Improving emergency medicine resident pediatric lumbar puncture procedural performance through a brief just-in-time video intervention.

BACKGROUND: Emergency medicine (EM) trainee comfort level with lumbar puncture (LP) has decreased over time due to changing practice guidelines, particularly amongst pediatric patients. We implemented a "just in time" (JIT) brief educational video based on a previously published LP Performance Scoring Checklist to improve trainee efficiency and competence in LP performance. METHODS: Our pilot quasi-experimental study took place January-June 2022 within a large, academic Midwestern emergency department (ED) with an established 3-year EM residency program. All 9 interns performed a timed diagnostic LP on an infant LP model in January, scored according to the LP Performance Scoring Checklist. In June, interns repeated the timed LP procedure directly after watching a brief educational video based on major checklist steps. The study was deemed exempt by the Institutional Review Board. RESULTS: All interns completed both assessments. At baseline, interns had logged performance of median 2 (IQR 0-5) LPs and spent 12.9 (10.3-14.4) minutes performing the procedure. Post-intervention, interns had logged an additional median 2 (0-5) LPs and completed the procedure faster with an average time of 10.3 (9.7-11.3) minutes (p = 0.004). A median of 5 (4-7) major steps were missed at baseline, compared to 1 (1-2) at time of post-intervention assessment (p = 0.015). CONCLUSION: Development of a brief educational video improved efficiency and competency amongst our intern class in performing an infant LP when viewed Just-In-Time. Similar efforts may improve education and performance of other rare (or decreasing in frequency) procedures within EM training.

The Impact of Routine Vaccinations on Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching.

BACKGROUND: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias. OBJECTIVE: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus. METHODS: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD. RESULTS: For the Tdap/Td vaccine, 7.2% (n = 8,370) of vaccinated patients and 10.2% (n = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68-0.72) and ARR was 0.03 (95% CI, 0.02-0.03). For the HZ vaccine, 8.1% (n = 16,106) of vaccinated patients and 10.7% (n = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73-0.76) and ARR was 0.02 (95% CI, 0.02-0.02). For the pneumococcal vaccine, 7.92% (n = 20,583) of vaccinated patients and 10.9% (n = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71-0.74) and ARR was 0.02 (95% CI, 0.02-0.03). CONCLUSION: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function.

Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1-FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.

Integrating self-assessment into feedback for emergency medicine residents.

BACKGROUND: In 2013 the Accreditation Council for Graduate Medical Education (ACGME) introduced "Milestones" designed to nationally standardize the assessment of resident physicians. Previous studies compare resident self-assessment on milestones to faculty assessment, with varying degrees of agreement, but integration of self-assessment into the formative feedback process has not yet been directly studied. This study uses a conceptual framework of self-determination theory, integrated with concepts from adult learning theory, to compare the perception of the feedback quality given in semiannual reviews before and after the incorporation of resident self-assessment into the feedback process. METHODS: This was an interventional study conducted in a single emergency medicine residency program at a major academic hospital over 1 calendar year. Residents first engaged in a semiannual review without self-assessment. At subsequent semiannual reviews, residents completed a Milestone-based self-assessment that was provided to the faculty member assigned to conduct their semiannual review. Residents and faculty completed surveys rating perception of feedback quality. Two-sided Wilcoxon signed-rank tests were used in comparison analysis. RESULTS: One resident did not self-assess prior to the semiannual review and was excluded leaving 25 paired surveys for analysis. Residents found feedback after the self-assessment more actionable (p = 0.013), insightful (p = 0.010), and better overall (p = 0.025). Similarly, faculty felt the feedback they provided was more actionable (p < 0.001), more insightful (p < 0.001), and better communicated (p < 0.001); led to improved resident understanding of milestones (p < 0.001); and were overall more satisfied (p < 0.001). Free-text comments explore pre- and postintervention perceptions of feedback. CONCLUSIONS: Integration of self-assessment into semiannual reviews improves perception of feedback given to residents as perceived by both residents and faculty. Although limited by sample size, the results are promising for a simple, evidence-based intervention to improve feedback during an existing mandated feedback opportunity.

Primary peripheral T-cell central nervous system lymphoma.

BACKGROUND: Primary peripheral T-cell central nervous system lymphoma (PCNSL) is a rare, aggressive tumor that arises in the craniospinal axis and has an increased risk in individuals who are immunocompromised. This lesion often mimics other benign and malignant processes on radiographic imaging, leading to misdiagnosis and delays in treatment. We present a case of a patient with a history of Sjögren's syndrome and progressive neurologic symptoms who underwent craniotomy for diagnosis. CASE DESCRIPTION: A 61-year-old woman with a history of Sjögren's syndrome, progressive aphasia, left facial droop, and right-sided paresthesias for 4 months presented for evaluation and management. An enhancing, infiltrative lesion in the left frontal lobe with underlying vasogenic edema was appreciated and suggestive of a primary or metastatic neoplasm. The patient underwent an open biopsy for further evaluation of the lesion. Extensive histopathologic evaluation revealed a diagnosis of T-cell PCNSL. The patient was started on induction methotrexate and temozolomide followed by consolidative radiotherapy. CONCLUSION: Autoimmune conditions are a risk factor for T-cell PCNSL development. T-cell PCNSL has radiographic and gross histologic features that are consistent with a broad differential, including gliomas and inflammatory processes. Prompt diagnosis and extensive histopathological evaluation is essential to ensure appropriate treatment.

Serendipitous Discovery of Leucine and Methionine Depletion Agents during the Search for Polyamine Transport Inhibitors.

Targeting polyamine metabolism is a proven anticancer strategy. Cancers often escape the polyamine biosynthesis inhibitors by increased polyamine import. Therefore, there is much interest in identifying polyamine transport inhibitors (PTIs) to be used in combination therapies. In a search for new PTIs, we serendipitously discovered a LAT-1 efflux agonist, which induces intracellular depletion of methionine, leucine, spermidine, and spermine, but not putrescine. Because S-adenosylmethioninamine is made from methionine, a loss of intracellular methionine leads to an inability to biosynthesize spermidine, and spermine. Importantly, we found that this methionine-depletion approach to polyamine depletion could not be rescued by exogenous polyamines, thereby obviating the need for a PTI. Using 3H-leucine (the gold standard for LAT-1 transport studies) and JPH-203 (a specific LAT-1 inhibitor), we showed that the efflux agonist did not inhibit the uptake of extracellular leucine but instead facilitated the efflux of intracellular leucine pools.

Parental Use of "Cry Out" in a Community Sample During the First Year of Infant Life.

OBJECTIVE: The primary objective was to identify the characteristics of parents and infants and parenting practices associated with delayed responsiveness to infant crying during the first year of infant life. A secondary objective was to evaluate, in a subsample of maternal-infant pairs, the associations between delayed responsiveness to infant crying and observational measures of maternal-infant interaction and infant-maternal attachment. METHOD: This is a secondary analysis of the data from a community sample of pregnant women recruited to the Alberta Pregnancy Outcomes and Nutrition study. Mothers completed questionnaires during the first year of infant life (n = 1826), and a convenience subsample of maternal-infant pairs (n = 137) participated in laboratory assessments of maternal-infant interaction at 6 months of age and infant-maternal attachment at 20 months. RESULTS: Parental use of "cry out" as a strategy to deal with a crying infant was associated with parental characteristics (being white and having a relatively higher income), infant characteristics (higher problematic behavior at 3 months and reduced problematic behavior at 12 months), sleep ecology (infants sleeping alone), and parental soothing strategies (less frequently taking the infant into the parent's bed, cuddling, or carrying the crying infant). Cry out was not associated with observational measures of maternal sensitivity or infant-maternal attachment. CONCLUSION: When used selectively and in response to the specific needs and characteristics of the infant, delayed responsiveness may reduce problematic behavior and does not harm the infant's socioemotional development.

Partner social support during pregnancy and the postpartum period and inflammation in 3-month-old infants.

Prenatal social stress "programs" offspring immune activity in animal models, but how the prenatal social environment affects human offspring inflammation is not known. Here, we test associations between prenatal partner support quality, i.e. positive/helpful support, negative/upsetting support, and their interaction, and infant inflammatory markers. A sample of 113 women from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort were followed from early pregnancy to 3-months postpartum. Partner support quality was measured during pregnancy and the postpartum period. Three-month-old infant blood samples were assayed for inflammatory markers, i.e., adaptive immune markers IFNγ, IL12p70 and IL10. The prenatal positive-by-negative partner support interaction predicted infant IFNγ, IL12p70, and IL10, p's<.035, independent of covariates and postpartum partner support. When negative partner support was high, high positive support predicted higher infant IFNγ, IL12p70, and IL10. As such, partner support during pregnancy that is both highly negative/upsetting and also highly positive/helpful predicted adaptive immunity markers in infants at 3 months of age.

Social buffering of the maternal and infant HPA axes: Mediation and moderation in the intergenerational transmission of adverse childhood experiences.

Supportive social relationships can reduce both psychological and physiological responses to stressful experiences. Recently, studies have also assessed the potential for social relationships to buffer the intergenerational transmission of stress. The majority of these studies, however, have focussed on social learning as a mechanism responsible for the intergenerational transmission of stress. Evidence of biological mechanisms is lacking. The objective of the current study was, therefore, to determine whether the association between maternal adverse childhood experiences (ACEs) and infant hypothalamic-pituitary-adrenal (HPA) axis function is mediated by maternal HPA axis function during pregnancy and moderated by social support. Data were from 243 mother-infant dyads enrolled in a prospective longitudinal cohort (the Alberta Pregnancy Outcomes and Nutrition Study). Maternal history of ACEs was retrospectively assessed while maternal perceived social support and salivary cortisol were assessed prospectively at 6-22 weeks gestation (Time 1) and 27-37 weeks gestation (Time 2), and infant cortisol reactivity to a laboratory stressor and maternal perceived social support were assessed at 5-10 months postnatal (Time 3). Results revealed that maternal HPA axis function during pregnancy mediated the effects of maternal ACEs on infant HPA axis reactivity, suggesting that the maternal HPA axis is a mechanism by which maternal early life stress is transmitted to offspring. Furthermore, social support in the prenatal and postnatal periods moderated the cascade from maternal ACEs to infant HPA axis reactivity. Specifically, prenatal social support moderated the association between ACEs and maternal HPA axis function during pregnancy, and postnatal social support moderated the association between maternal HPA axis function and infant cortisol reactivity. These findings highlight the social sensitivity of the HPA axis and suggest the utility of social relationships as an intervention target to reduce the effects of maternal early life stress on infant outcomes.

Investigation of Polyamine Metabolism and Homeostasis in Pancreatic Cancers.

Pancreatic cancers are currently the fourth leading cause of cancer-related death and new therapies are desperately needed. The most common pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). This report describes the development of therapies, which effectively deplete PDAC cells of their required polyamine growth factors. Of all human tissues, the pancreas has the highest level of the native polyamine spermidine. To sustain their high growth rates, PDACs have altered polyamine metabolism, which is reflected in their high intracellular polyamine levels and their upregulated import of exogenous polyamines. To understand how these cancers respond to interventions that target their specific polyamine pools, L3.6pl human pancreatic cancer cells were challenged with specific inhibitors of polyamine biosynthesis. We found that pancreatic cell lines have excess polyamine pools, which they rebalance to address deficiencies induced by inhibitors of specific steps in polyamine biosynthesis (e.g., ornithine decarboxylase (ODC), spermidine synthase (SRM), and spermine synthase (SMS)). We also discovered that combination therapies targeting ODC, SMS, and polyamine import were the most effective in reducing intracellular polyamine pools and reducing PDAC cell growth. A combination therapy containing difluoromethylornithine (DFMO, an ODC inhibitor) and a polyamine transport inhibitor (PTI) were shown to significantly deplete intracellular polyamine pools. The additional presence of an SMS inhibitor as low as 100 nM was sufficient to further potentiate the DFMO + PTI treatment.

Prenatal bisphenol a exposure and dysregulation of infant hypothalamic-pituitary-adrenal axis function: findings from the APrON cohort study.

BACKGROUND: Animal models show that prenatal bisphenol A (BPA) exposure leads to sexually dimorphic disruption of the neuroendocrine system in offspring, including the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system, but human data are lacking. In humans, prenatal BPA exposure is associated with sex-specific behavioural problems in children, and HPA axis dysregulation may be a biological mechanism. The objective of the current study was to examine sex differences in associations between prenatal maternal urinary BPA concentration and HPA axis function in 3 month old infants. METHODS: Mother-infant pairs (n = 132) were part of the Alberta Pregnancy Outcomes and Nutrition study, a longitudinal birth cohort recruited (2010-2012) during pregnancy. Maternal spot urine samples collected during the 2nd trimester were analyzed for total BPA and creatinine. Infant saliva samples collected prior to and after a blood draw were analyzed for cortisol. Linear growth curve models were used to characterize changes in infant cortisol as a function of prenatal BPA exposure. RESULTS: Higher maternal BPA was associated with increases in baseline cortisol among females (ß = 0.13 log µg/dL; 95% CI: 0.01, 0.26), but decreases among males (ß = -0.22 log µg/dL; 95% CI: -0.39, -0.05). In contrast, higher BPA was associated with increased reactivity in males (ß = .30 log µg/dL; 95% CI: 0.04, 0.56) but decreased reactivity in females (ß = -0.15 log µg/dL; 95% CI: -0.35, 0.05). Models adjusting for creatinine yielded similar results. CONCLUSIONS: Prenatal BPA exposure is associated with sex-specific changes in infant HPA axis function. The biological plausibility of these findings is supported by their consistency with evidence in rodent models. Furthermore, these data support the hypotheses that sexually dimorphic changes in children's behaviour following prenatal BPA exposure are mediated by sexually dimorphic changes in HPA axis function.

Developmental origins of infant emotion regulation: Mediation by temperamental negativity and moderation by maternal sensitivity.

Emotion regulation is essential to cognitive, social, and emotional development and difficulties with emotion regulation portend future socioemotional, academic, and behavioral difficulties. There is growing awareness that many developmental outcomes previously thought to begin their development in the postnatal period have their origins in the prenatal period. Thus, there is a need to integrate evidence of prenatal influences within established postnatal factors, such as infant temperament and maternal sensitivity. In the current study, prenatal depression, pregnancy anxiety, and diurnal cortisol patterns (i.e., the cortisol awakening response (CAR) and diurnal slope) were assessed in 254 relatively low-risk mother-infant pairs (primarily White, middle-class) in early (M = 15 weeks) and late pregnancy (M = 33 weeks). Mothers reported on infant temperamental negativity (Infant Behavior Questionnaire-Revised) at 3 months. At 6 months, maternal sensitivity (Parent Child Interaction Teaching Scale) and infant emotion regulation behavior (Laboratory Temperament Assessment Battery) were assessed. Greater pregnancy anxiety in early pregnancy and a blunted CAR in late pregnancy predicted higher infant temperamental negativity at 3 months, and those infants with higher temperamental negativity used fewer attentional regulation strategies and more avoidance (i.e., escape behavior) at 6 months. Furthermore, this indirect effect was moderated by maternal sensitivity whereby infants with elevated negativity demonstrated maladaptive emotion regulation at below average levels of maternal sensitivity. These findings suggest that the development of infant emotion regulation is influenced by the ways that prenatal exposures shape infant temperament and is further modified by postnatal caregiving. (PsycINFO Database Record

Biological embedding of perinatal social relationships in infant stress reactivity.

Whereas significant advances have been made in understanding how exposure to early adversity "gets under the skin" of children to result in long term changes in developmental outcomes, the processes by which positive social relationships become biologically embedded remain poorly understood. The aim of this study was to understand the pathways by which maternal and infant social environments become biologically embedded in infant cortisol reactivity. Two hundred seventy-two pregnant women and their infants were prospectively assessed during pregnancy and at 6 months postpartum. In serial mediation analyses, higher perceived social support from partners during pregnancy was associated with lower infant cortisol reactivity or larger decreases in cortisol in response to a stressor at 6 months of age via lower self-reported prenatal maternal depression and higher mother-infant interaction quality. The findings add to our understanding of how perinatal social relationships become biologically embedded in child development.

Developmental origins of infant stress reactivity profiles: A multi-system approach.

BACKGROUND: This study tested the hypothesis that maternal physiological and psychological variables during pregnancy discriminate between theoretically informed infant stress reactivity profiles. METHODS: The sample comprised 254 women and their infants. Maternal mood, salivary cortisol, respiratory sinus arrhythmia (RSA), and salivary α-amylase (sAA) were assessed at 15 and 32 weeks gestational age. Infant salivary cortisol, RSA, and sAA reactivity were assessed in response to a structured laboratory frustration task at 6 months of age. Infant responses were used to classify them into stress reactivity profiles using three different classification schemes: hypothalamic-pituitary-adrenal (HPA)-axis, autonomic, and multi-system. Discriminant function analyses evaluated the prenatal variables that best discriminated infant reactivity profiles within each classification scheme. RESULTS: Maternal stress biomarkers, along with self-reported psychological distress during pregnancy, discriminated between infant stress reactivity profiles. CONCLUSIONS: These results suggest that maternal psychological and physiological states during pregnancy have broad effects on the development of the infant stress response systems. © 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 578-599, 2016.

Older adults do not notice their names: a new twist to a classic attention task.

Although working memory spans are, on average, lower for older adults than young adults, we demonstrate in 5 experiments a way in which older adults paradoxically resemble higher capacity young adults. Specifically, in a selective-listening task, older adults almost always failed to notice their names presented in an unattended channel. This is an exaggeration of what high-span young adults show and the opposite of what low-span young adults show. This striking finding in older adults remained significant after controlling for working memory span and for noticing their names in an attended channel. The findings were replicated when presentation rate was slowed and when the ear in which the unattended name was presented was controlled. These results point to an account of older adults' performance involving not only an inhibition factor, which allows high-span young adults to suppress the channel to be ignored, but also an attentional capacity factor, with more unallocated capacity. This capacity allows low-span young adults to notice their names much more often than older adults with comparably low working memory spans do.

CRYAB modulates the activation of CD4+ T cells from relapsing-remitting multiple sclerosis patients.

BACKGROUND: Suppression of activation of pathogenic CD4(+) T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. OBJECTIVE: We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. METHODS: CD4(+) T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73-92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. RESULTS: The secretion of pro-inflammatory cytokines by CD4(+) T cells was decreased in the presence of CRYAB in a subset of relapsing-remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8(+) T cells, in CD4(+) T cells of MS patients that displayed suppressed cytokine production (responders). CONCLUSION: CRYAB may be capable of suppressing the activation of CD4(+) T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.

The effects of reality-based television programming on diet and exercise motivation and self-efficacy in young adults.

Grounded in social cognitive theory, this research examines the effects of reality entertainment programming and embedded commercials on viewers' perceived motivations and efficacy to exercise and consume a healthy diet as well as on food preference. In a 3 (program type) × 2 (advertisement type) study design, 253 female undergraduates were randomly assigned to watch an episode of a health-oriented reality program, a non-heath-oriented reality program, or a health-themed sitcom in which commercials for either healthy or unhealthy foods were embedded. Results indicated that perceived realism of the health-oriented reality program generated greater confidence to eat more healthily and exercise, as well as greater motivation to exercise. Additionally, program viewing differentially affected motivations to eat healthily and to exercise, but only when type of advertisement (high vs. low calorie food ads) was taken into consideration. Finally, women who watched the health-oriented reality program were more likely to choose a healthy snack at the conclusion of the experiment than those exposed to other programs, thus supporting the assertion that reality programming may potentiate positive health behaviors. The role of the embedded advertisements in altering the interpretation and health impact of the programming is also discussed.