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Little attention has been paid to olfactory changes during pregnancy with contemporary studies limited in number and sample size. We examined whether pregnancy is associated with differences in olfactory performance and if there were any specific gestational ages at which these differences occur through a comprehensive systematic review and meta-analysis of the current literature. An initial electronic database search identified 234 citations, which were screened at the abstract level. Twenty-three citations were germane for full-text review, and 13 met criteria for inclusion. Our review assessed 5 olfactory measures of interest: odor identification (n = 11 articles), threshold (n = 8), discrimination (n = 5), hedonics (n = 6), and intensity (n = 5). Nine of these 13 studies contained sufficient data for meta-analysis, and these studies included a total of 523 pregnant women and 365 non-pregnant controls. Despite previous subjective and objective reports of odor intolerances and odor hypersensitivity, we did not find any significant differences between pregnant and non-pregnant women in odor discrimination, thresholds, or hedonics. However, meta-analysis of 506 cases and 333 controls showed worse odor identification in pregnant women compared to controls in a random-effects model. Thus, we demonstrate worse performance at odor identification during pregnancy. In this review, we discuss the current evidence (and lack thereof) regarding olfaction in pregnancy as well as highlight current knowledge gaps in this field.

RGS (regulator of G protein signaling) family members catalyze the termination of G protein signaling cascades. Single nucleotide polymorphisms in theTo study cell-specific functions of RGS2, a novel gene-targeted mouse harboring a conditional allele for theWhereasThese results demonstrate the development of a novel mouse with conditional expression of

and purposeThe intent of this document is to highlight practical recommendations in a concise format designed to assist acute-care hospitals in implementing and prioritizing their surgical-site infection (SSI) prevention efforts. This document updates the Strategies to Prevent Surgical Site Infections in Acute Care Hospitals published in 2014.1 This expert guidance document is sponsored by the Society for Healthcare Epidemiology of America (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.

Production of IFN-γ by CD4 T cells is widely theorized to control Plasmodium parasite burden during blood-stage malaria. Surprisingly, the specific and crucial mechanisms through which this highly pleiotropic cytokine acts to confer protection against malarial disease remain largely untested in vivo. Here we used a CD4 T cell–restricted Cre-Lox IFN-γ excision mouse model to test whether and how CD4 T cell–derived IFN-γ controls blood-stage malaria. Although complete absence of IFN-γ compromised control of the acute and the chronic, recrudescent blood-stage infections with P. c. chabaudi, we identified a specific, albeit modest, role for CD4 T cell–derived IFN-γ in limiting parasite burden only during the chronic stages of P. c. chabaudi malaria. CD4 T cell IFN-γ promoted IgG Ab class switching to the IgG2c isotype during P. c. chabaudi malaria in C57BL/6 mice. Unexpectedly, our data do not support gross defects in phagocytic activity in IFN-γ-deficient hosts infected with blood-stage malaria. Together, our data confirm CD4 T cell–dependent roles for IFN-γ but suggest CD4 T cell–independent roles for IFN-γ in immune responses to blood-stage malaria.

Three-dimensional (3D) modeling and printing comprise an important tool for orthopaedic surgeons. One area in which 3D modeling has the potential to dramatically improve our understanding of biomechanical kinematics is pathologies of the patellofemoral joint, in particular trochlear dysplasia. We describe a method for creating 3D printed models of the patellofemoral joint, including computed tomography image acquisition, image segmentation, model creation, and 3D printing. The models created can help surgeons understand and plan surgery for recurrent patellar dislocations.

Background: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. Methods: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1–5; prednisone 60 mg/m2 orally on days 1–15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006–000995-33) and is completed. Findings: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1–69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3–89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8–92·5), for which the 95% CI included the 90% target rate. The most common grade 3–4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. Interpretation: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. Funding: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Hand surgery encompasses a diaspora of pathology and patients, but the surgeons treating this population are not commensurately diverse. A physician population that reflects the population it treats consistently leads to improved patient outcomes. Despite increasing diversity amongst surgeons entering into pipeline specialties such as General Surgery, Plastic Surgery, and Orthopaedic Surgery, the overall makeup of practicing hand surgeons remains largely homogenous. This article outlines organizations, such as the Perry Initiative, which have increased recruitment of women and underrepresented minorities into pipeline programs. Techniques of minimizing bias and increasing opportunities for underrepresented groups are also discussed.

Background: Biological biomarkers yielded from positron emission tomography (PET) brain scans serve as a pathway to understanding Alzheimer’s disease pathology. PET brain scan data remain limited for populations traditionally under-included in aging research. Objective: The purpose of this qualitative study was to examine participant-identified barriers to PET brain scan consent and characterize participant-informed elements of educational materials needed to facilitate PET brain scan participation among older Black and Latino adults. Methods: Participants (N = 31) were older adults (mean age = 71 years) who self-identified as either non-Latino Black (n = 15) or Latino (n = 16). Each participant took part in a one-time, in-depth individual interview. Researchers analyzed data guided by a Grounded Theory Approach with both Open Coding and Constant Comparative Coding. Results: Four overarching themes emerged across all participants: 1) knowledge limitations; 2) requirements for consent; 3) motivators for participation; and 4) social networks. Within the four themes, there were differences based on participant ethnoracial group. For example, for Theme Three, older Black adults indicated that they would expect compensation for PET brain scan participation. Conversely, older Latinos stated that they would appreciate, but not anticipate, a financial incentive. All participants stressed the importance of written educational materials with subsequent verbal discussions with studystaff. Conclusion: Findings inform the development and implementation of scientifically-relevant and culturally-cognizant engagement approaches, educational materials, and recruitment strategies to increase PET brain scan participation by diverse older adults.

Results from 45 parent respondents indicated a near-significant relationship between children with intellectual disability (ID) and comorbid autism spectrum disorder (ASD) and the Behavior Rating Inventory of Executive Function (BRIEF-2; Gioia et al., 2015) scale raw scores, emotional control scale and the behavioral regulation index. The manuscript raises an important message about the necessity to better understand the executive functioning and cognitive processes in children with ID, especially those children with comorbid ASD.

Accurately estimating portion sizes remains a challenge in dietary assessment. Digital images used in online 24-hour dietary recalls may be conducive to accuracy.The current analyses were conducted to examine the accuracy of portion size estimation by women with low incomes who completed 24-hour dietary recalls using the online Automated Self-Administered 24-hour Dietary Assessment Tool (ASA24) in the Food and Eating Assessment Study II.True dietary intake was observed for 3 meals on 1 day through a controlled feeding study conducted from May through July 2016. The following day, participants completed an unannounced 24-hour dietary recall using ASA24, independently or with assistance in a small-group setting.Participants included 302 women aged 18 to 82 years living in the Washington, DC, area who met the income thresholds for the Supplemental Nutrition Assistance Program.The accuracy of portion size estimation was assessed by comparing the weight truly consumed (observed) and the weight reported for predetermined categories of foods and beverages.The differences between observed and reported portions were examined and linear regression tested differences by recall condition. Analyses were conducted by condition and repeated with stratification by racial/ethnic identity, education, and body mass index.On average across foods and beverages, reported portion sizes were 7.4 g (95% CI, 4.3-10.5) and 6.4 g (95% CI, 2.8-10.0) higher than observed portion sizes in the independent and assisted conditions, respectively. Portion sizes were overestimated for small pieces and shaped foods in both conditions, as well as for amorphous/soft foods in the assisted condition and underestimated for single-unit foods in both conditions. Misestimation was fairly consistent by participants' race/ethnicity, education, and body mass index, to varying magnitudes.Women with low incomes overestimated the amounts of foods and beverages consumed across several categories using online 24-hour dietary recalls with digital images to support portion size estimation. Assistance with ASA24 had little impact on accuracy.

Objectives:To test the hypothesis that higher level of purpose in life is associated with lower likelihood of dementia and mild cognitive impairment (MCI) in older Brazilians.Methods:As part of the Pathology, Alzheimer’s and Related Dementias Study (PARDoS), informants of 1,514 older deceased Brazilians underwent a uniform structured interview. The informant interview included demographic data, the Clinical Dementia Rating scale to diagnose dementia and MCI, the National Institute of Mental Health Diagnostic Interview Schedule for depression, and a 6-item measure of purpose in life, a component of well-being.Results:Purpose scores ranged from 1.5 to 5.0 with higher values indicating higher levels of purpose. On the Clinical Dementia Rating Scale, 940 persons (62.1%) had no cognitive impairment, 121 (8.0%) had MCI, and 453 (29.9%) had dementia. In logistic regression models adjusted for age at death, sex, education, and race, higher purpose was associated with lower likelihood of MCI (odds ratio = .58; 95% confidence interval [CI]: .43, .79) and dementia (odds ratio = .49, 95% CI: .41, .59). Results were comparable after adjusting for depression (identified in 161 [10.6%]). Neither race nor education modified the association of purpose with cognitive diagnoses.Conclusions:Higher purpose in life is associated with lower likelihood of MCI and dementia in older black and white Brazilians.

Transmembrane protein 27 (TMEM27/collectrin), a glycoprotein and homolog of angiotensin-converting enzyme 2 (ACE2), is a regulator of renal amino acid uptake in the proximal tubule and may have a protective role in hypertension. Two previous reports have shown that the absence of TMEM27 expression in clear cell renal cell carcinoma (ccRCC) correlates with poorer cancer-related survival. We report our findings of TMEM27 expression in ccRCC and clinical outcomes in an independent third cohort.We conducted a retrospective analysis to identify all 321 cases of ccRCC diagnosed between 2010 and 2015 at the University of Rochester Medical Center. The intensity of TMEM27 immunostaining on tumor tissue was semi-quantitatively graded on a scale of 0, 0.5, 1, 1.5, 2, 2.5, and 3 by a single pathologist, and correlated with tumor characteristics and survival.There was evidence of metastasis at time of nephrectomy in 36 (11.2%) cases, and at the latest follow-up in 70 (21.8%) cases. As of Spring 2021, 82 (25.5%) had died. TMEM27 staining intensity correlated inversely with various tumor characteristics. Kaplan-Meier survival analysis showed worse overall all-cause mortality (The absence of TMEM27 expression is associated with more aggressive tumor characteristics and poorer all-cause mortality and disease-free survival in ccRCC. TMEM27 may be a useful biomarker to assess cancer prognosis. Further studies are needed to better assess if TMEM27 is protective in RCC, and its potential role in active surveillance and prediction of response to target therapy.

Retinoic acid (RA), a metabolite of vitamin A, is a small molecule and morphogen that is required for embryonic development. While normal RA signals are required for hepatic development in a variety of vertebrates, a role for RA during mammalian hepatic specification has yet to be defined. To examine the requirement for RA in murine liver induction, we performed whole embryo culture with the small molecule RA inhibitor, BMS493, to attenuate RA signaling immediately prior to hepatic induction and through liver bud formation. BMS493 treated embryos demonstrated a significant loss of hepatic specification that was confined to the prospective dorsal anterior liver bud. Examination of RA attenuated embryos demonstrates that while the liver bud displays normal expression of foregut endoderm markers and the hepato-pancreatobiliary domain marker, PROX1, the dorsal/anterior liver bud excludes the critical hepatic marker, HNF4α, indicating that RA signals are required for dorsal/anterior hepatic induction. These results were confirmed and extended by careful examination of Rdh10lt;supgt;trex/trexlt;/supgt; embryos, which carry a genetic perturbation in RA synthesis. At E9.5 Rdh10lt;supgt;trex/trexlt;/supgt; embryos display a similar yet more significant loss of the anterior/dorsal liver bud. Notably the anterior/dorsal liver bud loss correlates with the known dorsal-ventral gradient of the RA synthesis enzyme, Aldh1a2. In addition to altered hepatic specification, the mesoderm surrounding the liver bud is disorganized in RA abrogated embryos. Analysis of E10.5 Rdh10lt;supgt;trex/trexlt;/supgt; embryos reveals small livers that appear to lack the dorsal/caudal lobes. Finally, addition of exogenous RA prior to hepatic induction results in a liver bud that has failed to thicken and is largely unspecified. Taken together our ex vivo and in vivo evidence demonstrate that the generation of normal RA gradients is required for hepatic patterning, specification, and growth.

Social engagement is known to improve health; less is known about whether social activities at the core of African American life decrease mortality risk in this minoritized population. This study investigated whether and which aspects of social engagement predict mortality risk in older African Americans.Data from 768 African Americans (aged ∼73 years; nondemented at baseline) participating in the Minority Aging Research Study, a longitudinal community-based, cohort study of aging, was collected between 2004 and 2020 and analyzed in 2020. Participants self-reported late-life social activity, social network size, life space, and purpose in life at baseline and completed approximately 6.5 years of annual follow-up (range=15.70). Cox models included time from baseline to death or censoring and an indicator for death versus censored with age, sex, education, cardiovascular disease risk factor burden, depressive symptomatology, and motor gait performance as covariates.As of March 2020, 25% of participants died (n=192; age at death ∼83 years). In fully adjusted Cox models, mortality risk decreased by 34% (hazard ratio=0.66; 95% CI=0.48, 0.91; p=0.012) for those with higher compared with that for those with lower social activity generally, with community/volunteer-, group-, and socially-related activities specifically driving these results.Engaging in late-life social activity, especially group- and socially-based activities, was most consistently and robustly associated with reduced mortality risk in African Americans regardless of health. These results lay the foundation for considering community-based approaches to increase and/or maintain social participation in older African Americans as a potential means by which to increase longevity in this population.

Community engagement creates evidence-based, experiential learning opportunities for kinesiology programs seeking to enhance student experiences through meaningful connections. We argue that increasing community engagement through hands-on experiential learning opportunities should serve as a model for effectively creating a stronger sense of belonging among kinesiology students. Two cases explore kinesiology program initiatives at private universities emphasizing activist learning models with established community-service pedagogy. Both cases conceptualize research activities, including the design and implementation phases, as well as relevant outcomes developed on the respective campuses. We discuss how experiential learning and community engagement enable students’ sense of belonging and improve student engagement outcomes for kinesiology programs.

Copper is an essential micronutrient for brain health and dyshomeostasis of copper could have a pathophysiological role in Alzheimer's disease (AD), however, there are limited data from community-based samples. In this study, we investigate the association of brain copper (assessed using ICP-MS in four regions -inferior temporal, mid-frontal, anterior cingulate, and cerebellum) and dietary copper with cognitive decline and AD pathology burden (a quantitative summary of neurofibrillary tangles, diffuse and neuritic plaques in multiple brain regions) at autopsy examination among deceased participants (N = 657; age of death: 90.2(±6.2)years, 70% women, 25% APOE-ɛ4 carriers) in the Rush Memory and Aging Project. During annual visits, these participants completed cognitive assessments using a 19-test battery and dietary assessments (using a food frequency questionnaire). Regression, linear mixed-effects, and logistic models adjusted for age at death, sex, education, and APOE-ε4 status were used. Higher composite brain copper levels were associated with slower cognitive decline (β(SE) = 0.028(0.01), p = 0.001) and less global AD pathology (β(SE) = -0.069(0.02), p = 0.0004). Participants in the middle and highest tertile of dietary copper had slower cognitive decline (T2vs.T1: β = 0.038, p = 0.0008; T3vs.T1: β = 0.028, p = 0.01) than those in the lowest tertile. Dietary copper intake was not associated with brain copper levels or AD pathology. Associations of higher brain copper levels with slower cognitive decline and with less AD pathology support a role for copper dyshomeostasis in AD pathogenesis and suggest that lower brain copper may exacerbate or indicate disease severity. Dietary and brain copper are unrelated but dietary copper is associated with slower cognitive decline via an unknown mechanism.

African American (AA) adults have about twice the risk of developing dementia compared with white adults. However, evidence on dietary modification in preventing cognitive decline from diverse populations focusing on AA adults is minimal.We aimed to evaluate the association between a plant-based diet and the rate of cognitive decline in a population-based sample of AA and white adults.This study consisted of 3337 participants from the Chicago Health and Aging Project (60% AA participants, 64% female). Plant-based diet quality was evaluated by the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Global cognition was assessed using a composite score of 4 individual tests of cognition. We used mixed models to examine the associations of PDI, hPDI, and uPDI with the rates of decline in global cognition, perceptual speed, and episodic memory. Models were adjusted for age, sex, presence of apoE e4 allele, lifestyle factors including education, cognitive activities, smoking status, calorie intake, risk factors for cardiovascular disease, time, and the interaction terms of time × each covariate.AA and white participants had various dietary patterns. Higher hPDI was associated with a slower rate of decline in global cognition, perceptual speed, and episodic memory in AA participants but not white participants. AA study participants in the highest quintile of hPDI had significantly slower rates of global cognitive decline (β: 0.0183 ± 0.0086; P = 0.032), perceptual speed (β: 0.0179 ± 0.0088; P = 0.04), and episodic memory (β: 0.0163 ± 0.0118; P = 0.04) than individuals in the lowest quintile of hPDI. There were no associations of either PDI or uPDI with the rate of cognitive decline in either racial group.A healthy plant-based diet was associated with a slower rate of decline in global cognition, perceptual speed, and episodic memory in AA adults.

Background Acute flexor tendon injuries are challenging injuries for patients, surgeons, and therapists alike. There is ongoing debate about the optimal timing and amount of therapy after these injuries. Purpose We sought to investigate the relationship between hand therapy utilization and reoperation rates after flexor tendon repair and quantify reoperation rates and costs associated with flexor tendon repair. We hypothesize there will be an inverse relationship between the number of hand therapy visits and later reoperation rates and a positive correlation between reoperation rates and total cost of care. Study Design A retrospective cohort study of patients undergoing primary flexor tendon repair was pursued. Methods A commercially available database was utilized to access insurance claims data for 20.9 million patients in the US from 2007 to 2015. Patients undergoing primary flexor tendon repair were included and followed for one year. Patients with fractures, vascular injuries, or digit replantation were excluded. We studied post-operative rehabilitation utilization, reoperation rates, and costs. Chi-Square tests and multivariable logistic regressions were used to assess the relationship between therapy utilization and reoperation rates and costs. Results The one-year reoperation rate was 11.4 percent at a median time of 100.0 days amongst 1,129 patients undergoing primary tendon repair. In multivariable analysis, age between 30 and 59, male sex, and utilization of over 21 therapy sessions were associated with increased odds of reoperation. Mean insurance reimbursement one year following primary flexor repair was $14,533 per patient but $27,870 if patients went on to reoperation. Conclusion Continued therapy utilization after primary flexor tendon repair is an independent predictor of reoperation need. These findings may help surgeons counsel patients who require a large number of visits after flexor tendon repair on when to revisit surgical options.

Smutgrass is an invasive weed species that can quickly outcompete bahiagrass because of its aggressive growth, prolific seed production, and rhizomatous nature. Total renovation of bahiagrass pastures or hayfields is generally not a feasible or economically viable option for most producers. Therefore, controlling the continual spread of smutgrass will require an integrated weed management (IWM) plan that incorporates multiple strategies. The objective of this study was to test the interactions of herbicides and fertilizers on smutgrass control in bahiagrass and determine the most efficacious and economical IWM plan for low-input bahiagrass systems. This research was conducted on a mixture of ‘Tifton 9’ and ‘Pensacola’ bahiagrass at the Alapaha Beef Station in Alapaha, GA. The study design was a randomized complete block with a three-by-four factorial treatment arrangement with six replications. Fertility treatments included 56 kg N ha–1 (ammonium nitrate, 34% N) + 56 kg K2O ha–1, 56 kg N ha–1, and an unfertilized control. Smutgrass was reduced to 2O resulted in an improved bahiagrass stand as timely weed suppression removed competition, while fertilizer provided essential nutrients for optimum growth to fill in the gaps. Combining herbicide and fertilizer is a more economical option for producers when compared to a complete bahiagrass renovation.

The US Senate is unique in the United States and rare internationally for its total disregard of population differences among its representational units. To analyze malapportionment’s policy impact, we devised a hypothetical reapportionment scheme that more closely approximates state population but remains favorable to small states. We developed a formula to reweight senators’ roll-call votes to reflect better state population differences. We recalculated 804 key US Senate votes between 1961 and 2019 and found that state equality in the Senate systematically biases policy outcomes toward Republican preferences.

Understanding variability in distributions and habitat-use among populations of anadromous salmonids is essential for their sustainable management. Arctic char ( Salvelinus alpinus) is an important cultural and socioeconomic species; however, knowledge of their spatiotemporal habitat-use during the marine phase is limited. Here, a large-scale acoustic telemetry array was used to determine intraspecific variation in Arctic char summer marine habitat-use tied to overwintering lake occurrence in the Amundsen Gulf. Arctic char tagged in the ocean migrated to two main overwintering lakes, corresponding to distinct migration corridors and separate patterns of marine habitat-use, with one individual exhibiting among the longest recorded char marine migration to date (∼330 km). Arctic char that undertook longer migration distances initiated travel in the ocean towards fresh water 11 days earlier than those completing shorter migration distances; mean departure days (±SD) 2 August (±8.1 days) and 13 August (±6.8 days), corresponding to migration distances of 252 and 131 km, respectively. These findings identify that Arctic char from different populations can occupy distinct marine foraging grounds within a region, with consequences for variable interactions with fisheries.

The spaces we inhabit and the physical communities in which we learn all affect how we come to experience the world, construct what mathematics is to us, and develop how we teach mathematics. In this theory-to-practice article, we discuss why explicitly considering spatial ways of knowing is important in mathematics teacher education. We begin by providing theoretical arguments for the importance of considering space in mathematics education. We then present a rationale for why considering space is so important in mathematics teacher education, specifically discussing links to the practice of teaching mathematics. Examples of how to consider tasks related to spatial justice are provided to help reimagine what an mathematics teacher education task can look like.

Background: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. Methods: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. Results: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (

Ectopic pregnancy, derived from the Greek “ektopos” meaning ‘out-of-place’, describes a pregnancy where the conceptus implants and develops at an abnormal location, most commonly the Fallopian tube. It complicates 1-2% of all pregnancies and is life-threatening due to aberrant placental trophoblast invasion of maternal blood vessels, which can result in catastrophic intra-abdominal haemorrhage. Until the 21st century, the only treatment option was surgical, in most instances involving removal of the tube containing the pregnancy. Following advances in ultrasound and the introduction of quantitative serum measurement of human chorionic gonadotrophin (hCG), it is now possible to select ‘lower risk’ cases where it is safe to offer expectant monitoring (until spontaneous resolution) or medical management. Medical treatment, with the chemotherapeutic methotrexate, can be offered to 40% of women presenting with an ectopic pregnancy. However, the efficacy of methotrexate is such that it is only offered to women presenting with low hCG levels; a group in which reported success rates, time-to-resolution and risk of haemorrhage are similar to that of expectant monitoring. There is consequently a clinical need to develop more efficacious and less toxic medical therapies for ectopic pregnancy. Further advances in therapy require development of experimental model systems to allow pre-clinical testing of drugs and to improve understanding of the pathophysiology of this condition; the latter traditionally limited by the fundamental difficulty in differentiating cause from effect in ex vivo specimens. Using in vitro and in vivo systems, this thesis investigates: 1) new potential experimental models of ectopic pregnancy; 2) methotrexate’s mechanism of action at the level of the trophoblast in the treatment of ectopic pregnancy; and 3) use of gonadotrophin releasing hormone (GnRH) receptor antagonists as a new medical treatment for ectopic pregnancy. To develop an in vivo model of ectopic pregnancy, mouse blastocysts, hatched from the zona pellucida, were transferred to oviducts of recipient mice. I found, due to murine embryos inherent ability to undergo embryonic diapause (a phenomenon not seen in humans) that this process did not result in ectopic implantation. I was able to generate an in vitro model of ectopic pregnancy, where mouse blastocysts attached to human Fallopian tube cells at low frequency (in comparison to the high numbers of blastocysts which attach to endometrial cells). This mirrors the in vivo situation where ectopic implantation occurs in a minority of pregnancies. Manipulation of this system could offer new insights into the pathogenesis of ectopic pregnancy. The extravillous trophoblast (EVT) cells of an ectopic embryo, which invade the maternal Fallopian tube, are a therapeutic target in ectopic pregnancy. EVT cell lines are routinely used in placental research but there is some disagreement in the literature as to how closely they represent primary EVT cells. In my routine assessment of EVT cell lines for use in this thesis, I unexpectedly identified co-expression of cytokeratin 7 (an epithelial marker, traditionally used as a trophoblast marker) with vimentin (a mesenchymal marker, traditionally used to demonstrate non-trophoblastic origin). This suggests these cells may have retained the ability to undergo partial epithelial mesenchymal transition, a characteristic of the primary cells from which they are derived. It is widely presumed that the mechanism of action of methotrexate in ectopic pregnancy is inhibition of DNA synthesis, as is the case where it is used at a 20-fold higher dose in the treatment of certain cancers. However, in vitro replication of maternal serum concentrations achieved following treatment with the low dose of methotrexate used in ectopic pregnancy, demonstrated only mild inhibition of cell cycle progression in just one of three EVT cell lines tested. In contrast, persistently high methotrexate concentrations, which more closely replicate cancer therapy, were able to inhibit DNA synthesis. Countertherapeutically, methotrexate was noted to increase trophoblast production of the pro-pregnancy hormones, hCG and progesterone. In rheumatoid arthritis, a different mechanism of action for methotrexate has been identified secondary to the extracellular accumulation of the anti-inflammatory nucleoside adenosine. I showed that EVT cell lines express adenosine receptors and secrete adenosine, both of which are stimulated by treatment with methotrexate. What role this may have in treatment of ectopic pregnancy requires future investigation. Gonadotrophin releasing hormone (GnRH) is a peptide that acts via its G-protein coupled receptor (GnRHR) as a central regulator of the hypothalamic-pituitary-gonadal axis. GnRHR antagonists are used routinely in artificial reproductive technologies. The GnRHR is also expressed in some reproductive cancers, where antagonism inhibits proliferation and invasion, and in some peripheral tissues including the EVT cells of ectopic pregnancies. I have shown that GnRHR antagonists inhibit trophoblast proliferation and hCG production in vitro. In mouse pregnancy, the effect of GnRHR antagonism was gestation dependent, with treatment at e9.5 causing fetal growth restriction and increased mid-gestation fetal loss, and treatment at e7.5 inducing 100% litter loss. This pre-clinical study suggests that GnRHR antagonists could have utility as a future treatment for ectopic pregnancy. In conclusion, this thesis describes a novel in vitro model of ectopic pregnancy; identifies that the mechanism of action of methotrexate in ectopic pregnancy is not as presumed, perhaps explaining its limited efficacy; and that pre-clinical study of GnRHR antagonists suggest they may represent a promising new medical treatment for ectopic pregnancy.

Neuroimaging, neuropsychological, and psychophysical evidence indicates that concept retrieval selectively engages specific sensory and motor brain systems involved in the acquisition of the retrieved concept. However, it remains unclear which supramodal cortical regions contribute to this process and what kind of information they represent. Here, we used representational similarity analysis of two large fMRI data sets, with a searchlight approach, to generate a detailed map of human brain regions where the semantic similarity structure across individual lexical concepts can be reliably detected. We hypothesized that heteromodal cortical areas typically associated with the “default mode network” encode multimodal experiential information about concepts, consistent with their proposed role as cortical integration hubs. In two studies involving different sets of concepts and different participants (both sexes), we found a distributed, bihemispheric network engaged in concept representation, composed of high-level association areas in the anterior, lateral, and ventral temporal lobe; inferior parietal lobule; posterior cingulate gyrus and precuneus; and medial, dorsal, ventrolateral, and orbital prefrontal cortex. In both studies, a multimodal model combining sensory, motor, affective, and other types of experiential information explained significant variance in the neural similarity structure observed in these regions that was not explained by unimodal experiential models or by distributional semantics (i.e., word2vec similarity). These results indicate that, during concept retrieval, lexical concepts are represented across a vast expanse of high-level cortical regions, especially in the areas that make up the default mode network, and that these regions encode multimodal experiential information.Significance StatementConceptual knowledge includes information acquired through various modalities of experience, such as visual, auditory, tactile, and emotional information. We investigated which brain regions encode mental representations that combine information from multiple modalities when participants think about the meaning of a word. We found that such representations are encoded across a widely distributed network of cortical areas in both hemispheres, including temporal, parietal, limbic, and prefrontal association areas. Several areas not traditionally associated with semantic cognition were also implicated. Our results indicate that the retrieval of conceptual knowledge during word comprehension relies on a much larger portion of the cerebral cortex than previously thought, and that multimodal experiential information is represented throughout the entire network.

This study aimed to investigate the relationship between John Henryism, a psychological trait typified by high-effort active coping that has been associated with adverse health outcomes among Blacks, and cognitive decline.In a cohort of community-dwelling older Black adults ( N = 611), we investigated the relationship between John Henryism and cognitive decline. John Henryism was measured using the John Henryism Active Coping Scale (JHACS), a nine-item validated measure of self-reported high-effort coping (mean [standard deviation] = 16.9 [4.8]; range, 4-27). We implemented a three-step modeling process using mixed-effects models to assess the relationship between the JHACS and global cognitive function as well as five cognitive domains. We adjusted for demographics and for factors known to be associated with cognitive function and decline including vascular risk factors, discrimination, and income.The trait of high-effort active coping was associated with lower-average cognitive function ( β = -0.07, 95% confidence interval = -0.10 to -0.03), but not with decline. The results remained after further adjustment for experiences of discrimination, income, and vascular risk factors. In domain-specific analyses, we found that the JHACS was associated with baseline levels of working memory, semantic memory, and visuospatial ability, but not decline.These results highlight the importance of using culturally specific measures in considering the heterogeneity of cognitive health outcomes in minoritized populations. Understanding how stress responses relate to late-life cognition among older Black adults could help promote aspects of behavioral resilience along with healthful coping responses.

Objective To integrate an auto-notification system into clinical workflow, so timely communication of sentinel events (elective surgery, hospital admission, or ER visit) in immunosuppressed rheumatic disease patients happened by design. Methods We developed an algorithm that triggered auto-notification within the electronic medical record to rheumatology when a patient experienced a sentinel event. A telephone encounter was created that included event type, baseline therapy, and event date. This was forwarded to the rheumatologist, who recorded guideline-driven recommendations and returned it to nursing. Instructions were included to communicate recommendations to the patient, inpatient rheumatology team, or other clinician. This was studied over four months at a multi-specialty medical practice in Central Pennsylvania. Primary outcomes were percentage of total notifications, notifications by sentinel event type where a change in care plan was recommended, as well as percentage of time where rheumatologists were notified of sentinel events, compared to prior to the intervention. Secondary outcomes were staff work effort. Results 240 notifications were received - 57% for elective surgeries, 39% for ER visits, and 4% for admissions. The need for change in care plan was only 17% for ER visits but was 25% for hospital admissions and 44% for elective surgeries. The percentage of time rheumatologists were notified of events increased from 57.6% to 100%. The average number of messages received per week was 2.2, requiring a weekly average of 13 minutes of work per physician. Conclusion We developed an easy, well-received process that "hardwires" rheumatologist notification sentinel events to facilitate timely care.

Researchers have emphasized the detrimental effects of COVID-19 on mental health, but less attention has been given to personal strengths promoting resilience during the pandemic. One strength might be gratitude, which supports wellbeing amidst adversity. A two-wave examination of 201 college students revealed anxiety symptom severity increased to a lesser extent from pre-COVID (January-March 2020) to onset-COVID (April 2020) among those who reported greater pre-COVID gratitude. A similar trend appeared for depression symptom severity. Gratitude was also correlated with less negative changes in outlook, greater positive changes in outlook, and endorsement of positive experiences resulting from COVID-19. Thematic analysis showed "strengthened interpersonal connections" and "more time" were the most commonly reported positive experiences. Overall findings suggest gratitude lessened mental health difficulties and fostered positivity at the onset of the pandemic, but more research is needed to determine whether gratitude and other strengths promote resilience as COVID-19 continues.