The objective of this study was to explore Canadian emergency physicians' experiences, concerns, and perspectives during the first wave of the coronavirus disease (COVID-19) pandemic.
This ...cross-sectional survey of physician members of Pediatric Emergency Research Canada and the Canadian Association of Emergency Physicians explored: personal safety/responsibility to care; patient interactions; ethical issues in pandemic care; institutional dynamics and communication practices. Data analysis was descriptive: categorical data were summarised with frequency distributions, continuous data 100 mm visual analog scales (VAS) were analysed using measures of central tendency. Short open-ended items were coded to identify frequencies of responses.
From June 29 to July 29, 2020, 187 respondents (13% response rate) completed the survey: 39% were from Ontario and 20% from Quebec, trained in general (50%) or pediatric (37%) emergency medicine. Respondents reported a high moral obligation to care for patients (97/100, IQR: 85-100, on 100 mm VAS). Fear of contracting COVID-19 changed how 82% of respondents reported interacting with patients, while 97% reported PPE negatively impacted patient care. Despite reporting a high proportion of negative emotions (84%), respondents (59%) were not/slightly concerned about their mental health. Top concerns included a potential second wave, Canada's financial situation, worldwide solidarity, and youth mental health. Facilitators to provide emergency care included: teamwork, leadership, clear communications strategies.
Canadian emergency physicians felt a strong sense of responsibility to care, while dealing with several ethical dilemmas. Clear communication strategies, measures to ensure safety, and appropriate emergency department setups facilitate pandemic care. Emergency physicians were not concerned about their own mental health, requiring further exploration.
Children with medical complexity represent a fragile population and account for the majority of patients followed in pediatric palliative care. Little is known in regard to the role of the emergency ...department (ED) in caring for the families of children with medical complexity.
Semistructured focus groups were held with health care professionals from pediatric emergency medicine, palliative care, complex care, and intensive care to explore their perspective on pediatric palliative care in the ED. Data were transcribed and analyzed with NVivo software, and thematic analysis and theoretic sampling were performed.
From January to October 2016, 58 participants were interviewed. Difficulties providing pediatric palliative care in the ED are related on the one hand to characteristics specific to the ED, such as its culture and its health care professionals’ strong emotional responses when caring for children with medical complexity, and on the other hand to factors extrinsic to the ED; mainly, lack of continuity of care. For critically ill children with unknown goals of care and potential for end of life, professionals in the ED should evaluate the clinical situation, contact known health care teams, remain open to families’ preferences, alleviate distressing symptoms, and create a caring environment. Communication between teams is targeted by health care professionals to facilitate and improve patient flow and care.
Although perspectives differ in regard to how to provide care for pediatric palliative care patients in the ED, several barriers to providing high-quality emergency pediatric palliative care can be overcome.
Summary Background The inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for treatment of dyslipidaemia. Anacetrapib (MK-0859) is a CETP inhibitor ...currently under development. We aimed to assess anacetrapib's effects as monotherapy on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and on 24-h ambulatory blood pressure. Methods We did two double-blind, randomised, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100–190 mg/dL; 40 active, 10 placebo) aged 18–75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. Standard lipid and lipoprotein monitoring, safety monitoring, and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45–75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomised sequence, with at least a 14-day washout between the treatment periods. Continuous 24-h ambulatory blood pressure monitoring was done on day −1 and day 10 of each treatment period in this study. The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram, and laboratory safety. Analysis was per protocol. These trials are registered with ClinicalTrials.gov , number NCT00565292 and NCT00565006. Findings In the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51·1 SD 3·8−114·9 7·9 mg/dL) increase in HDL-C and a 38% (138·2 11·4−77·6 7·9 mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0·60 (90% CI −1·54 to 2·74; p=0·634) mm Hg for systolic blood pressure and 0·47 (90% CI −0·90 to 1·84; p=0·561) mm Hg for diastolic blood pressure. Interpretation Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure.
Pharmacokinetic analysis Sitagliptin was measured in plasma, urine, and dialysate samples by mass spectrometry detection following specialized high-performance liquid chromatography with an internal ...standard (3). The recommended sitagliptin dosage adjustments are as follows: no adjustment for patients with mild RI (creatinine clearance 50-80 ml/ min), a twofold decrease in the clinical dose of 100 mg q.d. (i.e., 50 mg q.d.) for patients with moderate RI (creatinine clearance 30-50 ml/min) (approximate serum creatinine levels >1.7 and ^3.0 mg/dl for men and > 1.5 and ^2.5 mg/dl for women), and a fourfold decrease in the clinical dose (25 mg q.d.) for patients with severe RI (creatinine clearance <30 ml/min) or ESRD (approximate serum creatinine levels >3.0 mg/dl for men, >2.5 mg/dl for women, or on dialysis).
¹⁸FMK-9470 is a selective, high-affinity, inverse agonist (human IC₅₀, 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies ...in rhesus monkey brain showed that ¹⁸FMK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4-5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of ¹⁸FMK-9470 very similar to that seen in monkeys, with very good test-retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in ¹⁸FMK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, ¹⁸FMK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.
Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density ...lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely ...elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer
18FMK-9470 confirmed central nervous system receptor occupancy levels (∼10%–40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.
Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis ...virus-based COVID-19 vaccine candidate.
In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18–54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 105; 2.40 × 106; 1.15 × 107; or 5.55 × 107 plaque-forming units pfu) or placebo. In Part 3, a single V590 dose level (5.55 × 10⁷ pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 P001-02.
232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 107 pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%).
V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development.
The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Aim
To explore and compare acute and long‐term care professionals' perspectives about paediatric palliative care.
Methods
Focus group interviews were conducted in 2016‐2017 with professionals from ...acute (Emergency Department, Intensive Care Unit) and long‐term care (Complex Care Service, Palliative Care) teams.
Results
Fifty‐eight participants were enrolled. Palliative care definitions were similar throughout groups: to provide active care early in the illness, focusing on the child as a whole and supporting families. Each group perceived a different role in the patient's illness trajectory, reflecting their own culture of care. They demonstrated important differences in their approach to palliative care. Disagreements regarding when or how to discuss goals of care were expressed. Acute care professionals reported discomfort when having to introduce these discussions for the first time, while long‐term care professionals perceived negative judgements about their patients' quality of life by acute care teams during health events. Personalised care, communication with families and continuity of care were thought to be key elements to improve care.
Conclusion
Paediatric palliative care is well recognised throughout specialties, yet continuity of care is challenged by groups' roles and interventions in a patient's illness. A reflective and mutual clinical approach is needed to improve quality of care and professionals' satisfaction.
Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) ...particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
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