MAGEL2 is one of several genes typically inactivated in the developmental obesity disorder Prader-Willi syndrome (PWS). The physiological consequences of loss of MAGEL2, but without the concurrent ...loss of other PWS genes, are not well understood. Gene-targeted mutation of Magel2 in mice disrupts circadian rhythm and metabolism causing reduced total activity, reduced weight gain before weaning, and increased adiposity after weaning.
We now show that loss of Magel2 in mice causes reduced fertility in both males and females through extended breeding intervals and early reproductive decline and termination. Female Magel2-null mice display extended and irregular estrous cycles, while males show decreased testosterone levels, and reduced olfactory preference for female odors.
Our results suggest that loss of MAGEL2 contributes to the reproductive deficits seen in people with PWS, and further highlights the role of normal circadian rhythm in the maintenance of fertility.
Highlights ► Postnatal but not germline manipulation of NPY or its receptors affect energy balance. ► NPY gene release and expression is modulated by a network of energy balance signals. ► Numerous ...approaches are needed to study different aspects of NPY-mediated feeding.
The financial impact of cancer medicines on health systems is not well known. We describe temporal trends in expenditure on cancer medicines within the single-payer health system of Ontario, Canada, ...and the extent of clinical benefit these treatments offer.
In this cross-sectional study, we identified cancer medicines and expenditures from formularies and costing databases (the New Drug Funding Program, Ontario Drug Benefit Program, and The High-Cost Therapy Funding Program) during 10 consecutive years (April 1, 2012, to March 31, 2022) in Ontario, Canada. For intravenous medicines, we applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to identify expenditures associated with substantial clinical benefit. We also identified treatments associated with improved overall survival or quality of life.
69 intravenous and 98 oral or injectable medicines were funded during 2012–22. Annual expenditure on cancer medicines increased by approximately 15% per year during 2012–22; the increase was more rapid in the most recent 4 years. Total expenditure on cancer medicines in the 2021–22 financial year was CA$1·7 billion. Immune checkpoint inhibitors were the single biggest expense by class ($284 million), representing 17% of the entire cancer medicine annual budget. Drugs with the highest individual costs were lenalidomide ($178 million) and pembrolizumab ($163 million), each accounting for around 10% of the entire budget. 29 (76%) of 38 indications eligible for ESMO-MCBS scoring met the threshold for substantial clinical benefit. Eight (21%) indications had no randomised trial evidence of improved overall survival, and only four (11%) were associated with improved QOL. $346 million (67% of the expenditure on intravenous cancer medicines) was spent on drugs that improved median overall survival by more than 6 months, $82 million (16%) was spent on medicines with overall survival gains of 3–6 months, and $32 million (6%) was spent on medicines with overall survival gains of less than 3 months. $53 million (10%) was spent on medicines with no established improvement in overall survival.
Costs of cancer medicines to the Canadian health system are increasing rapidly. Most funded indications met thresholds for substantial clinical benefit and two-thirds of the expenditure were for medicines that improve survival by more than 6 months. Whether this cost trajectory can be maintained in a sustainable, equitable, high-quality health system is unclear. Efforts are needed to ensure the price of medicines with substantial benefit is affordable and funding of treatments with very modest benefit might need to be re-assessed, particularly when alternative supportive and palliative therapies are available.
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The emergency medical services (EMS) workforce is a key component of healthcare in the U.S. Characteristics of active EMS professionals who are treating patients in the prehospital setting is ...unclear. The purpose of this study was to describe the roles and settings in which nationally certified EMS professionals are providing patient care and to evaluate similarities and differences of the demographics and practice settings of the three major certification levels.
We conducted a cross-sectional evaluation of all nationally certified EMS professionals in the U.S. that recertified between October 1, 2017 and March 31, 2018 and October 1, 2018 and March 31, 2019. Within the recertification application, EMS professionals completed an optional demographic profile. Those who were nationally certified, functioning as a patient care provider for at least one nonmilitary EMS organization, aged 18 to 85 years, and recertified at the EMT level or higher were included. Demographic, agency and job characteristics were assessed and descriptive statistics were calculated.
In 2017-2018, 101,363 EMS professionals recertified and 87,471 (86%) completed the profile; in 2018-2019, 106,893 EMS professionals recertified and 92,640 (87%) completed the profile. Of the 142,751 EMS professionals who met inclusion criteria, the population was primarily male (76%) and age increased by certification level. By race/ethnicity, 85% were white, 5% were Hispanic/Latino, 5% were Black/African American, 2% were American Indian/Alaskan Native, 2% were Asian and 1% were Native Hawaiian/Pacific Islander.
Paramedics had the highest proportion of associate degrees (EMT:16.0%; AEMT:16.6%; paramedic:28.5%); some college experience was common for all certification levels (EMT:34.7%; AEMT:37.2%; paramedic:31.6%). Most EMS professionals reported 3-7 years of experience, were working full-time (78%) and 28% were working for 2 or more agencies. Most were working for a fire department (48%) or private agency (21%) and providing 9-1-1 service (72%). No substantial differences were observed between the two recertification cycles.
This is the most comprehensive study evaluating the demographics of the national EMS workforce of active patient care providers. Understanding the characteristics of EMS professionals and the settings they practice in is important for educational and training initiatives, as well as protocols and policies.
ObjectiveEmergency medical services (EMS) clinicians operate in environments that predispose them to occupational hazards. Our objective was to evaluate the frequency of occupational hazards and ...associations with mitigation strategies in a national dataset.MethodsWe performed a cross-sectional analysis of currently working, nationally certified civilian EMS clinicians aged 18–85 in the USA. After recertifying their National EMS Certification, respondents were invited to complete a survey with questions regarding demographics, work experience and occupational hazards. Three multivariable logistic regression models (OR, 95% CI) were used to describe associations between these hazards and demographics, work characteristics and mitigation strategies. Models were adjusted for age, sex, minority status, years of experience, EMS agency type, service type and EMS role.ResultsA total of 13 218 respondents met inclusion criteria (response rate=12%). A high percentage of EMS clinicians reported occupational injuries (27%), exposures (38%) and violence (64%) in the past 12 months. Odds of injury were lower with the presence of a lifting policy (0.73, 0.67–0.80), lift training (0.74, 0.67–0.81) and always using a powered stretcher (0.87, 0.78–0.97). Odds of exposure decreased with chemical, biological and nuclear exposure protection training (0.75, 0.69–0.80). Training in de-escalation techniques was associated with lower odds of experiencing violence (0.87, 0.79–0.96).ConclusionsOccupational hazards are commonly experienced among EMS clinicians. Common mitigation efforts are associated with lower odds of reporting these hazards. Mitigation strategies were not widespread and associated with lower odds of occupational hazards. These findings may present actionable items to reduce occupational hazards for EMS clinicians.
Prader-Willi Syndrome is the most common syndromic form of human obesity and is caused by the loss of function of several genes, including MAGEL2. Mice lacking Magel2 display increased weight gain ...with excess adiposity and other defects suggestive of hypothalamic deficiency. We demonstrate Magel2-null mice are insensitive to the anorexic effect of peripherally administered leptin. Although their excessive adiposity and hyperleptinemia likely contribute to this physiological leptin resistance, we hypothesized that Magel2 may also have an essential role in intracellular leptin responses in hypothalamic neurons. We therefore measured neuronal activation by immunohistochemistry on brain sections from leptin-injected mice and found a reduced number of arcuate nucleus neurons activated after leptin injection in the Magel2-null animals, suggesting that most but not all leptin receptor-expressing neurons retain leptin sensitivity despite hyperleptinemia. Electrophysiological measurements of arcuate nucleus neurons expressing the leptin receptor demonstrated that although neurons exhibiting hyperpolarizing responses to leptin are present in normal numbers, there were no neurons exhibiting depolarizing responses to leptin in the mutant mice. Additional studies demonstrate that arcuate nucleus pro-opiomelanocortin (POMC) expressing neurons are unresponsive to leptin. Interestingly, Magel2-null mice are hypersensitive to the anorexigenic effects of the melanocortin receptor agonist MT-II. In Prader-Willi Syndrome, loss of MAGEL2 may likewise abolish leptin responses in POMC hypothalamic neurons. This neural defect, together with increased fat mass, blunted circadian rhythm, and growth hormone response pathway defects that are also linked to loss of MAGEL2, could contribute to the hyperphagia and obesity that are hallmarks of this disorder.
Trauma is a leading cause of death in the United States. Ultrasound use in the prehospital environment has the potential to change trauma management. Although ultrasound use for prehospital trauma is ...increasing, the role of this modality is not clearly defined.
We examined the use of prehospital ultrasound (PHUS) for trauma patients and the use by different provider types. Specific factors of interest were if prehospital ultrasound has been shown to improve providers' ability to recognize conditions that can be managed in the prehospital setting, treat these conditions, change transport destination, or improve overall mortality rates for trauma patients.
We searched MEDLINE/PubMed, EBSCOhost, Cochrane Library, and Embase medical literature databases for articles that addressed our outcomes. Abstracts and articles were examined and studies that did not specifically evaluate ultrasound in the prehospital setting for trauma and duplicates were eliminated. Studies included in this comprehensive review were assessed for the use of ultrasound in the prehospital setting to aid in the diagnosis, treatment, and transport of trauma patients. We also conducted an analysis of bias in the included articles. Due to the large heterogeneity in the included studies, no meta-analysis could be performed.
Sixteen studies were identified comprising 3,317 patients. One study evaluated Emergency Medical Services (EMS) professionals as the ultrasound operator while five studies involved mixed practitioners and ten studies involved only physicians. Diagnostic accuracy was similar amongst physicians and mixed practitioners with no studies reporting PHUS accuracy for EMS providers alone. Seven studies evaluated treatment and transport impact of PHUS though the variables measured were inconsistent and results varied by protocol and outcomes measured. There were no studies that evaluated PHUS and its impact on patient mortality.
Ultrasound use in the prehospital setting for trauma is feasible and demonstrates potential. However, the evidence in the medical literature mainly consists of prospective observational studies of physicians utilizing ultrasound for trauma in a HEMS setting. Further scientific research must be undertaken to firmly establish the role of prehospital ultrasound in trauma management by all types of EMS providers.
BackgroundOncology therapy is becoming increasingly more expensive and challenging the affordability and sustainability of drug programmes around the world. When new drugs are evaluated, health ...technology assessment organisations rely on clinical trials to inform funding decisions. However, clinical trials are not able to assess overall survival and generalises evidence in a real-world setting. As a result, policy makers have little information on whether drug funding decisions based on clinical trials ultimately yield the outcomes and value for money that might be expected.ObjectiveThe Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration, consisting of researchers, recommendation-makers, decision makers, payers, patients and caregivers, are developing and testing a framework for Canadian provinces to generate and use real-world evidence (RWE) for cancer drug funding in a consistent and integrated manner.StrategyThe CanREValue collaboration has established five formal working groups (WGs) to focus on specific processes in the generation and use of RWE for cancer drug funding decisions in Canada. The different RWE WGs are: (1) Planning and Drug Selection; (2) Methods; (3) Data; (4) Reassessment and Uptake; (5) Engagement. These WGs are acting collaboratively to develop a framework for RWE evaluation, validate the framework through the multiprovince RWE projects and help to integrate the final RWE framework into the Canadian healthcare system.OutcomesThe framework will enable the reassessment of cancer drugs, refinement of funding recommendations and use of novel funding mechanisms by decision-makers/payers across Canada to ensure the healthcare system is providing clinical benefits and value for money.
The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to ...evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.
Despite wide support for patient involvement in health technology assessments (HTA), determining meaningful engagement is complex. This article explores experiences and perceptions among patient ...groups participating in the Canadian Agency for Drugs and Technologies in Health (CADTH)’s pan-Canadian Oncology Drug Review (pCODR) process.
We created a qualitative interview study comprising 22 semi-structured telephone interviews with individuals representing 21 different patient groups registered with the pCODR process. The analysis used a qualitative descriptive approach employing techniques from grounded theory.
Patient groups view the ability to make submissions to the pCODR process as a meaningful activity closely aligned with organizational priorities. Concurrently, they face substantial resource challenges to prepare submissions, including high opportunity costs and difficulty accessing needed literature and finding relevant patients. Although patient groups felt that CADTH is committed to transparency, they expressed considerable uncertainty around the direct impact of their submissions and desired additional avenues for engagement.
This study suggests a strong commitment by patient groups to participate in the pCODR process despite uncertainty about how their submissions are used to inform HTA recommendations. Identifying opportunities to provide both financial and nonfinancial resources to patient groups is crucial to encouraging and supporting their meaningful participation in HTA processes.
•Although there is widespread support for patient engagement in health technology assessments (HTA), there is limited evidence about why and how patient input is important and a limited understanding of the experiences and perspectives of participating patient groups.•Our study identifies a deep commitment from patient groups to participate in the pan-Canadian Oncology Drug Review (pCODR) process. They especially value the opportunity to provide information not available in trials, such as patient/caregiver priorities, but their participation is limited by substantial challenges including significant opportunity costs (eg, displacing patient support activities), difficulty accessing literature, or trouble finding relevant patients. Patient groups are uncertain regarding the impact of their submissions and expressed a desire for additional avenues of engagement.•Our work makes a substantial contribution to the literature by providing detailed, specific examples of what patient groups experienced as meaningful and what they experienced as challenges when making a pCODR submission. Coupled with our earlier examination of stakeholder perspectives, we believe our work has practical implications for better supporting patient engagement in the drug review process as well as within HTA more generally.
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