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Stressful events, such as the COVID-19 pandemic, are major contributors to anxiety and depression, but only a subset of individuals develop psychopathology. In a population-based sample (N = 174) with a high representation of marginalized individuals, this study examined adolescent functional network connectivity as a marker of susceptibility to anxiety and depression in the context of adverse experiences.Data-driven network-based subgroups were identified using an unsupervised community detection algorithm within functional neural connectivity. Neuroimaging data collected during emotion processing (age 15) were extracted from a priori regions of interest linked to anxiety and depression. Symptoms were self-reported at ages 15, 17, and 21 (during COVID-19). During COVID-19, participants reported on pandemic-related economic adversity. Differences across subgroup networks were first examined, then subgroup membership and subgroup-adversity interaction were tested to predict change in symptoms over time.Two subgroups were identified: Subgroup A, characterized by relatively greater neural network variation (i.e., heterogeneity) and density with more connections involving the amygdala, subgenual cingulate, and ventral striatum; and the more homogenous Subgroup B, with more connections involving the insula and dorsal anterior cingulate. Accounting for initial symptoms, subgroup A individuals had greater increases in symptoms across time (β = .138, p = .042), and this result remained after adjusting for additional covariates (β = .194, p = .023). Furthermore, there was a subgroup-adversity interaction: compared with Subgroup B, Subgroup A reported greater anxiety during the pandemic in response to reported economic adversity (β = .307, p = .006), and this remained after accounting for initial symptoms and many covariates (β = .237, p = .021).A subgrouping algorithm identified young adults who were susceptible to adversity using their personalized functional network profiles derived from a priori brain regions. These results highlight potential prospective neural signatures involving heterogeneous emotion networks that predict individuals at the greatest risk for anxiety when experiencing adverse events.

Introduction We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). Methods Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. Results The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). Discussion PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.

Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug-resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase-independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2

OBJECTIVES: Existing curricula and recommendations on the incorporation of structural competency and vulnerability into medical education have not provided clear guidance on how best to do so within emergency medicine (EM). The goal of this scoping review and consensus building process was to provide a comprehensive overview of structural competency, link structural competency to educational and patient care outcomes, and identify existing gaps in the literature to inform curricular implementation and future research in EM. METHODS: A scoping review focused on structural competency and vulnerability following Arksey and O’Malley’s six‐step framework was performed in concurrence with a multistep consensus process culminating in the 2021 SAEM Consensus Conference. Feedback was incorporated in developing a framework for a national structural competency curriculum in EM. RESULTS: A literature search identified 291 articles that underwent initial screening. Of these, 51 were determined to be relevant to EM education. The papers consistently conceptualized structural competency as an interdisciplinary framework that requires learners and educators to consider historical power and privilege to develop a professional commitment to justice. However, the papers varied in their operationalization, and no consensus existed on how to observe or measure the effects of structural competency on learners or patients. None of the studies examined the structural constraints of the learners studied. CONCLUSIONS: Findings emphasize the need for training structurally competent physicians via national structural competency curricula focusing on standardized core competency proficiencies. Moreover, the findings highlight the need to assess the impact of such curricula on patient outcomes and learners’ knowledge, attitudes, and clinical care delivery. The framework aims to standardize EM education while highlighting the need for further research in how structural competency interventions would translate to an ED setting and affect patient outcomes and experiences.

The potential benefit of the anti‐amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti‐amyloid drug therapies. The two trials of 18‐month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high‐dose EMERGE trial initially also showed no benefit but with longer follow‐up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti‐amyloid drugs is very substantial as well as the brain amyloid‐AD‐dementia hypothesis.

BACKGROUND Quantitative muscle MRI is a robust tool to monitor intramuscular fatty replacement and disease activity in patients with neuromuscular disorders (NMDs). PURPOSE To implement a 3D sequence for quantifying simultaneously fat fraction (FF) and water T1 (T1,H2O ) in the skeletal muscle, evaluate regular undersampling in the partition-encoding direction, and compare it to a recently proposed 2D MR fingerprinting sequence with water and fat separation (MRF T1 -FF). STUDY TYPE Prospective. PHANTOM/SUBJECTS Seventeen-vial phantom at different FF and T1,H2O , 11 healthy volunteers, and 6 subjects with different NMDs. FIELD STRENGTH/SEQUENCE 3T/3D MRF T1 -FF, 2D MRF T1 -FF, STEAM MRS ASSESSMENT: FF and T1,H2O measured with the 2D and 3D sequences were compared in the phantom and in vivo at different undersampling factors (US). Data were acquired in healthy subjects before and after plantar dorsiflexions and at rest in patients. STATISTICAL TESTS Linear correlations, Bland-Altman analysis, two-way repeated measures analysis of variance (ANOVA), Student's t-test. RESULTS Up to a US factor of 3, the undersampled acquisitions were in good agreement with the fully sampled sequence (R2 ≥ 0.98, T1,H2O bias ≤10 msec, FF bias ≤4 × 10-4 ) both in phantom and in vivo. The 2D and 3D MRF T1 -FF sequences provided comparable T1,H2O and FF values (R2 ≥ 0.95, absolute T1,H2O bias ≤35 msec, and absolute FF bias ≤0.003). The plantar dorsiflexion induced a significant increase of T1,H2O in the tibialis anterior and extensor digitorum (relative increase of +10.8 ± 1.7% and + 7.7 ± 1.4%, respectively, P

Background Eligibility criteria and endpoints for cancer cachexia trials—and whether weight loss should be included—remain controversial. Although most cachexia trials enrol patients after initial cancer diagnosis, few studies have addressed whether weight loss well after a cancer diagnosis is prognostic. Methods We pooled data from non‐small cell lung cancer patients from prospectively conducted trials within the Alliance for Clinical Trials in Oncology (1998–2008), a nationally funded infrastructure. We examined (i) weight data availability and weight changes and (ii) survival. Results A total of 822 patients were examined. Of these, 659 (80%) were on treatment at the beginning of Cycle 2 of chemotherapy; weight was available for 656 (80%). By Cycles 3 and 4, weight was available for 448 (55%) and 384 (47%), respectively. From baseline to immediately prior to Cycle 2, 208 (32%) gained weight; 225 (34%) lost

Objectives To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR‐DNA binding protein of 43kDA (TDP‐43) in Alzheimer’s disease (AD) patients. Methods The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA‐Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37‐95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP‐43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE‐4 allele, and presence of Lewy bodies (LB). Results HS was present in 18% (n = 64) and TDP‐43 in 51.5% (n = 185) of the patients. HS and TDP‐43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP‐43. Age at onset was not associated with TDP‐43 or HS. HS was associated with duration of symptoms and LB, TDP‐43, and atherosclerosis in the CW. TDP‐43 was associated with duration of symptoms, LB, and HS. Interpretation HS and TDP‐43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP‐43 are part of the later neuropathological changes in AD.

Introduction This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild‐to‐moderate Alzheimer's disease (AD). Methods Three hundred forty‐seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6‐week period of weekly conventional PE followed by a 12‐month period of monthly low‐volume PE), and placebo (sham). Results PE‐treated patients performed significantly better than placebo for the co‐primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS‐ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS‐Cog; P = .06; 66% less decline) scores at month 14. Moderate‐AD patients (baseline Mini‐Mental State Examination [MMSE] 18‐21) scored better on ADCS‐ADL (P = .002) and ADAS‐Cog (P = .05), 61% less decline both. There were no changes in mild‐AD patients (MMSE 22‐26). PE‐treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR‐sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC) (P

Introduction Recent studies suggest that Alzheimer's disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers. Methods Randomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow-up. Results Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms. Discussion These findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.

Introduction Both high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. Methods We examined baseline plasma β-amyloid (Aβ) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. Results Increased plasma Aβ1-40 and Aβ1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aβ1-42 and Aβ1-42/Aβ1-40 ratio compared with those who did not. Aβ levels did not predict dementia in mild cognitive impairment participants. Discussion There was an inverse association between Aβ1-42 and Aβ1-42/Aβ1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aβ levels and must be considered in evaluations of relationship of plasma Aβ and subsequent risk of dementia.

The response of seeds from 23 wild plant species to a range of seed enhancing treatments was studied. We tested the hypothesis that sensitivity of the 23 species to these compounds is related to their ecological niche. The three ecological niches considered were open land, open-pioneer and woodland. Hence, the germination of a species is likely adapted to different light conditions and other environmental signals related to the niche. As representatives of environmental signals, the effects of smoke-related compounds (karrikinolide, KAR1 ), nitrate and plant growth regulator (gibberellic acid, GA3 ) on germination were studied. Seeds were exposed to these additives in the imbibition medium; all described as germination cues. We also investigated the effect of light regimes and additives on germination parameters, which included final germination, germination rate and uniformity of germination. Seeds were placed to germinate under three light conditions: constant red light, constant darkness and 12 h white light photoperiod. We observed inhibition by KAR under light in some species, which may have ecological implications. The results showed that no single treatment increased the germination of all the tested species, rather a wide variation of responsiveness of the different species to the three compounds was found. Additionally, no interaction was found between responsiveness to compounds and ecological niche. However, species in the same ecological niche and dormancy class showed a similar responsiveness to light. Species that share a similar environment have similar light requirements for germination, while differences exist among species in their responsiveness to other germination cues.

Author(s): Leverenz, James B; Bekris, Lynn M; Berman, Sarah; Fleisher, Jori E; Galasko, Doug R; Galvin, James E; Goldman, Jennifer; Hall, Deborah A; Irwin, David J; Kaufer, Daniel; Lippa, Carol; Litvan, Irene; Lopez, Oscar L; Sabbagh, Marwan N; Tsuang, Debby W; Zabetian, Cyrus P

The mouse embryo is an established model for investigation of regulatory mechanisms controlling cardiac development and congenital heart defects in humans. Since cultured mouse embryos are very sensitive to any manipulations and environmental fluctuations, controlled alterations in mouse embryonic cardiac function are extremely challenging, which is a major hurdle in mammalian cardiac biomechanics research. This manuscript presents first optogenetic manipulation of cardiodynamics and hemodynamics in cultured mouse embryos. Optogenetic pacing was combined with 4D (3D + time) optical coherence tomography structural and Doppler imaging, demonstrating that embryonic hearts under optogenetic pacing can function efficiently and produce strong blood flows. This study demonstrates that the presented method is a powerful tool giving quick, consistent, reversible control over heart dynamics and blood flow under real time visualization, enabling various live cardiac biomechanics studies toward better understanding of normal cardiogenesis and congenital heart defects in humans.

Introduction Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti‐oxidant and anti‐amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aβ) deposition. Methods From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using 11C‐Pittsburgh compound‐B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers. Results The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aβ positive, and 51% were equol producers. Equol‐producing status (non‐producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend P

Introduction Hearing and vision loss are independently associated with dementia, but the impact of dual sensory impairment (DSI) on dementia risk is not well understood. Methods Self‐reported measures of hearing and vision were taken from 2051 participants at baseline from the Gingko Evaluation of Memory Study. Dementia status was ascertained using standardized criteria. Cox models were used to estimate risk of dementia associated with number of sensory impairments (none, one, or two). Results DSI was significantly associated with higher risk of all‐cause dementia (hazard ratio [HR] = 1.86; 95% confidence interval [CI] = 1.25‐2.76) and Alzheimer's disease (HR = 2.12; 95% CI = 1.34‐3.36). Individually only visual impairment was independently associated with an increased risk of all‐cause dementia (HR = 1.32; 95% CI = 1.02‐1.71). Discussion Older adults with DSI are at a significantly increased risk for dementia. Further studies are needed to evaluate whether treatments can modify this risk.

Objective Prior research suggests that health care providers are susceptible to implicit biases, specifically prowhite biases, and that these may contribute to health care disparities by influencing physician behavior. Despite these findings, implicit bias training is not currently embedded into emergency medicine (EM) residency training and few studies exist that evaluate the effectiveness of implicit bias training on awareness during residency conference. We sought to conduct a mixed-methods program evaluation of a formalized educational intervention targeted on the topic of implicit bias. Methods We used a design thinking framework to develop a curricular intervention. The intervention consisted of taking the Harvard Implicit Association Test (IAT) on race to introduce the concept of implicit bias, followed by a facilitated discussion to explore participant's perceptions on whether implicit bias may lead to variations in care. The facilitated discussion was audio recorded, transcribed, and coded for emerging themes. An online survey assessed participant awareness of these topics before and after the intervention and was analyzed using paired t-tests. Results After the intervention, participant's awareness of their individual implicit biases increased by 33.3% (p = 0.003) and their awareness of how their IAT results influences how they deliver care to patients increased by 9.1% (p = 0.03). Emerging themes included skepticism of the implicit bias test results with the desire to have "neutral" results, acknowledgment that pattern recognition may lead to "blind spots" in care, recognition that bias exists on a personal and systemic level, and interest in regular educational interventions to address implicit bias. Conclusions This novel educational intervention on implicit bias resulted in improvement in participants' awareness of their implicit biases and how it may affect their patient care. Our intervention can serve as a model for other residency programs to develop and implement an intervention to create awareness of implicit bias and its potential impact on patient care.

BACKGROUND: The benefits of a diverse workforce in medicine have been previously described. While the population of the United States has become increasingly diverse, this has not occurred in the physician workforce. In academic medicine, underrepresented in medicine (URiM) faculty are less likely to be promoted or retained in academic institutions. Studies suggest that mentorship and engagement increase the likelihood of development, retention, and promotion. However, it is not clear what form of mentorship creates these changes. The Academy for Diversity and Inclusion in Emergency Medicine (ADIEM), an academy within the Society for Academic Emergency Medicine, is a group focused on advancing diversity and inclusion as well as promoting the development of its URiM students, residents, and faculty. The Academy serves many of the functions of a mentoring program. We assessed whether active involvement in ADIEM led to increased publications, promotion, or leadership advancement in the areas of diversity, equity, and inclusion. METHODS: We performed a survey of ADIEM members to determine if career development and productivity, defined as written scholarly products, presentations, and mentorship in the area of diversity, equity, and inclusion was enhanced by the establishment of the academy. To determine whether there were significant changes in academic accomplishments after the formation of ADIEM, two groups, ADIEM leaders and ADIEM nonleader members, were examined. RESULTS: Thirteen ADIEM leaders and 14 ADIEM nonleader members completed the survey. Academic productivity in the area of diversity, equity, and inclusion increased significantly among ADIEM leaders when compared to ADIEM nonleader members after the founding of ADIEM. In particular, in the ADIEM leader group, there were significant increases in manuscript publications (1.31 ± 1.6 to 5.5 ± 7.96, p = 0.12), didactic presentations (3.85 ± 7.36 to 23.46 ± 44.52, p

As the emergency department (ED) is the "front door" of the hospital and the primary site by which most patients access the health care system, issues of inequity are especially salient for emergency medicine (EM) practice. Improving the health of ED patients, especially those who are stigmatized and disenfranchised, depends on having emergency physicians that are cognizant and attentive to their needs in and out of the medical encounter. EM resident education has traditionally incorporated a "cultural competency" model to equip residents with tools to combat individual bias and stigma. Although this framework has been influential in drawing attention to health inequities, it has also been criticized for its potential to efface differences within groups (such as socioeconomic differences), overstate cultural or racial differences, and unintentionally reinforce stereotypes or blaming of patients for their ill health or difficult circumstances. In contrast, emerging frameworks of structural competency call for physicians to recognize the ways in which health outcomes are influenced by complex, interrelated structural forces (e.g., poverty, racism, gender discrimination, immigration policy) and to attend to these causes of poor health. We present here the framework of structural competency, extending it to the unique ED setting. We provide tangible illustrations of the ways in which this framework is relevant to the ED setting and can be incorporated in EM education.

Rabies is an endemic disease in the Philippines. Addressing the disease at source, massive efforts towards dog vaccination and public awareness on rabies have been pursued by various Local Government Units (LGUs) in the country. While marked improvements have been seen, rabies continues to persist where it exists, largely owing to poor surveillance of the disease in animals and weak coordination between the human and animal health sectors. To bridge these critical gaps, the BAI-OIE STANDZ Rabies Project in the Philippines, together with the key rabies stakeholders in Bicol Region, developed the "Practical Inter-sectoral Linking"-an operational protocol and practical network of local key players (human health, animal health and LGUs) involved in rabies detection, reporting and implementation of appropriate interventions. It is initiated by recognized triggers such as detection of confirmed or probable rabies cases and is closely linked with early detection in animals, case investigation, quarantine, diagnosis, reporting and post-exposure prophylaxis. People down to the village level are informed about the routine, protocol and contact details of relevant people in responding to bite victims with the flowchart provided by the tool. This tool was initially rolled out in pilot provinces in the Bicol Region and to date has already documented success in initiating timely actions to 31 laboratory confirmed rabies cases being investigated, which actually saved 46 human lives upon further investigation. With this established at the LGU level, the goal to timely detect suspect or probable rabies cases and promptly implement appropriate interventions are expected to improve, while local officials are empowered with their roles as frontline workers in the prevention and control of rabies.

Aims The mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) are not yet elucidated. Chronotropic incompetence has emerged as a potential mechanism. We aimed to evaluate whether heart rate (HR) response to exercise is associated to functional capacity in patients with symptomatic HFpEF. Methods and results We prospectively studied 74 HFpEF patients [35.1% New York Heart Association Class III, 53% female, age (mean ± standard deviation) 72.5 ± 9.1 years, and 59.5% atrial fibrillation]. Functional performance was assessed by peak oxygen consumption (peak VO2 ). The mean (standard deviation) peak VO2 was 10 ± 2.8 mL/min/kg. The following chronotropic parameters were calculated: Delta-HR (HR at peak exercise - HR at rest), chronotropic index (CI) = (HR at peak exercise - resting HR)/[(220 - age) - resting HR], and CI according to the equation developed by Keteyian et al. (CIK) (HR at peak exercise - HR at rest)/[119 + (HR at rest/2) - (age/2) - 5 - HR at rest]. In a bivariate setting, peak VO2 was positively and significantly correlated with Delta-HR (r = 0.35, P = 0.003), CI (r = 0.27, P = 0.022), CIK (r = 0.28, P = 0.018), and borderline with HR at peak exercise (r = 0.22, P = 0.055). In a multivariable linear regression analysis that included clinical, analytical, echocardiographic, and functional capacity covariates, the chronotropic parameters were positively associated with peak VO2 . We found a linear relationship between Delta-HR and peak VO2 (β coefficient of 0.03; 95% confidence interval: 0.004-0.05; P = 0.030); conversely, the association among CIs and peak VO2 was exponentially shaped. Conclusions In patients with chronic HFpEF, the HR response to exercise was positively associated to patient's functional capacity.