2 variants suggest that COVID-19 is here to stay. Seasonal viruses such as influenza virus and respiratory syncytial virus (RSV) could rebound in the following winter, with the loosening of restrictions.Differentiating between COVID-19 and other respiratory viral illnesses on clinical grounds alone can be very challenging. These viral infections share similarities in the transmission route and symptoms (26-28). Several small studies attempted to delineate the differences in the clinical presentation of SARS-CoV-2 and influenza infections (29-31). In this study, we aimed to identify demographic and laboratory parameters that can assist in the early differentiation between SARS-CoV-2, influenza, and RSV infections in the emergency department.     

Mapping changes in the obesity stigma discourse through Obesity Canada: a content analysis

BackgroundStigmatization of persons living with obesity is an important public health issue. In 2015, Obesity Canada adopted person-first language in all internal documentation produced by the organization, and, from 2017, required all authors to use person-first language in abstract submissions to Obesity Canada hosted conferences. The impact of this intentional shift in strategic focus is not known. Therefore, the aim of this study was to conduct a content analysis of proceedings at conferences hosted by Obesity Canada to identify whether or how constructs related to weight bias and obesity stigma have changed over time.MethodsOf 1790 abstracts accepted to conferences between 2008–2019, we excluded 353 abstracts that featured animal or cellular models, leaving 1437 abstracts that were reviewed for the presence of five constructs of interest and if they changed over time: 1) use of person-first versus use of disease-first terminology, 2) incorporation of lived experience of obesity, 3) weight bias and stigma, 4) aggressive or alarmist framing and 5) obesity framed as a modifiable risk factor versus as a disease. We calculated and analyzed through linear regression: 1) the overall frequency of use of each construct over time as a proportion of the total number of abstracts reviewed, and 2) the ratio of abstracts where the construct appeared at least once based on the total number of abstracts.ResultsWe found a significant positive correlation between use of person-first language in abstracts and time (R2 = 0.51, p < 0.01 for frequency, R2 = 0.65, p < 0.05 for ratio) and a corresponding negative correlation for the use of disease-first terminology (R2 = 0.48, p = 0.01 for frequency, R2 = 0.75, p < 0.001 for ratio). There was a significant positive correlation between mentions of weight bias and time (R2 = 0.53 and 0.57, p < 0.01 for frequency and ratio respectively).ConclusionUse of person-first language and attention to weight bias increased, while disease-first terminology decreased in accepted abstracts over the past 11 years since Obesity Canada began hosting conferences and particularly since more explicit actions for expectations to use person-first language were put in place in 2015 and 2017.     

Exploring the reasons for low pertussis vaccine effectiveness in Ontario,Canada, 2006–2008: a Canadian Immunization Research Network study

ObjectivesAlthough pertussis vaccines have been widely used for many decades, a burden of illness persists. Resurgences in Ontario, Canada, have not been substantial in the past decade, but an outbreak of pertussis occurred in Toronto between 1 October 2005 and 31 March 2006. Previous Ontario studies found high vaccine effectiveness (VE) in the initial years post-immunization. In order to explore the impact of outbreaks and external factors on VE, we investigated pertussis VE during the period 2006–2008.MethodsWe assessed pertussis VE using a frequency-matched case-control study for the period 1 March 2006 to 31 December 2008. We used logistic regression to estimate VE by age, time since last vaccination, and vaccination status according to the Ontario recommended schedule. We compared analyses including and excluding cases from Toronto, and to two recent Ontario pertussis VE studies.ResultsWe included 1797 confirmed cases and 7188 matched controls. Most cases were under 4 years of age during the study period. Pertussis VE was 3.8% (95% CI: − 21.0, 24.0) in the period 15–364 days following the last pertussis vaccine dose, and increased with increasing time since vaccination. Pertussis VE in the first 15–364 days excluding Toronto increased to 57.1% (95% CI: 26.0, 75.1), but the trend of increasing VE with time since vaccination persisted. Although VE was higher in older (6–11 years) than younger (0–5 years) children, it was lower at 12–13 years than after 14 years.ConclusionVE was lower in comparison with other studies conducted in Ontario, particularly in younger children. Various factors occurring during the study period may have influenced the results, including clinical testing of asymptomatic contacts, laboratory testing and methods and reporting practice, and a sensitive case definition. Further studies are needed to optimize methods for measuring VE to inform pertussis vaccine policy.     

Personality adjustment differences in the BEM masculinity and femininity scales

Reproted two investigations. In the first, 40 mental health professionals rated the Bem Masculinity and Femininity Scale items for personality adjustment level. Our female judges gave the Masculinity items higher ratings than the Femininity items, but no difference appeared in the mean ratings of the male judges. Five items then were deleted from each scale to provide modified measures apparently matched for adjustment value. In the second study (N = 106) the MMPI scores, vocational satisfaction scores, and job tenures of psychiatric patients categorized as androgynous, masculine, feminine, or undifferentiated were compared. Significant differences appeared on three MMPI measures when the original scales were used to define gender type, but not when the adjustment-matched scales were used and Ss with invalid MMPIs were deleted. Thus previous findings interpreted as supporting the view that androgyny and masculinity are associated with good adjustment may be artifacts that resulted from differences in the adjustment values of the original scales.     

Benzodiazepine use in older adults enrolled in a health maintenance organization.

OBJECTIVES: The authors examined patterns of benzodiazepine use in older adults. Specifically, they describe prevalence and incidence of benzodiazepine use during the index year, describe persistence and intensity of benzodiazepine use over a 4-year period; and examine factors associated with benzodiazepine use in the upcoming year. METHODS: Authors performed a secondary analysis of data collected as part of a health promotion intervention trial conducted from 1986 to 1992 in older health maintenance organization enrollees (N=1,505). Benzodiazepine use was ascertained from computerized pharmacy records. Demographic characteristics, health status, and health behaviors were ascertained from mailed questionnaires. RESULTS: During the index year, the prevalence and incidence of benzodiazepine use was 12.3% and 6.6%, respectively. Of those using during the index year, 16% of new users and 63% of previous users continued to use for the following 3 years. The factors significantly associated with benzodiazepine use in the following year were female gender, high school education, higher chronic disease score, higher levels of self-reported pain and stress, low-to-normal body mass index (BMI), and self-reported nervous disorder. CONCLUSIONS: New users had low intensity of use and a low probability of continuing use over the following 3 years. A very small percentage of this sample had evidence of daily use for 4 years. Of concern, benzodiazepines were used by the segment of the sample that were at greatest risk for hip fractures (women with normal/low BMI). Clinicians should assess the need for continued benzodiazepine use at regular intervals.     

Ultrasound-guided, vacuum-assisted, percutaneous excision of breast lesions: an accurate technique in the diagnosis of atypical ductal hyperplasia

BACKGROUND: In October 2002, ultrasound-guided, vacuum-assisted, percutaneous excision was shown to facilitate the complete removal of benign breast lesions up to 3 cm in diameter. This study was performed to ascertain the overall accuracy of ultrasound-guided, vacuum-assisted, percutaneous excision as evidenced by the frequency of atypical ductal hyperplasia (ADH) underestimation. STUDY DESIGN: A retrospective review was conducted of 542 consecutive ultrasound-guided, vacuum-assisted breast biopsies performed between February 2000 and September 2004. Before July 2002, no attempt was made to completely remove all imaged lesion evidence. After July 2002, all patients underwent complete percutaneous excision of all imaged lesion evidence. Pathology review revealed 52 lesions that demonstrated ADH and no evidence of malignancy. Each patient with this diagnosis was offered surgical excision. Pathologic reports for each group were compared with the subsequent open surgical specimens. RESULTS: Of 542 consecutively diagnosed lesions, 52 displayed ADH with no evidence of malignancy (10%). Five patients refused operation. Of the 47 patients who underwent open excision, 6 (13%) were found to have malignancies. The rate of ADH underestimation was 6 of 18 (33%) in incisional biopsies and 0 of 29 performed with complete imaged lesion evidence (p=0.002). The rate of ADH underestimation in women who underwent ultrasound-guided, vacuum-assisted, percutaneous excision was zero, a result equivalent to open surgical biopsy. CONCLUSIONS: ADH is a more common finding in sonographic lesions than has been previously reported. Complete ultrasound-guided, vacuum-assisted, percutaneous excision is more accurate than nonexcisional ultrasound-guided biopsy. Patients so diagnosed have very low underestimation rates and may not require open surgical reexcision.