Citations

Abstract Purpose Both overuse and underuse of clinician referrals can compromise high-value health care. The authors sought to systematically identify and synthesize published research examining associations between physician continuous professional development (CPD) and referral patterns. Method The authors searched MEDLINE, Embase, PsycInfo, and the Cochrane Database on April 23, 2020, for comparative studies evaluating CPD for practicing physicians and reporting physician referral outcomes. Two reviewers, working independently, screened all articles for inclusion. Two reviewers reviewed all included articles to extract information, including data on participants, educational interventions, study design, and outcomes (referral rate, intended direction of change, appropriateness of referral). Quantitative results were pooled using meta-analysis. Results Of 3,338 articles screened, 31 were included. These studies enrolled at least 14,458 physicians and reported 381,165 referral events. Among studies comparing CPD with no intervention, 17 studies with intent to increase referrals had a pooled risk ratio of 1.91 (95% confidence interval: 1.50, 2.44; P < .001), and 7 studies with intent to decrease referrals had a pooled risk ratio of 0.68 (95% confidence interval: 0.55, 0.83; P < .001). Five studies did not indicate the intended direction of change. Subgroup analyses revealed similarly favorable effects for specific instructional approaches (including lectures, small groups, Internet-based instruction, and audit/feedback) and for activities of varying duration. Four studies reported head-to-head comparisons of alternate CPD approaches, revealing no clear superiority for any approach. Seven studies adjudicated the appropriateness of referral, and 9 studies counted referrals that were actually completed (versus merely requested). Conclusions Although between-study differences are large, CPD is associated with statistically significant changes in patient referral rates in the intended direction of impact. There are few head-to-head comparisons of alternate CPD interventions using referrals as outcomes.

Purpose Nearly all health care professionals engage in continuous professional development (CPD), yet little is known about the cost and cost-effectiveness of physician CPD. Clarification of key concepts, comprehensive identification of published work, and determination of research gaps would facilitate application of existing evidence and planning for future investigations. The authors sought to systematically map study themes, methods, and outcomes in peer-reviewed literature on the cost and value of physician CPD. Method The authors conducted a scoping review, systematically searching MEDLINE, Embase, PsycInfo, and Cochrane Library databases for comparative economic evaluations of CPD for practicing physicians through April 2020. Two reviewers, working independently, screened all articles for inclusion. Three reviewers iteratively reviewed all included articles to inductively identify key features including participants, educational interventions, study designs, cost ingredients, and cost analyses. Two reviewers then independently reexamined all included articles to code these features. Results Of 3,338 potentially eligible studies, 111 were included. Physician specialties included internal, family, or general medicine (80 studies [72%]), surgery (14 studies [13%]), and medicine subspecialties (7 studies [6%]). Topics most often addressed general medicine (45 studies [41%]) or appropriate drug use (37 studies [33%]). Eighty-seven studies (78%) compared CPD with no intervention. Sixty-three studies (57%) reported the cost of training, and 79 (71%) evaluated the economic impact (money saved/lost following CPD). Training cost ingredients (median 3 itemized per study) and economic impact ingredients (median 1 per study) were infrequently and incompletely identified, quantified, or priced. Twenty-seven studies (24%) reported cost–impact expressions such as cost-effectiveness ratio or net value. Nineteen studies (17%) reported sensitivity analyses. Conclusions Studies evaluating the costs and economic impact of physician CPD are few. Gaps exist in identification, quantification, pricing, and analysis of cost outcomes. The authors propose a comprehensive framework for appraising ingredients and a preliminary reference case for economic evaluations.

BackgroundA low‐cryogen, compact 3T (C3T) MRI scanner with high‐performance gradients capable of simultaneously achieving 80 mT/m gradient amplitude and 700 T/m/second slew rate has been in use to study research patients since March 2016 but has not been implemented in the clinical practice.PurposeTo compare head MRI examinations obtained with the C3T system and a conventional whole‐body 3T (WB3T) scanner in seven parameters across five commonly used brain imaging sequences.Study TypeProspective.SubjectsThirty patients with a clinically indicated head MRI.Sequence 3T; T1 FLAIR, T1 MP‐RAGE, 3D T2 FLAIR, T2 FSE, and DWI.AssessmentAll patients tolerated the scans well. Three board‐certified neuroradiologists scored the comparative quality of C3T and WB3T images in blinded fashion using a five‐point Likert scale in terms of: signal‐to‐noise ratio, lesion conspicuity, motion artifact, gray/white matter contrast, cerebellar folia, susceptibility artifact, and overall quality.Statistical TestLeft‐sided, right‐sided, and two‐sided Wilcoxon signed rank test; Fisher's method. A P value <0.05 was considered statistically significant.ResultsThe C3T system performed better than the WB3T in virtually all comparisons, except for motion artifacts for the T1 FLAIR and T1 MP‐RAGE sequences, where the WB3T system was deemed better. When combining all sequences together, the C3T system outperformed the WB3T system in all image quality parameters evaluated, except for motion artifact (P = 0.13).Data ConclusionThe C3T scanner provided better overall image quality for all sequences, and performed better in all individual categories, except for motion artifact on the T1 FLAIR and T1 MP‐RAGE.Level of Evidence2Technical Efficacy Stage1

Background The aggressive clinical behavior of poorly differentiated and anaplastic thyroid cancers (PDTC and ATC) has proven challenging to treat, and survival beyond a few months from diagnosis is rare. Although 30%–60% of these tumors contain mutations in the BRAF gene, inhibitors designed specifically to target oncogenic BRAF have shown limited and only short-lasting therapeutic benefits as single agents, thus highlighting the need for improved treatment strategies, including novel combinations. Methods Using a BRAFV600E-driven mouse model of ATC, we investigated the therapeutic efficacy of the combination of BRAF inhibition and oncolytic herpes simplex virus (oHSV). Analyses of samples from tumor-bearing mice were performed to immunologically characterize the effects of different treatments. These immune data were used to inform the incorporation of immune checkpoint inhibitors into triple combination therapies. Results We characterized the immune landscape in vivo following BRAF inhibitor treatment and detected only modest immune changes. We, therefore, hypothesized that the addition of oncolytic virotherapy to BRAF inhibition in thyroid cancer would create a more favorable tumor immune microenvironment, boost the inflammatory status of tumors and improve BRAF inhibitor therapy. First, we showed that thyroid cancer cells were susceptible to infection with oHSV and that this process was associated with activation of the immune tumor microenvironment in vivo. Next, we showed improved therapeutic responses when combining oHSV and BRAF inhibition in vivo, although no synergistic effects were seen in vitro, further confirming that the dominant effect of oHSV in this context was likely immune-mediated. Importantly, both gene and protein expression data revealed an increase in activation of T cells and natural killer (NK) cells in the tumor in combination-treated samples. The benefit of combination oHSV and BRAF inhibitor therapy was abrogated when T cells or NK cells were depleted in vivo. In addition, we showed upregulation of PD-L1 and CTLA-4 following combined treatment and demonstrated that blockade of the PD-1/PD-L1 axis or CTLA-4 further improved combination therapy. Conclusions The combination of oHSV and BRAF inhibition significantly improved survival in a mouse model of ATC by enhancing immune-mediated antitumor effects, and triple combination therapies, including either PD-1 or CTLA-4 blockade, further improved therapy.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

PurposeWe investigate the importance of high gradient‐amplitude and high slew‐rate on oscillating gradient spin echo (OGSE) diffusion imaging for human brain imaging and evaluate human brain imaging with OGSE on the MAGNUS head‐gradient insert (200 mT/m amplitude and 500 T/m/s slew rate).MethodsSimulations with cosine‐modulated and trapezoidal‐cosine OGSE at various gradient amplitudes and slew rates were performed. Six healthy subjects were imaged with the MAGNUS gradient at 3T with OGSE at frequencies up to 100 Hz and b = 450 s/mm2. Comparisons were made against standard pulsed gradient spin echo (PGSE) diffusion in vivo and in an isotropic diffusion phantom.ResultsSimulations show that to achieve high frequency and b‐value simultaneously for OGSE, high gradient amplitude, high slew rates, and high peripheral nerve stimulation limits are required. A strong linear trend for increased diffusivity (mean: 8–19%, radial: 9–27%, parallel: 8–15%) was observed in normal white matter with OGSE (20 Hz to 100 Hz) as compared to PGSE. Linear fitting to frequency provided excellent correlation, and using a short‐range disorder model provided radial long‐term diffusivities of D∞,MD = 911 ± 72 µm2/s, D∞,PD = 1519 ± 164 µm2/s, and D∞,RD = 640 ± 111 µm2/s and correlation lengths of lc,MD = 0.802 ± 0.156 µm, lc,PD = 0.837 ± 0.172 µm, and lc,RD = 0.780 ± 0.174 µm. Diffusivity changes with OGSE frequency were negligible in the phantom, as expected.ConclusionThe high gradient amplitude, high slew rate, and high peripheral nerve stimulation thresholds of the MAGNUS head‐gradient enables OGSE acquisition for in vivo human brain imaging.

Context High‐quality research into education costs can inform better decision making. Improvements to cost research can be guided by information about the research questions, methods and reporting of studies evaluating costs in health professions education (HPE). Our objective was to appraise the overall state of the field and evaluate temporal trends in the methods and reporting quality of cost evaluations in HPE research. Methods We searched the MEDLINE , CINAHL (Cumulative Index to Nursing and Allied Health Literature), EMBASE , Business Source Complete and ERIC (Education Resources Information Centre) databases on 31 July 2017. To evaluate trends over time, we sampled research reports at 5‐year intervals (2001, 2006, 2011 and 2016). All original research studies in HPE that reported a cost outcome were included. The Medical Education Research Study Quality Instrument ( MERSQI ) and the BMJ economic checklist were used to appraise methodological and reporting quality, respectively. Trends in quality over time were analysed. Results A total of 78 studies were included, of which 16 were published in 2001, 15 in 2006, 20 in 2011 and 27 in 2016. The region most commonly represented was the USA ( n = 43). The profession most commonly referred to was that of the physician ( n = 46). The mean ± standard deviation ( SD ) MERSQI score was 10.9 ± 2.6 out of 18, with no significant change over time (p = 0.55). The mean ± SD BMJ score was 13.5 ± 7.1 out of 35, with no significant change over time (p = 0.39). A total of 49 (63%) studies stated a cost‐related research question, 23 (29%) stated the type of cost evaluation used, and 31 (40%) described the method of estimating resource quantities and unit costs. A total of 16 studies compared two or more interventions and reported both cost and learning outcomes. Conclusions The absolute number of cost evaluations in HPE is increasing. However, there are shortcomings in the quality of methodology and reporting, and these are not improving over time.

Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O6-methylguanine–DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM—surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis.