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Luis Puig1, Tao Fan,2 Qian Ding,2 Nancy E Smith2 1Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; 2Global Health Outcomes, Merck and Co., Inc., USA Background: Biologic therapies represent a significant advance in the treatment of psoriasis. However, no studies have examined the patient characteristics predictive of biologic treatment of psoriasis. The purpose of this study was to ascertain the frequency and predictors of treatment of psoriasis with biologics in three European countries, ie, France, Spain, and the UK. Methods: This was a cross-sectional analysis of physician-recorded demographic and clinical data on patients receiving either conventional or biologic treatments for psoriasis. Data were drawn from the Adelphi 2007 Psoriasis Disease Specific Program (DSP®), a multinational, real-world survey of patients with psoriasis consulting practicing dermatologists. The numbers of patients treated with biologic and nonbiologic agents were recorded. Data were subjected to bivariate analysis according to treatment regimen (biologic versus nonbiologic). Predictors of treatment with biologics were identified by logistic regression analysis. Results: A total of 2,509 psoriasis patients were included in this study (1,374 from France, 561 from Spain, and 574 from the UK). Biologic use was most prevalent in Spain (19.4% of patients), followed by the UK (9.1%), and France (8.4%). In the logistic regression analysis, psoriatic arthritis was a statistically significant predictor of increased biologic use in France (odds ratio [OR] 5.38, 95% confidence interval [CI] 3.32–8.77), Spain (OR 2.71, 95% CI 1.16–6.33), and the UK (OR 8.70, 95% CI 3.65–20.83). Physician-assessed moderate-to-severe disease was also a statistically significant predictor of increased biologic use in France (OR 5.08, 95% CI 2.01–12.82), Spain (OR 11.11, 95% CI 4.33–28.57), and the UK (OR 8.55, 95% CI 1.11–66.67). Conclusion: In this study, an average of about one tenth of psoriasis patients enrolled in Spain, France, and the UK were treated with biologics in 2007. Physician-assessed moderate-to-severe disease and presence of psoriatic arthritis were significantly associated with biologic use in all three countries. Keywords: psoriasis, drug therapy, tumor necrosis factor-alpha, antagonists, inhibitors, dermatologic agents, therapeutic use

A kritikai geográfusok 1997-es alakuló vancouveri konferenciája világossá tette, hogy szükség van nemzetközi kritikai geográfia létrehozására, kiteljesítésére – de, hogy mi számít kritikainak, az nagyon bizonytalanul definiált. E cikk igyekszik megragadni e kibontakozó politikai és szellemi csoport fő jellemzőit, illetve „jelszavait”. Ma a baloldal hagyományos tanítása a befogadásra és az önreflexivitásra buzdít. Olyan vélemény is létezik, hogy minden politikai harc egyenlő, a politikát pedig gyakran összekeverik az etikával. A cikk vitatja ezeknek az álláspontoknak a hasznosságát a 21. századi nemzetközi kritikai geográfia kontextusában, s a marxista kritika erejének újragondolására szólít fel.

Abstract Background To date there has been relatively little published about how research priorities are set, and even less about methods by which decision-makers can be engaged in defining a relevant and appropriate research agenda. We report on a recent effort in British Columbia to have researchers and decision-makers jointly establish an agenda for future research into questions of resource allocation. Methods The researchers enlisted decision-maker partners from each of British Columbia's six health authorities. Three forums were held, at which researchers and decision-makers from various levels in the health authorities considered possible research areas related to three key focus areas: (1) generation and use of decision criteria and measurement of 'benefit' against such criteria; (2) identification of so-called 'disinvestment' opportunities; and (3) evaluation of the effectiveness of priority setting procedures. Detailed notes were taken from each forum and synthesized into a set of qualitative themes. Results Forum participants suggested that future research into healthcare priority setting would benefit from studies that were longitudinal, comparative, and/or interdisciplinary. As well, participants identified two broad theme areas in which specific research projects were deemed desirable. First, future research might usefully consider how formal priority setting and resource allocation projects are situated within a larger organizational and political context. Second, additional research efforts should be devoted to better understanding and improving the actual implementation of priority setting frameworks, particularly with respect to issues of change management and the resolution of impediments to action on recommendations for resource allocation. Conclusion We were able to validate the importance of initial areas posed to the group and observed emergence of additional concerns and directions of critical importance to these decision-makers at this time. It is likely that the results are broadly applicable to other healthcare contexts. The implementation of this research agenda in British Columbia will depend upon the ability of the researchers and decision-makers to develop particular projects that fit within the constraints of existing funding opportunities. The process of engagement itself had benefits in terms of connecting decision-makers with their peers and sparking increased interest in the use and refinement of priority setting frameworks.

Abstract Background Depressive disorders are highly prevalent and of significant societal burden. In fall 2004, the 'Alberta Depression Initiative' (ADI) research program was formed with a mission to enhance the mental health of the Alberta population. A key expectation of the ADI is that research findings will be effectively translated to appropriate research users. To help ensure this, one of the initiatives funded through the ADI focused specifically on knowledge transfer and exchange (KTE). The objectives of this project were first to examine the state of the KTE literature, and then based on this review and a set of key informant interviews, design a KTE strategy for the ADI. Methods Face to face interviews were conducted with 15 key informants familiar with KTE and/or mental health policy and programs in Alberta. Interviews were transcribed and analyzed using the constant comparison method. Results This paper reports on findings from the qualitative interviews. Respondents were familiar with the barriers to and facilitators of KTE as identified in the existing literature. Four key themes related to the nature of effective KTE were identified in the data analysis: personal relationships, cultivating champions, supporting communities of practice, and building receptor capacity. These recommendations informed the design of a contextually appropriate KTE strategy for the ADI. The three-phased strategy involves preliminary research, public workshops, on-going networking and linkage activities and rigorous evaluation against pre-defined and mutually agreed outcome measures. Conclusion Interest in KTE on the part of ADI has led to the development of a strategy for engaging decision makers, researchers, and other mental health stakeholders in an on-going network related to depression programs and policy. A similarly engaged process might benefit other policy areas.

Abstract Background Decisions regarding the allocation of available resources are a source of growing dissatisfaction for healthcare decision-makers. This dissatisfaction has led to increased interest in research on evidence-based resource allocation processes. An emerging area of interest has been the empirical analysis of the characteristics of existing and desired priority setting processes from the perspective of decision-makers. Methods We conducted in-depth, face-to-face interviews with 18 senior managers and medical directors with the Vancouver Island Health Authority, an integrated health care provider in British Columbia responsible for a population of approximately 730,000. Interviews were transcribed and content-analyzed, and major themes and sub-themes were identified and reported. Results Respondents identified nine key features of a desirable priority setting process: inclusion of baseline assessment, use of best evidence, clarity, consistency, clear and measurable criteria, dissemination of information, fair representation, alignment with the strategic direction and evaluation of results. Existing priority setting processes were found to be lacking on most of these desired features. In addition, respondents identified and explicated several factors that influence resource allocation, including political considerations and organizational culture and capacity. Conclusion This study makes a contribution to a growing body of knowledge which provides the type of contextual evidence that is required if priority setting processes are to be used successfully by health care decision-makers.

Abstract Background Despite the high prevalence of co-morbid substance use among mental health service users (dual diagnosis), very few mental health workers in the UK have had training and/or clinical experience to equip them to deliver targeted interventions to this client group. Method In a randomised controlled trial of training for dual diagnosis interventions, 79 case managers from 12 community mental health teams in South London were randomly allocated to either receive training and follow-up supervision (experimental group) or no training and supervision (control group). Baseline measures of attitude, self-efficacy and knowledge were collected prior to randomisation, and were repeated at 18 months post-training. An intention to treat analysis of follow-up data (adjusted for baseline score for that outcome and team) was performed. Results At 18 months post-training, the AAPPQ (The Alcohol and Alcohol Problems Perception Questionnaire) total score was did not differ significantly between the two groups (adjusted difference 7.43 [95% CI -0.86 to 15.71], p = 0.08). There were significant differences in favour of the experimental group on 2 of the 6 subscales of the AAPPQ: 'adequacy of knowledge and skills in working with alcohol" (adjusted difference 3.598 [95% CI 1.03 to 6.16], p = 0.007) and "self-esteem in working with alcohol" (adjusted difference 3.00 [95% CI 0.46 to 5.54], p = 0.021). In addition there were significant improvements for the experimental group on "Knowledge About Dual Diagnosis" (adjusted difference 2.00 [95% CI 0.80 to 3.22], p = 0.002) and "Self-Efficacy Scale" (adjusted difference 13.55 [95% CI 8.00 to 26.86], p = 0.001). The effect of membership of teams was added to the analysis of covariance and this changed the results for only one variable: "self-esteem working with drinkers" was no longer significant. Conclusion A brief training course in dual diagnosis interventions had a significant effect on secondary measures of knowledge and self-efficacy that was detectable at 18 months post-training. Improvements in attitudes towards working with drinkers and drug users in mental health settings failed to reach statistical significance. Future research should explore the effects of dose of dual diagnosis training, and the successful integration of skills gained into routine care. Trial Registration: ISRCTN98891022 14th March 2007

Introduction: Despite recent advancements in policies supporting pregnancy and parenting-related resources for physician assistant (PA) students, there remains a paucity of data on the perceptions of family planning or available resources during training. The purpose of this study was to explore the perceptions of support for, and impact on, family planning and parenting, including lactation, among PA students., Methods: This cross-sectional study used data collected from the American Academy of Physician Associates Student Survey between January and March 2023. Descriptive and inferential statistics were performed., Results: A total of 557 students (557/1353; 41.2%) completed the survey. Less than 15% of students (14.4%) believed their program provides resources to support parental leave, and many students (52.1%) remained unsure whether resources exist(ed). There was a significant difference for PA students ( P = .005) by gender in whether family planning affected the decision to pursue PA training over another profession, with female students proportionately affected more than male students. Medical school was the most often considered aside from PA training. Most PA students (311/548; 56.8%) also felt pressure to wait until after training to have children. In addition, multiple students (26/554; 4.7%) admitted to being asked questions they believed were biased or inappropriate regarding pregnancy or parenting during the interview process for, or after beginning, PA school., Discussion: Programs should seek opportunities to support students through all stages of family planning. Support will require both cultural and structural shifts beginning with peer stigma and extending through admissions interview question audits, faculty training, university policies, and accreditation requirements., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 PA Education Association.)

Abstract: The prevalence of suicidal ideation is unknown and limited information exists about depression and anxiety among physician associates/assistants (PAs). We set out to understand the degree of depression, anxiety, and suicidal ideation in PAs and PA students. In total, 728 PAs and 322 PA students took an online survey. Risk of depression and anxiety were present at higher levels in PA students compared with employed PAs. PA students indicated higher levels of suicidal ideation compared with clinically active PAs. One-third of those with suicidal ideation did not reveal it to anyone; among those who did, 16.2% feared the results of disclosure. This study establishes that PAs and PA students are at risk for suicidal ideation and often bypass help. The COVID-19 pandemic may have led to elevated rates of emotional distress, and longitudinal studies are needed to understand the basis for such ideation and if it is transitory., (Copyright © 2023 American Academy of Physician Associates.)

Introduction: The purpose of this research was to assess physician assistant (PA) education and training on the diagnosis, management, and treatment of survivors of intimate partner violence (IPV), as well as perceived current vs. desired skills in tasks related to the management and treatment of IPV., Methods: Participants in 2 studies included a convenience sample of attendees at an annual PA conference (study 1) and PAs in the United States who were randomly selected to be administered an online survey related to their PA practice (study 2)., Results: In 2 studies, PAs reported low perceived competence to treat and manage patients who are survivors of IPV. More than half of the respondents (51.2%) had received training to work with survivors of IPV. Almost 3 in 5 indicated that they felt adequately prepared, and almost 3 in 10 regularly asked patients about IPV. Gaps between current and desired perceived skills to treat and manage survivors of IPV were larger among PAs who had previous training related to IPV compared with PAs with no prior training., Discussion: Guidance for PA educators may improve PA education and increase competencies among new PAs. Without more substantial guidance from an accrediting body, PA programs are left responsible for implementing IPV curriculum. Professional associations as well as constituent and specialty organizations that provide continuing medical education have an equally important role in strengthening skills and abilities among PAs., Competing Interests: Katherine M. Thompson is the Founder of IPV Educators. The remaining authors declare no conflict of interest., (Copyright © 2022 Physician Assistant Education Association.)

The kinetics of hydride transfer from Re( R bpy)(CO) 3 H (bpy = 4,4'-R-2,2'-bipyridine; R = OMe, t Bu, Me, H, Br, COOMe, CF 3 ) to CO 2 and seven different cationic N-heterocycles were determined. Additionally, the thermodynamic hydricities of complexes of the type Re( R bpy)(CO) 3 H were established primarily using computational methods. Linear free-energy relationships (LFERs) derived by correlating thermodynamic and kinetic hydricities indicate that, in general, the rate of hydride transfer increases as the thermodynamic driving force for the reaction increases. Kinetic isotope effects range from inverse for hydride transfer reactions with a small driving force to normal for reactions with a large driving force. Hammett analysis indicates that hydride transfer reactions with greater thermodynamic driving force are less sensitive to changes in the electronic properties of the metal hydride, presumably because there is less buildup of charge in the increasingly early transition state. Bronsted α values were obtained for a range of hydride transfer reactions and along with DFT calculations suggest the reactions are concerted, which enables the use of Marcus theory to analyze hydride transfer reactions involving transition metal hydrides. It is notable, however, that even slight perturbations in the steric properties of the Re hydride or the hydride acceptor result in large deviations in the predicted rate of hydride transfer based on thermodynamic driving forces. This indicates that thermodynamic considerations alone cannot be used to predict the rate of hydride transfer, which has implications for catalyst design.

The long noncoding RNA NEAT1 is known to be heavily dysregulated in many cancers. A single exon gene produces two isoforms, NEAT1_1 and NEAT1_2, through alternative 3'-end processing. As the longer isoform, NEAT1_2 is an essential scaffold for nuclear paraspeckle formation. It was previously thought that the short NEAT1_1 isoform only exists to keep the NEAT1 locus active for rapid paraspeckle formation. However, a recent glycolysis-enhancing function for NEAT1_1 , contributing to cancer cell proliferation and the Warburg effect, has been demonstrated. Previous studies have mainly focused on quantifying total NEAT1 and NEAT1_2 expression levels. However, in light of the NEAT1_1 role in cancer cell metabolism, the contribution from specific NEAT1 isoforms is no longer clear. Here, the roles of NEAT1_1 and NEAT1_2 in metabolism and cancer progression are discussed.

Introduction: The purpose of this study was to identify perceived barriers faced by physician assistant (PA) students who identified as an underrepresented minority in medicine (URM-med), sexual or gender minority (SGM), coming from low socioeconomic status (low SES), or a person with a disability (PWD)., Methods: More than 2700 PA students across the United States provided information regarding their PA school application process and program experiences. This study examined differences among URM-med, SGM, low SES, and PWD compared to those who were not in those groups to determine the relationship between these factors and student concerns about bias in the application process, as well as a variety of experiences in PA school., Results: Using ordinal logistic regression analyses to examine the odds of experiencing a variety of barriers or experiences in applying to PA school and postmatriculation experiences, results suggested that, among disadvantaged groups within the PA student body, barriers include concerns about bias in the application process, lack of belonging, and the lack of academic and social support., Discussion: PA students who identified as URM-med, SGM, low SES, and/or PWD faced barriers as they navigated the path to becoming a PA. To decrease these barriers, emphasis on raising awareness and interest in pursuing a career as a PA should occur early. Programs should work to identify biases within admissions processes, diversify faculty, and identify ways to support minority students once matriculated. Ultimately, increasing the diversity of healthcare providers has the potential to increase access to and quality of care for patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Physician Assistant Education Association.)

Introduction: Nearly half of all medical students suffer from burnout, which not only has detrimental effects on the students themselves but can transfer into the clinical realm. Yet, studies exploring burnout and interpersonal toxicity in physician assistant (PA) students are rare. This study examined the role that interpersonal toxicity and abuse play in PA student burnout., Methods: Nearly 2500 PA students in the United States responded to a survey about well-being, stress, and experiences with interpersonal toxicity in PA school as part of a larger cross-sectional study on PA student experiences in their didactic and clinical years. The present research focuses on overall measures among all PA students, as well as differences between didactic and clinical students, including the extent to which experiences of interpersonal toxicity predict symptoms associated with burnout., Results: Overall, PA students reported high levels of satisfaction and happiness in school and life, but enthusiasm for school decreased for clinical students. More than two-thirds of students reported moderate to high levels of life stress, and more than 9 in 10 reported moderate to high levels of school stress. Symptoms of burnout were reported by many students, with clinical students reporting interpersonal toxicity exposure more often than didactic students. Experiencing interpersonal toxicity or abuse predicted symptoms of burnout., Discussion: While PA students report high levels of life and school satisfaction, given the high levels of stress also reported, burnout metrics and well-being programs are needed. PA programs should work to create a supportive and engaging educational environment to ensure students' long-term career success., Competing Interests: Talia Sierra and Heidi Brown have co-founded The Burn Clinic, a non-profit burnout organization for PAs, and serve on the American Academy of PAs Burnout Task Force. Noel Smith and Tim McCall have no conflicts of interest., (Copyright © 2022 Physician Assistant Education Association.)

Context.—: Acquiring objective, timely, and comprehensive feedback on resident diagnostic performance is notoriously difficult., Objective.—: To implement a custom software application (Resident Case Tracker) to improve evaluative diagnostic analysis for residency programs., Design.—: Residents and faculty use a graphical user interface with restricted access to their own cases and evaluations. For each sign-out, residents enter their diagnoses and comments for each case. Faculty are provided a sign-out queue to review the resident diagnosis and select their level of agreement alongside optional comments. After sign-out, residents can review the agreement level and comments for each case, overall sign-out statistics, and organ-specific performance, and they have the option of opening and reviewing groups of cases by agreement status. A sign-out evaluation is automatically generated and stored alongside additional reports. Administrative access allows privileged users to readily review data analytics at both an individual and residency-wide global level., Results.—: A marked increase in completed evaluations and feedback was noted in the initial 36 months of implementation. During a 3-year academic period, faculty completed individual feedback on 33 685 cases and 1073 overall sign-out evaluations., Conclusions.—: Resident Case Tracker is an invaluable tool for our residency program and has provided unparalleled feedback and data analytics. Throughout residency, trainees have access to each completed sign-out, with the ability to learn from discrepant cases while also monitoring improvements in diagnostic acumen over time. Faculty are able to assess resident milestones much more effectively while more readily identifying residents who would benefit from targeted study., Competing Interests: The views expressed herein are those of the author and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force and Department of Defense, or the US government.

Purpose: The purpose of this study was to determine physician assistants' (PAs') current level of confidence to engage in nutrition-related tasks and their satisfaction with the nutrition education they received in PA school., Methods: To achieve this goal, a mixed-methods approach that consisted of 3 data collection phases (qualitative online discussions, quantitative survey, and qualitative interviews) was used to explore and measure PAs' perceptions of the education they received in PA school and through other sources and how confident they felt addressing nutrition-related issues in clinical practice., Results: While 80% of PAs endorse the idea that PAs should be more involved in providing nutritional care to patients, the majority reported basic or no knowledge of the nutritional implications of chronic conditions (69%), inflammatory bowel disease (69%), nutritional needs over the lifespan (67%), and food allergies and intolerances (64%). Barriers to patient care included knowledge-related challenges when selecting lab tests based on patient profile (46%) and identifying needs based on various gastrointestinal diseases (67%) and when using diagnostic data to identify deficiencies (74%). Overall, 59% of PAs reported being slightly or very dissatisfied with the nutrition-related content in the curricula used to formally train PAs., Conclusions: The primary goal of every PA program is to prepare its graduates to be competent to enter clinical practice. Regarding nutrition, these data indicate that programs are failing to do so. PAs lack the confidence and ability to provide optimal nutritional care, which is staggering considering that nutrition is the first line of treatment in the prevention and management of numerous chronic diseases., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Physician Assistant Education Association.)

Objective: To evaluate characteristics, training, and self-reported skills and abilities in vision and ocular care among PAs not specializing in ophthalmology., Methods: A survey on PA practice was administered to 5,763 randomly selected US-based PAs, and 537 respondents who completed the survey were invited to complete a separate vision and ocular care survey. Of those respondents, 382 completed the vision and ocular care survey., Results: Among respondents, 23% of PAs were involved in eyecare by providing patient information, answering questions, and initiating discussions about vision care and ocular health more than once per month. More than 77% received vision and ocular care training in and/or outside PA training. PAs involved in eyecare had significantly greater odds of reporting higher desired and current skill and ability levels compared with PAs not involved in eyecare, in six of eight vision and ocular care domains., Conclusions: PAs who do not practice in ophthalmology provide vision and ocular care but have varying amounts of training and desire higher skill and ability levels. Ophthalmologists and PA institutions may develop vision and ocular care training for PA schools and continuing medical education., (Copyright © 2022 American Academy of Physician Assistants.)

The objective of this study was to examine differences in principles from the cognitive load theory (CLT) combined with active learning strategies. To examine these differences, simple to complex activities were imbedded into two active learning instructional strategies: cooperative learning (CPL) and problem-based learning (PBL) and evaluated for its impact on mental effort for learning and intrinsic cognitive load. A two-within repeated-measures design was used in a nursing fundamentals classroom. The simple and complex activities were grounded in recommendations from the CLT and validated by nurse experts. The instructional strategies of CPL and PBL were chosen based on recommendations from the literature. Results revealed no statistically significant differences. A small interaction showed a decrease in mental effort and intrinsic load when problem-based learning was used. Progressing learning activities from simple to complex, informed by the CLT, offers an approach to designing instruction in nursing classrooms when using active learning strategies., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: This study examined the effect of depression and burnout on PA professional fulfillment and medical errors., Methods: Eight hundred eighty PAs completed an online survey containing the Professional Fulfillment Index, PHQ-2, GAD-7, and demographic questions. Two serial mediation models examined the relationship between depression, burnout, and professional outcomes., Results: Burnout fully mediated the relationship between depression and outcomes in both models and the present research indicates that burnout plays a stronger role in job satisfaction than symptoms of depression., Conclusions: Understanding the underpinnings of professional satisfaction may mitigate clinician turnover, which in turn may lead to cost savings for the organization, better resilience and mental health for clinicians, and potentially better patient outcomes., (Copyright © 2021 American Academy of Physician Assistants.)

The synthesis of triarylmethanes via Pd-catalyzed Suzuki-Miyaura reactions between diarylmethyl 2,3,4,5,6-pentafluorobenzoates and aryl boronic acids is described. The system operates at mild conditions and has a broad substrate scope, including the coupling of diphenylmethanol derivatives that do not contain extended aromatic substituents. This is significant as these substrates, which result in the types of triarylmethane products that are prevalent in pharmaceuticals, have not previously been compatible with systems for diarylmethyl ester coupling. Further, the reaction can be performed stereospecifically to generate stereo-inverted products. On the basis of DFT calculations, it is proposed that the oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrate occurs via an S N 2 pathway, which results in the inverted products. Mechanistic studies indicate that oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrates to (IPr)Pd(0) results in the selective cleavage of the O-C(benzyl) bond in part because of a stabilizing η 3 -interaction between the benzyl ligand and Pd. This is in contrast to previously described Pd-catalyzed Suzuki-Miyaura reactions involving phenyl esters, which involve selective cleavage of the C(acyl)-O bond, because there is no stabilizing η 3 -interaction. It is anticipated that this fundamental knowledge will aid the development of new catalytic systems, which use esters as electrophiles in cross-coupling reactions., Competing Interests: Competing Financial Interests The authors declare no competing financial interests.

Epigenetics are known to be involved in various disorders, including neurobiological disorders like autism. Dietary factors such as folic acid can affect epigenetic marks using methylenetetrahydrofolate reductase (MTHFR) to metabolize folic acid to a one-carbon methyl group. As MTHFR mutations are frequent, it is curious as to whether excess folic acid, with or without functioning MTHFR, could affect gene expression, epigenetics, and neuromorphology. Here, we investigated gene expression and activity of epigenetic modifying enzymes, genome-wide DNA methylation, histone 3 modifications, and dendritic spine densities in SH-SY5Y cells with or without a knockdown of MTHFR and with or without an excess of folic acid. We found alterations to gene expression of epigenetic modifying enzymes, including those associated with disorders like autism. Grouping the epigenetic modifying enzymes by function indicated that gene expression was widely affected for genes that code for enzymes affecting DNA methylation, histone acetylation, histone methylation, histone phosphorylation, and histone ubiquitination when excess folic acid treatment occurred with or without the knockdown of MTHFR. MTHFR was significantly reduced upon excess folic acid treatment whether MTHFR was knocked-down or not. Further, methyl-CpG binding protein 2 expression was significantly decreased with excess folic acid treatment with and without proper MTHFR expression. Global DNA methylation decreased due to the knockdown alone while global hydroxymethylated DNA increased due to the knockdown alone. TET2 expression significantly increased with the MTHFR knockdown alone. Excess folic acid alone induced a decrease in TET3 expression. Excess folic acid induced an increase in dendritic spines without the MTHFR knockdown, but folic acid induced a decrease in dendritic spines when MTHFR was knocked-down. The knockdown alone also increased the dendritic spines significantly. Histone 3 acetylation at lysine 18 was significantly increased when excess folic acid was applied to cells with the MTHFR knockdown, as was histone 3 phosphorylation at serine 10. Broadly, our results indicate that excess folic acid, even with functioning MTHFR, could have detrimental effects on cells., Competing Interests: No authors have competing interests.

The prevalence of transition metal-mediated hydride transfer reactions in chemical synthesis, catalysis, and biology has inspired the development of methods for characterizing the reactivity of transition metal hydride complexes. Thermodynamic hydricity represents the free energy required for heterolytic cleavage of the metal-hydride bond to release a free hydride ion, H - , as determined through equilibrium measurements and thermochemical cycles. Kinetic hydricity represents the rate of hydride transfer from one species to another, as measured through kinetic analysis. This tutorial review describes the common methods for experimental and computational determination of thermodynamic and kinetic hydricity, including advice on best practices and precautions to help avoid pitfalls. The influence of solvation on hydricity is emphasized, including opportunities and challenges arising from comparisons across several different solvents. Connections between thermodynamic and kinetic hydricity are discussed, and opportunities for utilizing these connections to rationally improve catalytic processes involving hydride transfer are highlighted.

Objective: To determine the magnitude of any difference in total compensation between male and female physician assistants (PAs) after controlling for personal and workplace factors related to compensation., Methods: Using data from the 2019 AAPA Salary Survey, the authors conducted a sequential regression analysis to examine the relationship between a variety of personal and practice demographics and total compensation., Results: After controlling for compensation-related factors, a wage gap between male and female PAs persisted: female PAs were paid almost $0.93 for every $1 male PAs were paid in the first year of work ($9,010 less). This wage gap widened by $201 for every year of work experience., Conclusions: A wage gap between male and female PAs persists even after including all compensation types and controlling for compensation-related factors that may differ between male and female PAs. Proposed policy implications could begin to mitigate the gap.

We analysed gross primary productivity (GPP), total ecosystem respiration (TER) and the resulting net ecosystem exchange (NEE) of carbon dioxide (CO 2 ) by the terrestrial biosphere during the summer of 2018 through observed changes across the Integrated Carbon Observation System (ICOS) network, through biosphere and inverse modelling, and through remote sensing. Highly correlated yet independently-derived reductions in productivity from sun-induced fluorescence, vegetative near-infrared reflectance, and GPP simulated by the Simple Biosphere model version 4 (SiB4) suggest a 130-340 TgC GPP reduction in July-August-September (JAS) of 2018. This occurs over an area of 1.6 × 10 6 km 2 with anomalously low precipitation in northwestern and central Europe. In this drought-affected area, reduced GPP, TER, NEE and soil moisture at ICOS ecosystem sites are reproduced satisfactorily by the SiB4 model. We found that, in contrast to the preceding 5 years, low soil moisture is the main stress factor across the affected area. SiB4's NEE reduction by 57 TgC for JAS coincides with anomalously high atmospheric CO 2 observations in 2018, and this is closely matched by the NEE anomaly derived by CarbonTracker Europe (52 to 83 TgC). Increased NEE during the spring (May-June) of 2018 (SiB4 -52 TgC; CTE -46 to -55 TgC) largely offset this loss, as ecosystems took advantage of favourable growth conditions. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

Purpose: To evaluate the scope of practice and training of current physician assistants (PAs) in ophthalmology and gauge their interest in further training and involvement in ophthalmology., Design: Cross-sectional survey study., Methods: An anonymous survey on vision and ocular care in the PA profession was administered to PAs in ophthalmology within the American Academy of Physician Assistants member database. All survey questions were optional., Results: A total response rate of 47/94 (50.0%) was obtained. Respondents reported an average of 9.8 years (SD = 9.0) of experience as a PA in ophthalmology. Over half of the respondents (59.5%) did not have previous experience in vision and ocular health before becoming a PA. Most respondents (79.5%) reported that they are able to provide their primary clinical responsibilities for ophthalmic care independently. In addition to providing clinical ophthalmic care, many of the respondents have duties that involve consenting patients for ophthalmic surgery and procedures (62.5%) and assisting in ophthalmic surgery and minor procedures (65.0%). Only a minority of respondents independently perform procedures, such as intravitreal injections (23.1%) and minor lid procedures (38.5%). Most respondents reported interest in additional training in providing vision and ocular care (69.0%), in continuing their career as a PA in ophthalmology (87.5%), and in joining a specialty organization for PAs in ophthalmology (88.1%)., Conclusions: The PAs participating in this survey provide a range of clinical and some procedural ophthalmic care. The development of formal PA postgraduate training programs in ophthalmology may expand the pool of PAs qualified to practice ophthalmology., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Physician assistants (PAs) are health professionals who have received advance medical training and are licensed to diagnose illness, develop and manage treatment plans, prescribe medications, and serve as principal health care provider. Although the U.S. federal government is the largest single employer of PAs, at the same time little is known about them across the wide array of diverse settings and agencies. The objective of this project was to determine the census of PAs in federal employment, their location, and personal characteristics. This included approximating the number of uniformed PAs. Taking stock of a unique labor force sets the stage for more granular analyses of how and where PAs are utilized and are deployed., Methods: No one central database identifies all federally employed PAs. To undertake this project, three sources were examined. Data were derived from the U.S. Office of Personnel Management and the National Commission on Certification of Physician Assistants. Uniformed PA numbers were the result of networking with senior chiefs in the military services and the U.S. Public Health Service. The data were collolated and summarized for comparison and discussion., Results: As of 2018, approximately 5,200 PAs were dispersed in most branches and agencies of the government that provide health care services, including the Departments of Defense, Veterans Affairs, Health and Human Services, Justice, and Homeland Security. Federally employed PAs are civil servants or hold a commission in the uniformed services (ie, Army, Navy, Air Force, Coast Guard, and Public Health Service). Most PAs are in clinical roles, although a few hundred are in management positions. Approximately 81% of civilian PAs have had less than 15 years of federal employment., Conclusion: The diverse utilization and deployment of PAs validate the importance of the role they serve as medical professionals in the federal government. From 2008 to 2019, PA employment in the federal government grew by approximately 50% supporting the forecast that substantial national PA growth is on track., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in communication and reciprocal social interactions. Little research has focused on the evaluation of developmental/behavioral pediatric education in the physician assistant (PA) curriculum. Therefore, the aims of this study were to evaluate whether PA students received training in identifying the red flags of ASD, using screening tests such as the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F). Additionally, the study sought to determine if PA students received education on the evaluation and management of children with ASD along with the methods to communicate effectively with their caretakers., Methods: A survey open to PA students was administered by the American Academy of PAs. Demographic information along with questions on knowledge and perceptions related to ASD were asked. Perceptions of preparation to discuss ASD with patient caregivers were assessed, along with vaccination beliefs, and training information was collected., Results: A total of 213 PA students answered the survey. Students received training regarding the red flags for ASD as well as ASD-related skills. Of note, 58.2% did not receive training on administration of the M-CHAT-(R/F) and 54.9% did not receive training to provide care to patients with ASD; 77.8% received training to understand pediatric developmental milestones. PA students overwhelmingly rejected the suggestion that there is a link between vaccines and ASD., Conclusion: The importance of diagnosing ASD as early as possible has been demonstrated by years of research; yet, this study concludes that many students still do not feel comfortable recognizing the red flags or using screening tools. Although the majority of PA students received training to understand developmental milestones, many did not know how to administer the M-CHAT-(R/F), which is key to making an early diagnosis.

Background: Accurate staging of lung cancer is paramount for directing treatment. After an internal audit suggested a higher than expected rate of synchronous multiple primary lung cancers (SMPLC), we have sought to evaluate the prevalence of SMPLC at our single, large academic center., Methods: From January 2019 to September 2019, patients with non-small cell lung cancer who underwent surgical resection were retrospectively reviewed. Clinical characteristics, pre- and post-op imaging, 30-day morbidity and mortality, as well as pathological findings were reviewed. SMPLCs were defined using modified Martini criteria., Results: Among 83 patients who underwent surgical resection for primary lung cancer with the intention of cure, 17 (20.5%) had pathologically confirmed SMPLC's, 53 (64%) were single primary lung cancers, and 13 (16%) had metastatic lesions from primary lung cancer or extra-thoracic cancers. Mean length of stay was 2 days with no mortalities. Of the SMPLC group, 9 (53%) had previous extra-thoracic neoplasms, compared with 8 (15%) in the single primary group. Four (24%) had a history of resected lung cancers more than 2 years previously, and were participating in lung cancer surveillance programs., Conclusions: The rate of SMPLC at our institution appears to be considerably higher than traditionally reported. Failure to recognize the high incidence of synchronous primary lung cancers exposes patients to the risks of under treatment and poor outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-19-3990). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Early detection is imperative for children with autism spectrum disorder (ASD) to achieve optimal functioning. Knowledge of early signs of ASD, as well as open communication, can mitigate delayed diagnosis. This study explored physician assistants' (PA) abilities to diagnosis ASD as well as gathered information on their training. A majority of respondents who see pediatric patients received training on developmental milestones, but far fewer received training to identify red flags for ASD. Few PAs are talking with every patient's caregivers about a variety of behavioral health conditions, not just ASD. Overall, PAs rated their current skills working with patients with ASD lower than their desired level, suggesting a desire to become more adept at meeting their patients' needs.

The reversible activation of H 2 via a pathway involving metal-ligand cooperation (MLC) is proposed to be important in many transition metal catalyzed hydrogenation and dehydrogenation reactions. Nevertheless, there is a paucity of experimental information probing the mechanism of this transformation. Here, we present an in-depth kinetic study of the 1,2-addition of H 2 via an MLC pathway to the widely used iron catalyst [( i Pr PNP)FeH(CO)] ( 1 ) ( i Pr PNP = N(CH 2 CH 2 P i Pr 2 ) 2 - ). We report one of the first experimental demonstrations of an enhancement in rate for the activation of H 2 using protic additives, which operate as "proton shuttles". Our results indicate that proton shuttles need to be able to both simultaneously donate and accept a proton, and the best shuttles are molecules that are strong hydrogen bond donors but sufficiently weak acids to avoid deleterious protonation of the transition metal complex. Additionally, comparison of the rate of H 2 activation via an MLC pathway between 1 and two widely used ruthenium catalysts enables more general conclusions about the role of the metal, ancillary ligand, and proton shuttles in H 2 activation. The results of this study provide guidance about the design of catalysts and additives to promote H 2 activation via an MLC pathway.

Context.—: A common concern in pathology residency training is the variability with which incoming trainees have attained basic pathology competencies during undergraduate medical education. While multifactorial deficiencies are likely due to recent de-emphasis of dedicated pathology courses during preclinical training, accelerating the transition from medical student to pathology resident is critical-particularly in military practice where a greater degree of autonomy is required of recent graduates., Objective.—: To describe the implementation and results of a 4-week surgical pathology "boot camp" in the largest military pathology residency program in the United States., Design.—: Interns were administered an assessment on basic pathology knowledge, slide practicals, and a skills self-assessment. All specimens were grossed by interns with constant direct supervision. A daily microscopic didactic session was given by an upper level resident and a daily gross conference was led by the interns. Subsequent academic performance was evaluated via monthly slide practicals and diagnostic agreement with faculty., Results.—: Following boot camp, average scores on the knowledge assessment increased from 36.0% ± 16.2% (standard deviation [SD]) to 80.0% ± 12.6% (SD) ( P < .001). Slide practical scores showed an increase from 32% ± 12.0% (SD) to 74.0% ± 16.2% (SD) ( P < .001). Skills self-assessment showed a global increase across all measures. Throughout the following academic year, postgraduate year 1 (PGY1) residents performed at the same level of current PGY2 residents, based on surgical pathology faculty diagnostic agreement and slide practical performance., Conclusions.—: An intense 4-week surgical pathology rotation specifically tailored to incoming interns was successful in transitioning medical students to pathology residents within a relatively short time.

The tropical carbon balance dominates year-to-year variations in the CO 2 exchange with the atmosphere through photosynthesis, respiration and fires. Because of its high correlation with gross primary productivity (GPP), observations of sun-induced fluorescence (SIF) are of great interest. We developed a new remotely sensed SIF product with improved signal-to-noise in the tropics, and use it here to quantify the impact of the 2015/2016 El Niño Amazon drought. We find that SIF was strongly suppressed over areas with anomalously high temperatures and decreased levels of water in the soil. SIF went below its climatological range starting from the end of the 2015 dry season (October) and returned to normal levels by February 2016 when atmospheric conditions returned to normal, but well before the end of anomalously low precipitation that persisted through June 2016. Impacts were not uniform across the Amazon basin, with the eastern part experiencing much larger (10-15%) SIF reductions than the western part of the basin (2-5%). We estimate the integrated loss of GPP relative to eight previous years to be 0.34-0.48 PgC in the three-month period October-November-December 2015.This article is part of a discussion meeting issue 'The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications'., (© 2018 The Authors.)

The 2015/2016 El Niño event caused severe changes in precipitation across the tropics. This impacted surface hydrology, such as river run-off and soil moisture availability, thereby triggering reductions in gross primary production (GPP). Many biosphere models lack the detailed hydrological component required to accurately quantify anomalies in surface hydrology and GPP during droughts in tropical regions. Here, we take the novel approach of coupling the biosphere model SiBCASA with the advanced hydrological model PCR-GLOBWB to attempt such a quantification across the Amazon basin during the drought in 2015/2016. We calculate 30-40% reduced river discharge in the Amazon starting in October 2015, lagging behind the precipitation anomaly by approximately one month and in good agreement with river gauge observations. Soil moisture shows distinctly asymmetrical spatial anomalies with large reductions across the north-eastern part of the basin, which persisted into the following dry season. This added to drought stress in vegetation, already present owing to vapour pressure deficits at the leaf, resulting in a loss of GPP of 0.95 (0.69 to 1.20) PgC between October 2015 and March 2016 compared with the 2007-2014 average. Only 11% (10-12%) of the reduction in GPP was found in the (wetter) north-western part of the basin, whereas the north-eastern and southern regions were affected more strongly, with 56% (54-56%) and 33% (31-33%) of the total, respectively. Uncertainty on this anomaly mostly reflects the unknown rooting depths of vegetation.This article is part of a discussion meeting issue 'The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications'., (© 2018 The Authors.)

Plant protection products containing nanomaterials that alter the functionality or risk profile of active ingredients (nano-enabled pesticides) promise many benefits over conventional pesticide products. These benefits may include improved formulation characteristics, easier application, better targeting of pest species, increased efficacy, lower application rates, and enhanced environmental safety. After many years of research and development, nano-enabled pesticides are starting to make their way into the market. The introduction of this technology raises a number of issues for regulators, including how does the ecological risk assessment of nano-enabled pesticide products differ from that of conventional plant protection products? In this paper, a group drawn from regulatory agencies, academia, research, and the agrochemicals industry offers a perspective on relevant considerations pertaining to the problem formulation phase of the ecological risk assessment of nano-enabled pesticides.