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Alan Morrison,1 Melissa E Stauffer,1,2 Anna S Kaufman1 1ScribCo, Albrightsville, PA, USA; 2Scientific Editing Solutions, Walworth, WI, USACorrespondence: Alan MorrisonScribCo, 111 Gower Road, Albrightsville, PA, 18210, USATel +1 610 389-0843Email scribcopersonnel@gmail.comIntroduction: Patients rarely, if ever, take their medications exactly as prescribed. The extent to which missed doses interfere with a drug’s therapeutic effect remains unclear.Methods: After weekly oral dosing of methotrexate (MTX) for rheumatoid arthritis, its polyglutamate derivatives (MTXglu) accumulate in red blood cells, where they are markers for the drug’s therapeutic effectiveness. We used Medication Event Monitoring System data and pharmacokinetic modeling to analyze whether missing MTX doses causes the MTXglu level in red blood cells to fall below the range associated with the drug’s clinical effect.Results: For patients initiating oral MTX, the threshold for clinical effectiveness and the steady state level were reached in medians of 6 weeks and 22 weeks, respectively. For patients at steady state who discontinued MTX, the MTXglu level fell below the therapeutic threshold after a median of 3 weeks. After initiating MTX, single missed doses did not cause a loss of therapeutic effect in the median patient if they occurred after 10 weeks, while runs of ≥ 3 consecutive missed doses did cause the MTXglu level to fall below the therapeutic threshold.Conclusion: While there is considerable variation between patients, pharmacokinetic modeling indicates that instances of isolated single missed doses of MTX typically will not cause polyglutamated methotrexate levels in red blood cells to fall below the range associated with the therapeutic effect. Runs of ≥ 3 consecutive missed doses, however, are typically expected to result in a loss of the therapeutic effect.Keywords: therapeutic effect, adherence, pharmacokinetic modeling, antirheumatic agents, rheumatoid arthritis, drug therapy

Healthcare Professionals Working in Schools (HPWS) are responsible for providing health services to students and play a role in providing education to prevent illnesses, including tickborne diseases (TBD). Providing TBD education to children has been shown to increase prevention behaviors and knowledge of TBD symptoms, but little is known regarding the current state of TBD awareness among HPWS. In spring 2019 we conducted a cross-sectional knowledge, attitudes, and practices (KAP) survey of HPWS in two states with a high incidence of Lyme disease (LD) to inform design of TBD prevention programs. The survey queried general knowledge of TBDs, school practices regarding TBDs, and availability of TBD resources. Overall, higher confidence, experience, risk perception, prior training on TBD, and more years employed as a HPWS were independently associated with knowledge of LD transmission, symptoms, and correct tick removal practices. State and local health departments should consider prioritizing engagement with HPWS to provide educational opportunities about tickborne diseases.

The present study sought to evaluate the reproducibility of prominent findings stated by Fehr et al. in their developmental resource allocation experiment "Egalitarianism in Young Children", published in 2008. The experiment involved children making decisions about distributing sweets between themselves and either an in-group or an out-group recipient. Fehr et al. found that (1) inequity aversion develops with age; (2) 3- to 4-year-old children are inclined toward self-advantageous allocations, whereas 7- to 8-year-olds distribute sweets more evenly in divisions, and (3) the influence of group status increases as children age. The original article stated that 229 Swiss school students aged 3 to 8 years (102 boys, 127 girls) participated in the study. However, no further demographics were reported. In our attempts to reproduce Fehr et al.'s original analyses and reanalyse the raw dataset, we found that one of the key variables was miscoded. After rectifying the miscoded variable, the reproduction results revealed only one ambiguously irreproducible result regarding a group status main effect in the sharing mini-game--with three other tests exhibiting either strong reproducibility or ambiguous reproducibility. Reanalysis results indicated that Fehr et al.'s conclusions are robust when tested with alternative analytical tests.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

Jeffrey Gudin,1,2 Andrew G Kaufman,1 Samyadev Datta1,3 1Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Anesthesiology, Englewood Hospital and Medical Center, Englewood, NJ, USA; 3Center for Pain Management, Hackensack, NJ, USACorrespondence: Jeffrey GudinEnglewood Hospital and Medical Center, 350 Engle St #1808, Englewood, NJ 07631, USATel +1 201-894-3322Email healthmd@optonline.netAbstract: The continued prevalence of chronic low back pain (CLBP) is a testament to our lack of understanding of the potential causes, leading to significant treatment challenges. CLBP is the leading cause of years lived with disability and the fifth leading cause of disability-adjusted life-years. No single non-pharmacologic, pharmacologic, or interventional therapy has proven effective as treatment for the majority of patients with CLBP. Although non-pharmacologic therapies are generally helpful, they are often ineffective as monotherapy and many patients lack adequate access to these treatments. Noninvasive treatment measures supported by evidence include physical and chiropractic therapy, yoga, acupuncture, and non-opioid and opioid pharmacologic therapy; data suggest a moderate benefit, at most, for any of these therapies. Until our understanding of the pathophysiology and treatment of CLBP advances, clinicians must continue to utilize rational multimodal treatment protocols. Recent Centers for Disease Control and Prevention guidelines for opioid prescribing recommend that opioids not be utilized as first-line therapy and to limit the doses when possible for fear of bothersome or dangerous adverse effects. In combination with the current opioid crisis, this has caused providers to minimize or eliminate opioid therapy when treating patients with chronic pain, leaving many patients suffering despite optimal nonopioid therapies. Therefore, there remains an unmet need for effective and tolerable opioid receptor agonists for the treatment of CLBP with improved safety properties over legacy opioids. There are several such agents in development, including opioids and other agents with novel mechanisms of action. This review critiques non-pharmacologic and pharmacologic treatment modalities for CLBP and examines the potential of novel opioids and other analgesics that may be a useful addition to the treatment options for patients with chronic pain.Keywords: non-pharmacologic, opioid, chronic low back pain, analgesia

This paper provides an overview of the state-of-the-art studies of oscillatory processes in solar and stellar flares, based on modern observational data from ground-based and space-borne instruments with high temporal, spatial, and spectral resolution in different bands of the electromagnetic spectrum. We examine the mecha-nisms that generate flare emission and its quasi-periodic modulation. We discuss similarities and differences be-tween solar and stellar flares, and address associated problems of superflares on the Sun and space weather. Quasi-periodic pulsations (QPPs) of flare emission are shown to be an effective tool for diagnosing both the flare processes themselves and the parameters of flaring plasmas and accelerated particles. We consider types of QPPs, their statistical properties, and methods of analysis, taking into account the non-stationarity of the QPPs’ parameters. We review the proposed mechanisms of QPPs and summarize open questions.

This exploratory mixed methods study investigates the school psychology workforce shortage phenomenon and underlying contributing factors. The development of an Education Specialist school psychology program in the middle of the COVID-19 pandemic prompted the authors to explore variables impacting awareness of the school psychology profession. State policies were reviewed to identify how many states have adopted the nationally recommended 1:500 ratio for school psychologists. Additionally, undergraduate and postbaccalaureate student knowledge of the work of school-based mental health professionals, specifically school psychologists, was surveyed. Finally, the authors explore the need for new action frameworks to achieve this awareness and to promote workforce policy development. Based on findings, three key points for practitioners are the need to promote the adoption of policies that align with the 1:500 recommended ratio for school psychologists, increase awareness of the profession with preservice and in-service educators, and create coordinated training pathways and career opportunities for individuals to become school psychologists.

Anna S Kaufman, Alan Morrison ScribCo, Effort, PA, USA Purpose: The therapeutic effect of a once-daily oral drug will be maintained if there are no occurrences of consecutively missed doses that exceed the duration of the drug’s effect. The durations of effect of antiretroviral drugs are typically in the range of 1–4 days. Here, we report the observed frequencies of ≥2, ≥3, and ≥4 consecutively missed doses for patients taking a once-daily oral antiretroviral drug for HIV infection. Patients and methods: Medication Event Monitoring System (MEMS) data were extracted from an electronic database of MEMS records, for a 30-day period for 555 patients taking once-daily oral HIV drug therapy. We recorded the number of days with missed doses and occurrences of ≥2, ≥3, or ≥4 consecutively missed doses. Distributions of the observed frequencies of ≥2, ≥3, and ≥4 consecutively missed doses as a proportion of number of missed doses were compared to calculated random distributions using the Wilcoxon signed-rank test. Results: The frequencies of 0, 1, and ≥2 missed daily doses were 0.279, 0.312, and 0.409, respectively. The frequencies of ≥2, ≥3, and ≥4 consecutively missed doses were 0.184, 0.110, and 0.065, respectively. The probabilities that the observed frequencies of ≥2, ≥3, and ≥4 consecutively missed doses were as expected from random chance were P=0.345, P

Reproductive success relies on proper establishment and maintenance of biological sex. In many animals, including mammals, the primary gonad is initially ovary biased. We previously showed the RNA binding protein (RNAbp), Rbpms2, is required for ovary fate in zebrafish. Here, we identified Rbpms2 targets in oocytes (Rbpms2-bound oocyte RNAs; rboRNAs). We identify Rbpms2 as a translational regulator of rboRNAs, which include testis factors and ribosome biogenesis factors. Further, genetic analyses indicate that Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway, specifically through the mTorc1-activating Gap activity towards Rags 2 (Gator2) component, Missing oocyte (Mios). Cumulatively, our findings indicate that early gonocytes are in a dual poised, bipotential state in which Rbpms2 acts as a binary fate-switch. Specifically, Rbpms2 represses testis factors and promotes oocyte factors to promote oocyte progression through an essential Gator2-mediated checkpoint, thereby integrating regulation of sexual differentiation factors and nutritional availability pathways in zebrafish oogenesis.

BACKGROUND: Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke. METHODS: In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI). RESULTS: Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032-1.053) vs OR = 1.009 (95% CI, 0.996-1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019-1.047), RERI = 0.039 (95% CI, 0.025-0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users. CONCLUSIONS: The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.

The absolute band-edge potentials of semiconductors and their positions relative to solution redox potentials are often invoked as design principles for photoelectrochemical devices and particulate photocatalysts. Here we show that these criteria are not necessary and limit the exploration of materials that may advance the fields of photoelectrochemistry, photochemistry and photocatalysis. We discuss how band-edge energies are not singular parameters and instead shift with pH, electrolyte type and surface chemistry. The free energies of electrons and holes, rather than those of solution redox couples, dictate overall reaction spontaneity and thus reactivity. Favourable charge-transfer kinetics can occur even when the relevant electrolyte redox potential(s) appear outside the bandgap, enabled by the inversion or accumulation of electronic charge at the semiconductor surface. This discussion informs design principles for photocatalytic systems engineering for both one-electron and multi-electron redox reactions (for example, H2 evolution, H2O oxidation and CO2 reduction). (Figure presented.)

In our paper, we encompass the topic of socioeconomic disparities intrinsic to drug pricing and look at ways to ensure that every individual in the United States can access antibiotics equally and equitably. In the United States, a multitude of individuals find themselves struggling with high, out-of-pocket costs for necessary antibiotics or medications.  These issues are generally caused by factors surrounding monopolistic drug markets, high costs for development, and the severity of disease that an individual is facing. We explore these challenges from a plethora of perspectives, such as; the role of specialty pharmacies, limited distribution networks, and the usage of psychotropic medications among youth with Autism Spectrum Disorders (ASD). High prices and restricted access of certain antibiotics for conditions like Hepatitis C highlight the systemic and intrinsic issues within the pharmaceutical industry and how it affects individuals who suffer from this disease or diseases similar to it. On a similar topic to that, ongoing shortages of ADHD medications continue to show the consistent and heavy impact of supply constraints amongst the pharmaceutical industry in the United States. We discuss potential solutions, including but not limited to, accelerating the approval of basic drugs, implementing ceiling prices to prevent high costs, and better integrating health-system specialty pharmacies. By concentrating on the need for policy reforms within the United States and collaboration amongst the various stakeholders that remain involved with drug pricing disparities, this study aims to offer a varied approach in reducing drug pricing disparities and making necessary medications accessible to every individual in the United States, regardless of socioeconomic or health status.

BackgroundNatural killer (NK) cells are key effector cells of antitumor immunity. However, tumors can acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying mechanisms that mediate this resistance enables us to define approaches to improve immune-mediate antitumor activity. In previous studies from our group, a genome-wide CRISPR-Cas9 screen identified Charged Multivesicular Body Protein 2A (CHMP2A) as a novel mechanism that mediates tumor intrinsic resistance to NK cell activity.MethodsHere, we use an immunocompetent mouse model to demonstrate that CHMP2A serves as a targetable regulator of not only NK cell-mediated immunity but also other immune cell populations. Using the recently characterized murine 4MOSC model system, a syngeneic, tobacco-signature murine head and neck squamous cell carcinoma model, we deleted mCHMP2A using CRISPR/Cas9-mediated knock-out (KO), following orthotopic transplantation into immunocompetent hosts.ResultsWe found that mCHMP2A KO in 4MOSC1 cells leads to more potent NK-mediated tumor cell killing in vitro in these tumor cells. Moreover, following orthotopic transplantation, KO of mCHMP2A in 4MOSC1 cells, but not the more immune-resistant 4MOSC2 cells enables both T cells and NK cells to better mediate antitumor activity compared with wild type (WT) tumors. However, there was no difference in tumor development between WT and mCHMP2A KO 4MOSC1 or 4MOSC2 tumors when implanted in immunodeficient mice. Mechanistically, we find that mCHMP2A KO 4MOSC1 tumors transplanted into the immunocompetent mice had significantly increased CD4+T cells, CD8+T cells. NK cell, as well as fewer myeloid-derived suppressor cells (MDSC).ConclusionsTogether, these studies demonstrate that CHMP2A is a targetable inhibitor of cellular antitumor immunity.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

IMPORTANCE: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. OBJECTIVE: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. EVIDENCE REVIEW: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. FINDINGS: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. CONCLUSIONS AND RELEVANCE: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

OBJECTIVE: To develop evidence- and consensus-based clinical practice guidelines for management of high-tone pelvic floor dysfunction (HTPFD). High-tone pelvic floor dysfunction is a neuromuscular disorder of the pelvic floor characterized by non-relaxing pelvic floor muscles, resulting in lower urinary tract and defecatory symptoms, sexual dysfunction, and pelvic pain. Despite affecting 80% of women with chronic pelvic pain, there are no uniformly accepted guidelines to direct the management of these patients. METHODS: A Delphi method of consensus development was used, comprising three survey rounds administered anonymously via web-based platform (Qualtrics XM) to national experts in the field of HTPFD recruited through targeted invitation between September and December 2021. Eleven experts participated with backgrounds in urology, urogynecology, minimally invasive gynecology, and pelvic floor physical therapy (PFPT) participated. Panelists were asked to rate their agreement with rated evidence-based statements regarding HTPFD treatment. Statements reaching consensus were used to generate a consensus treatment algorithm. RESULTS: A total of 31 statements were reviewed by group members at the first Delphi round with 10 statements reaching consensus. 28 statements were reposed in the second round with 17 reaching consensus. The putative algorithm met clinical consensus in the third round. There was universal agreement for PFPT as first-line treatment for HTPFD. If satisfactory symptom improvement is reached with PFPT, the patient can be discharged with a home exercise program. If no improvement after PFPT, second-line options include trigger or tender point injections, vaginal muscle relaxants, and cognitive behavioral therapy, all of which can also be used in conjunction with PFPT. Onabotulinumtoxin A injections should be used as third line with symptom assessment after 2-4 weeks. There was universal agreement that sacral neuromodulation is fourth-line intervention. The largest identified barrier to care for these patients is access to PFPT. For patients who cannot access PFPT, experts recommend at-home, guided pelvic floor relaxation, self-massage with vaginal wands, and virtual PFPT visits. CONCLUSION: A stepwise approach to the treatment of HTPFD is recommended, with patients often necessitating multiple lines of treatment either sequentially or in conjunction. However, PFPT should be offered first line.

Inequities in urban greenspace have been identified, though patterns by race and socioeconomic status vary across US settings. We estimated the magnitude of the relationship between a broad mixture of neighborhood-level factors and residential greenspace using weighted quantile sum (WQS) regression, and compared predictive models of greenspace using only neighborhood-level, only individual-level, or multi-level predictors. Greenspace measures included the Normalized Difference Vegetation Index (NDVI), tree canopy, and proximity of the nearest park, for residential locations in Shelby County, Tennessee of children in the CANDLE cohort. Neighborhood measures include socioeconomic and education resources, as well as racial composition and racial residential segregation. In this sample of 1012 mother-child dyads, neighborhood factors were associated with higher NDVI and tree canopy (0.021 unit higher NDVI [95% CI: 0.014, 0.028] per quintile increase in WQS index); homeownership rate, proximity of and enrollment at early childhood education centers, and racial composition, were highly weighted in the WQS index. In models constrained in the opposite direction (0.028 unit lower NDVI [95% CI: - 0.036, - 0.020]), high school graduation rate and teacher experience were highly weighted. In prediction models, adding individual-level predictors to the suite of neighborhood characteristics did not meaningfully improve prediction accuracy for greenspace measures. Our findings highlight disparities in greenspace for families by neighborhood socioeconomic and early education factors, and by race, suggesting several neighborhood indicators for consideration both as potential confounders in studies of greenspace and pediatric health as well as in the development of policies and programs to improve equity in greenspace access.

BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter [less than or equal to]2.5 [micro]m ([PM.sub.2.5]) is associated with poorer brain health and increased risk for Alzheimer's disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants. OBJECTIVE: Our aim was to investigate if exposure to [PM.sub.2.5] was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia. METHODS: We examined the relationship between [PM.sub.2.5] and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio ([LC.sub.CNR]) in 381 men [mean age = 67.3; standard deviation (SD) = 2.6] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to [PM.sub.2.5] was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on [LC.sub.CNR] in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between [PM.sub.2.5] exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment. RESULTS: Multiple linear regressions revealed a significant association between [PM.sub.2.5] and rostral-middle [LC.sub.CNR] (b = -0.16; p = 0.02), whereby higher exposure to [PM.sub.2.5] was associated with lower [LC.sub.CNR]. A co-twin control analysis found that, within monozygotic pairs, individuals with higher [PM.sub.2.5] exposure showed lower [LC.sub.CNR] (b = - 0.11; p = 0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between [PM.sub.2.5] and caudal [LC.sub.CNR] or hippocampal volume, suggesting a degree of specificity to the rostral-middle portion of the LC. DISCUSSION: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. https://doi.org/10.1289/EHP14344, Introduction Neuropathological studies indicate that abnormal tau may first appear in the locus coeruleus (LC) starting early in life, (1,2) with substantial accumulation occurring during the course of Alzheimer's disease [...]

edTPA is a widely used teacher performance assessment. However, studies have raised concerns with its use. We conducted a study of candidates' and faculty members' perceptions of edTPA on their learning and performance. Analysis of responses revealed six themes: confusion about the meaning of "ready to teach"; interference with relationship building; narrowed responsive teaching practices; concern for placements' impact on assessments; mistrust of evaluators' understanding of their contexts; and increased barriers for marginalized candidates. Findings suggest that edTPA can be interpreted as perpetrating forms of "epistemic injustice" and "slow violence" that impede diversity in the profession. To realize the promise of a more diverse teacher workforce--equity for all students and justice for marginalized communities--teacher educators and policymakers must ensure that the ways in which they prepare and evaluate teachers are increasingly more relational, diverse, equitable, and just.