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Purpose: To report novel multimodal imaging features and long-term follow-up of Orthodenticle Homeobox 2 (OTX2)-associated pattern Gdystrophy. Methods: A 14-year-old boy referred with glaucoma suspect and macular pigmentation underwent fundus autofluorescence imaging, optical coherence tomography, fluorescein and indocyanine green angiography, visual field test, microperimetry and electrophysiology over a ten-year period. Next-generation sequencing panel identified a de novo heterozygous likely pathogenic OTX2 variant, c.259G>A, [p.(Glu87Lys)]. Results: Visual acuity was 20/40 OD and 20/30 OS. Examination showed bilateral enlarged optic nerve heads and increased disc cupping, multiple cilioretinal arteries, a pigmentary maculopathy with stellate-shaped region of hypoautofluorescence, shallow serous macular detachment, subretinal deposits and temporal avascular retina. Angiography showed no source of leakage and absence of retinal neovascularisation despite extensive peripheral non perfusion. Electrophysiological assessments demonstrated mild progressive rod and cone pathway abnormalities, reduced light-adapted b:a ratio, and reduced Arden ratio on electro-oculogram. Ten-year follow-up confirmed a stable disease course despite persistent submacular fluid. There was no associated pituitary structural abnormality or dysfunction. Conclusions: This case study contributes to further understanding of OTX2-associated pattern dystrophy, highlighting its stability over 10 years. Further investigation into inter-individual and intrafamilial variability is warranted. [ABSTRACT FROM AUTHOR]

Since the introduction and widespread adoption of chemical herbicides, "weed management" has become almost synonymous with "herbicide management." Over-reliance on herbicides and herbicide-resistant crops has given rise to herbicide resistant weeds. Integrated weed management (IWM) identifies three strategies for weed management— biological-cultural, chemical-technological, mechanical-physical—and recommends combining all three to mitigate herbicide resistance. However, adoption of IWM has stalled, and research to understand the adoption of IWM practices has focused on single stakeholder groups, especially farmers. In contrast, decisions about weed management often occur within a social ecosystem where multiple stakeholder groups co-create knowledge and practices. To more holistically investigate perceptions and decision-making related to herbicide resistant weed management, we conducted 23 in-depth interviews in combination with Q methodology with farmers and public-/private-sector agricultural professionals in the state of Georgia (U.S.). Our investigation focused on the management of an increasingly herbicide resistant weed, Palmer amaranth, which enabled broader conversations about agricultural systems, farmer livelihoods, and sustainability. Factor and thematic analyses allowed us to identify and characterize two distinct typologies: one primarily valued agronomic efficiency and relied upon chemical-technological management practices, while the other valued diversifying weed management strategies as the pathway to agronomic and economic success. Typologies diverged substantially in attitudes toward the three weed management strategies, the role of technology, and systems management generally. These two viewpoints have implications for how we understand underlying stakeholder motivations and choices around weed management strategies, both of which are crucial in promoting and supporting farmer use of diverse, ecologically-sound, weed management strategies. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness. Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives. Results: Among 991 participants with a median age (interquartile range, IQR) of 62 [53–72] years and enrollment SOFA of 9 [7–11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4–2.3]), IL-8 (1.3 [1.1–1.5]), IL-10 (1.5 [1.2–1.8]), TNF-α (1.2 [1.0–1.4]), and TNFR1 (1.3 [1.1–1.6]) and lower concentrations of protein C (0.7 [0.6–0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1–1.7]), IFN-γ (1.3 [1.1–1.5]), IL-6 (2.3 [1.8–3.0]), IL-8 (1.8 [1.4–2.3]), and IL-10 (1.5 [1.2–2.0]) and lower concentrations of protein C (0.6 [0.5–0.8]) were associated with coma the following day. IL-1β, IL-12, and MMP-9 were not associated with mental status. Conclusion: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness. [ABSTRACT FROM AUTHOR]

The online proliferation of COVID-19 misinformation led to adverse health and societal consequences. This study investigated possible differences in COVID-19 headline accuracy discernment and online sharing of COVID-19 misinformation between older and younger adults, as well as the role of individual differences in global cognition, health literacy and verbal IQ. Fifty-two younger (18–35 years old) and fifty older adults (age 50 and older) completed a neurocognitive battery, health literacy and numeracy measures, and self-report questionnaires via telephone. Participants also completed a social media headline-sharing experiment (Pennycook et al., Psychological science, 31(7), 770–780, 2020) in which they were presented with true and false COVID-19 headlines about which they indicated: 1) the likelihood that they would share the story on social media; and 2) the factual accuracy of the story. A repeated measures multivariate analysis of variance controlling for gender and race/ethnicity showed no effects of age (p =.099) but a significant interaction between actual COVID-19 headline accuracy and the likelihood of sharing (p <.001), such that accuracy was more strongly related to sharing false headlines (r = −.64) versus true headlines (r = −.43). Moreover, a higher likelihood of sharing false COVID-19 headlines was associated with lower verbal IQ and numeracy skills in older adults (rs = −.51--.40) and with lower verbal IQ, numeracy, and global cognition in younger adults (rs = −.66--.60). Findings indicate that headline accuracy judgements, numeracy, and verbal IQ are important contributors to sharing COVID-19 misinformation in both older and younger adults. Future work might examine the benefits of psychoeducation for improving health and science literacy for COVID-19. [ABSTRACT FROM AUTHOR]

Background: Modifiable lifestyle factors such as engagement with technology may be beneficial to cognition in older adults, but we know little about these relationships in older persons with chronic medical conditions. Aims: The current study examined the association between computer use frequency and cognition in younger and older adults with and without HIV disease. Methods: Participants included 110 older persons with HIV (pwHIV; age ≥ 50 years), 84 younger pwHIV (age ≤ 40 years), 76 older HIV−, and 66 younger HIV− adults who completed a comprehensive medical, psychiatric, and cognitive research assessment. Demographically adjusted scores were derived from a well-validated clinical battery of performance-based neuropsychological tests. Participants also completed self-reported measures of cognitive symptoms in daily life and the Brief Computer Use and Anxiety Questionnaire (BCUAQ). Results: Older age was associated with less frequent computer use among persons with and without HIV disease. More frequent computer use was strongly and independently related to better cognitive performance, particularly in higher order domains (e.g., episodic memory and executive functions) and among the older seronegative adults. A small, univariable correlation between more frequent computer use and fewer cognitive symptoms in daily life was observed in the full sample, but that relationship was better explained by computer-related anxiety and HIV/age study group. Discussion: These findings add to the existing literature that suggests regular engagement with digital technologies may have a beneficial impact on cognitive functioning, consistent with the technological reserve hypothesis. [ABSTRACT FROM AUTHOR]

Background: Delirium remains understudied after traumatic brain injury (TBI). We sought to identify independent predictors of delirium among intensive care unit (ICU) patients with TBI. Methods: This single-center retrospective cohort study evaluated adult patients with TBI requiring ICU admission. Outcomes included delirium days within the first 14 days, as assessed by the Confusion Assessment Method-ICU (CAM-ICU). Models were adjusted for age, sex, insurance, Marshall head computed tomography classification, presence of subarachnoid hemorrhage (SAH), Injury Severity Score (ISS), need for cardiopulmonary resuscitation, maximum admission Glasgow Coma motor score, glucose level, hemoglobin level, and pupil reactivity. Results: Delirium prevalence was 60%, with a median duration of 4 days (interquartile range: 2–8) among ICU patients with TBI (n = 2,664). Older age, higher ISS, maximum motor score < 6, Marshall class II–IV, and SAH were associated with risk of increased delirium duration (all p < 0.001). Conclusions: In this large cohort, ICU delirium after TBI affected three of five patients for a median duration of 4 days. Age, general injury severity, motor score, and features of intracranial hemorrhage were predictive of more TBI-associated delirium days. Given the high prevalence of ICU delirium after TBI and its impact on hospitalization, further work is needed to understand the impact of delirium and TBI on outcomes and to determine whether delirium risk can be minimized. [ABSTRACT FROM AUTHOR]

Background: Apraxia has been identified in all clinical forms of frontotemporal lobar degeneration (FTLD). The characteristics of apraxia symptoms and their underlying cognitive/motor basis are not fully understood. This study investigated apraxia in pathological subtypes of FTLD.The study constituted a retrospective review of 115 pathologically confirmed cases of FTLD from a single cognitive neurology centre. Patients in whom apraxia had been documented as a notable clinical characteristic were identified. Apraxia features, demographic, cognitive, neurological, and imaging findings were recorded.Eighteen patients were identified: 12 with FTLD-tau pathology (7 corticobasal degeneration (CBD), four Pick type and one progressive supranuclear palsy (PSP)) and six with FTLD-TDP pathology, all type A and four linked to progranulin gene mutations. Apraxia as a dominant presenting feature was typically associated with tau pathologies, whereas it emerged in the context of aphasia in TDP pathology. Apraxia typically predominated in one body part (face or limb) in tau but not TDP pathology. Relatively preserved activities in daily life were associated with TDP. Apraxia of speech was associated with tau pathology. Pick-type pathology was linked to symmetrical atrophy and late development of limb rigidity.Apraxia in FTLD subtypes has variable characteristics. Apraxia associated with CBD pathology conformed to criteria for probable corticobasal syndrome (CBS), whereas apraxia with Pick-type pathology did not. Apraxia in patients with TDP-A pathology was interpreted as one manifestation of their generalised communication disorder. Apraxia in FTLD may have distinct cognitive and motor substrates that require prospective investigation.Methods: Apraxia has been identified in all clinical forms of frontotemporal lobar degeneration (FTLD). The characteristics of apraxia symptoms and their underlying cognitive/motor basis are not fully understood. This study investigated apraxia in pathological subtypes of FTLD.The study constituted a retrospective review of 115 pathologically confirmed cases of FTLD from a single cognitive neurology centre. Patients in whom apraxia had been documented as a notable clinical characteristic were identified. Apraxia features, demographic, cognitive, neurological, and imaging findings were recorded.Eighteen patients were identified: 12 with FTLD-tau pathology (7 corticobasal degeneration (CBD), four Pick type and one progressive supranuclear palsy (PSP)) and six with FTLD-TDP pathology, all type A and four linked to progranulin gene mutations. Apraxia as a dominant presenting feature was typically associated with tau pathologies, whereas it emerged in the context of aphasia in TDP pathology. Apraxia typically predominated in one body part (face or limb) in tau but not TDP pathology. Relatively preserved activities in daily life were associated with TDP. Apraxia of speech was associated with tau pathology. Pick-type pathology was linked to symmetrical atrophy and late development of limb rigidity.Apraxia in FTLD subtypes has variable characteristics. Apraxia associated with CBD pathology conformed to criteria for probable corticobasal syndrome (CBS), whereas apraxia with Pick-type pathology did not. Apraxia in patients with TDP-A pathology was interpreted as one manifestation of their generalised communication disorder. Apraxia in FTLD may have distinct cognitive and motor substrates that require prospective investigation.Results: Apraxia has been identified in all clinical forms of frontotemporal lobar degeneration (FTLD). The characteristics of apraxia symptoms and their underlying cognitive/motor basis are not fully understood. This study investigated apraxia in pathological subtypes of FTLD.The study constituted a retrospective review of 115 pathologically confirmed cases of FTLD from a single cognitive neurology centre. Patients in whom apraxia had been documented as a notable clinical characteristic were identified. Apraxia features, demographic, cognitive, neurological, and imaging findings were recorded.Eighteen patients were identified: 12 with FTLD-tau pathology (7 corticobasal degeneration (CBD), four Pick type and one progressive supranuclear palsy (PSP)) and six with FTLD-TDP pathology, all type A and four linked to progranulin gene mutations. Apraxia as a dominant presenting feature was typically associated with tau pathologies, whereas it emerged in the context of aphasia in TDP pathology. Apraxia typically predominated in one body part (face or limb) in tau but not TDP pathology. Relatively preserved activities in daily life were associated with TDP. Apraxia of speech was associated with tau pathology. Pick-type pathology was linked to symmetrical atrophy and late development of limb rigidity.Apraxia in FTLD subtypes has variable characteristics. Apraxia associated with CBD pathology conformed to criteria for probable corticobasal syndrome (CBS), whereas apraxia with Pick-type pathology did not. Apraxia in patients with TDP-A pathology was interpreted as one manifestation of their generalised communication disorder. Apraxia in FTLD may have distinct cognitive and motor substrates that require prospective investigation.Conclusion: Apraxia has been identified in all clinical forms of frontotemporal lobar degeneration (FTLD). The characteristics of apraxia symptoms and their underlying cognitive/motor basis are not fully understood. This study investigated apraxia in pathological subtypes of FTLD.The study constituted a retrospective review of 115 pathologically confirmed cases of FTLD from a single cognitive neurology centre. Patients in whom apraxia had been documented as a notable clinical characteristic were identified. Apraxia features, demographic, cognitive, neurological, and imaging findings were recorded.Eighteen patients were identified: 12 with FTLD-tau pathology (7 corticobasal degeneration (CBD), four Pick type and one progressive supranuclear palsy (PSP)) and six with FTLD-TDP pathology, all type A and four linked to progranulin gene mutations. Apraxia as a dominant presenting feature was typically associated with tau pathologies, whereas it emerged in the context of aphasia in TDP pathology. Apraxia typically predominated in one body part (face or limb) in tau but not TDP pathology. Relatively preserved activities in daily life were associated with TDP. Apraxia of speech was associated with tau pathology. Pick-type pathology was linked to symmetrical atrophy and late development of limb rigidity.Apraxia in FTLD subtypes has variable characteristics. Apraxia associated with CBD pathology conformed to criteria for probable corticobasal syndrome (CBS), whereas apraxia with Pick-type pathology did not. Apraxia in patients with TDP-A pathology was interpreted as one manifestation of their generalised communication disorder. Apraxia in FTLD may have distinct cognitive and motor substrates that require prospective investigation. [ABSTRACT FROM AUTHOR]

Purpose of Review: Statins are the pillar of secondary prevention in reducing cardiovascular disease in high-risk adults. However, statin discontinuation is the standard recommendation in pregnant and lactating patients. This review evaluates whether we can justify the early treatment of reproductive aged women with statin therapy. Recent Findings: Statins have several potential benefits including its antioxidant, anti-inflammatory, and anti-thrombogenic properties that may prevent the worsening of atherosclerosis in high-risk women. Nevertheless, most studies on statins and teratogenicity have a limited sample size and the effects of long-term statin use on fetal and neonatal health remain unknown. Not all statins may be safe and pravastatin's cholesterol-lowering properties may be too limited to provide much maternal benefit in pregnancy. Summary: While emerging evidence supports the use of pravastatin in pregnancy, we need to better assess the risk of early cardiovascular disease and acute progression of atherosclerosis before and during pregnancy to better understand the risks and benefits of statin use. [ABSTRACT FROM AUTHOR]

Older age and HIV disease are independent risk factors for problems in many aspects of everyday functioning. However, less is known about how these risk factors may combine to influence everyday functioning over time. The current study examined the possible combined effects of age and HIV serostatus on change in everyday functioning over a 1-year period and its specific associations with changes in neurocognition. A repeated measures factorial design was employed. Participants included 77 older persons with HIV (PWH), 35 younger PWH, 44 older HIV-, and 27 younger HIV-adults who each completed baseline and follow-up visits approximately 14 months apart. Everyday functioning was assessed using a standardized self-report measure of activities of daily living (ADLs) at each visit. A comprehensive clinical battery assessed six domains of neurocognition. Raw scores on each neurocognitive measure were converted to sample-based z-scores, from which a global neurocognitive z-score was derived. Older PWH reported the poorest everyday functioning at baseline and follow-up visits at medium-to-large effect sizes. However, these ADL disruptions among older PWH were relatively stable over time, differing significantly from younger PWH who evidenced mild ADL improvements from baseline to follow-up. Within the entire sample, everyday functioning at baseline predicted neurocognitive performance at follow-up, but the reciprocal relationship was not significant. Older adults with HIV have high rates of ADL problems, which appear stable over 1 year, the trajectory of which differed from younger adults with HIV for whom mild improvements were observed. Importantly, the results also suggest that problems with ADLs may sometimes precede neurocognitive declines. Further examination of longitudinal data is needed to elucidate the long-term trajectory of neurocognitive and functional changes in older PWH to support early detection and proper management of clinical care. [ABSTRACT FROM AUTHOR]

Purpose: The c.1430A > G (Asp477Gly) variant in RPE65 has been reported in Irish and Scottish families with either an autosomal dominant retinal dystrophy (adRD) that resembles choroideremia, a vitelliform macular dystrophy or an isolated macular atrophy. We report novel features on multimodal imaging and the natural history of a family harbouring this variant in combination with the BEST1 c.37C > T (Arg13Cys) variant. Methods: Members of a family with an adRD were examined clinically to ascertain phenotype and underwent genetic testing. Multimodal imaging included widefield colour fundus photography, quantitative autofluorescence (qAF) and spectral domain optical coherence tomography. Electrophysiology and microperimetry were also performed. Results: Vision loss was attributed to foveal atrophy in the proband and choroidal neovascularisation and a vitello-eruptive lesion in one affected son. Peripheral retinal white dots corresponding to subretinal deposits were seen in three patients. The median qAF8 values in the proband (I:1) were low (40 and 101 in OD and OS) at age 79. Similarly, the qAF8 values for the middle son (II:2) were also low (100 and 87 in ODS and OS) at age 60. Electrophysiology showed disproportionate reduction in Arden ratio prior to the gradual loss of full-field responses. Microperimetry demonstrated an enlarging scotoma in the proband. Conclusions: The coexistence of the pathogenic BEST1 c.37C > T variant may modify clinical features observed in RPE65 adRD. This study expands our understanding of RPE65 adRD as a retinoid cycle disorder supported by the reduced qAF, fine white retinal dots and corresponding subretinal deposits on OCT in affected members. [ABSTRACT FROM AUTHOR]

Host membrane remodeling is indispensable for viruses, bacteria, and parasites, to subvert the membrane barrier and obtain entry into cells. The malaria parasite Plasmodium spp. induces biophysical and molecular changes to the erythrocyte membrane through the ordered secretion of its apical organelles. To understand this process and address the debate regarding how the parasitophorous vacuole membrane (PVM) is formed, we developed an approach using lattice light-sheet microscopy, which enables the parasite interaction with the host cell membrane to be tracked and characterized during invasion. Our results show that the PVM is predominantly formed from the erythrocyte membrane, which undergoes biophysical changes as it is remodeled across all stages of invasion, from pre-invasion through to PVM sealing. This approach enables a functional interrogation of parasite-derived lipids and proteins in PVM biogenesis and echinocytosis during Plasmodium falciparum invasion and promises to yield mechanistic insights regarding how this is more generally orchestrated by other intracellular pathogens. Here, Geoghegan, Evelyn et al. provide a lattice light-sheet microscopy based 4D imaging pipeline to quantitatively investigate Plasmodium spp. invasion and show that the nascent parasitophorous vacuole is predominantly formed from host's erythrocyte membrane and undergoes continuous remodeling throughout invasion. [ABSTRACT FROM AUTHOR]

Farm to school (FTS) is a popular approach to food systems education in K-12 schools across the United States. FTS programs are highly heterogeneous, but generally include serving locally grown fruits and vegetables in school nutrition programs, planting and maintaining school gardens, and engaging students in garden and food-based learning across the school curriculum. While FTS has been promoted as a "win–win–win" for children, farmers, and communities, it has also been critiqued for reinscribing neoliberal trends (i.e., individualism, private funding, and volunteerism) that exacerbate social inequalities. Through a year-long, ethnographic study of FTS within one public middle school in the Southeast US, this paper contributes to these debates. Drawing upon theoretical frameworks of materiality and affective labor, we investigate how engagement with FTS activities can transform the social practice of everyday life in school for students, staff, and teachers. We find that FTS can reframe success in collaborative terms, engage the school around collective responsibility, and foster relationships across socioeconomic and racial difference. Although there is continued need to expand policies to ensure equitable funding for FTS, our research demonstrates that the hands-on work and collective subjectivities produced through FTS can mitigate the harms of neoliberalism and be a force for positive social change within a school. [ABSTRACT FROM AUTHOR]

Family health history (FHH) screening plays a key role in disease risk identification and tailored disease prevention strategies. Primary care physicians (PCPs) are in a frontline position to provide personalized medicine recommendations identified through FHH screening; however, adoption of FHH screening tools has been slow and inconsistent in practice. Information is also lacking on PCP facilitators and barriers of utilizing family history tools with clinical decision support (CDS) embedded in the electronic health record (EHR). This study reports on PCPs' initial experiences with the Genetic and Wellness Assessment (GWA), a patient-administered FHH screening tool utilizing the EHR and CDS. Semi-structured interviews were conducted with 24 PCPs who use the GWA in a network of community-based practices. Four main themes regarding GWA implementation emerged: benefits to clinical care, challenges in practice, CDS-specific issues, and physician-recommended improvements. Sub-themes included value in improving patient access to genetic services, inadequate time to discuss GWA recommendations, lack of patient follow-through with recommendations, and alert fatigue. While PCPs valued the GWA's clinical utility, a number of challenges were identified in the administration and use of the GWA in practice. Based on participants' recommendations, iterative changes have been made to the GWA and workflow to increase efficiency, upgrade the CDS process, and provide additional education to PCPs and patients. Future studies are needed to assess a diverse sample of physicians' and patients' perspectives on the utility of FHH screening utilizing EHR-based genomics recommendations. [ABSTRACT FROM AUTHOR]

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing. Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite's secretory pathway, affecting protein trafficking and export. [ABSTRACT FROM AUTHOR]

This article reviews existing research on the particular conditions of gender inequity, how it is formed, and what sustains it in academic contexts, and connects those studies to the context of Jewish Studies. It also discusses what we still need to know in order to try to address gender inequity thoroughly in Jewish Studies. Ambient and direct sexual and gender-based harassment, lack of senior women mentors, exclusion from collaboration opportunities, gender stereotyping concerning personality and maternal duties, poor institutional policies, and lack of enforcement of existing nondiscrimination and anti-harassment policies all contribute to a leaking pipeline, that is, a dearth of women in senior academic positions compared to the number who enter academia. Academic Jewish Studies is unique in its overlap with Jewish religious and communal organizations; reform in one area must go hand-in-hand with the others. Areas for further research are suggested. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: Our aim was to determine whether postoperative telephone follow-up was noninferior to in-person clinic visits based on patient satisfaction. Secondary outcomes were safety and clinical outcomes. Methods: Women scheduled for pelvic surgery were recruited from a single academic institution and randomized to clinic or telephone follow-up. The clinic group returned for visits 2, 6, and 12 weeks postoperatively and the telephone group received a call from a nurse at the same time intervals. Women completed the Consumer Assessment of Healthcare Providers and Systems Surgical Care Survey (S-CAHPS) questionnaire, Pelvic Floor Distress Inventory (PFDI)-20, and pain scales prior to and 3 months postoperatively. Randomized patients who completed the S-CAHPS at 3 months were included for analysis. Sample size calculations, based on a 15% noninferiority limit in the S-CAHPS global assessment surgeon rating, required 100 participants, with power = 80% and alpha = 0.025. Results: From October 2016 to November 2017, 100 participants were consented, underwent surgery, were randomized, and included in the final analysis (clinic group n = 50, telephone group n = 50). Mean age was 58.5 ± 12.2 years. Demographic data and surgery type, dichotomized into outpatient and inpatient, did not differ between groups. The S-CAHPS global assessment surgeon rating from patients in the telephone group was noninferior to the clinic group (92 vs 88%, respectively, rated their surgeons 9 and10, with a noninferiority limit of 36.1; p = 0.006). Adverse events did not differ between groups (n = 26; 57% fclinic vs 43% telephone; p = 0.36). Patients in the telephone group did not require additional emergency room or primary care visits. Clinical outcome measures improved in both groups, with no differences (all p > 0.05). Conclusions: Telephone follow-up after pelvic floor surgery results in noninferior patient satisfaction, without differences in clinical outcomes or adverse events. Telephone follow-up may improve healthcare quality and decrease patient and provider burden for postoperative care. Clinical trial registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02891187. [ABSTRACT FROM AUTHOR]

Natural turfgrass sports field properties exhibit within-field variations due to foot traffic from play, field construction, management, and weather. Little is known about the influences these variations may have on athletes' perceptions of field playability and injury risk. Information regarding athletes' perceptions of within-field variability could be fundamental for identifying key surface properties important to athletes, which may also be useful for the progression and implementation of Precision Turfgrass Management on sports fields. A case study using mixed methods was conducted on a recreational-level turfgrass sports field to better understand athletes' perceptions of within-field variability. Geo-referenced normalized difference vegetation index, surface hardness, and turfgrass shear strength data were obtained to create hot spot maps for identification of significant within-field variations. Walking interviews were conducted in situ with 25 male and female collegiate Club Sports rugby and ultimate frisbee athletes to develop knowledge about athletes' perceptions of within-field variability. Field data, hot spot maps, and walking interview responses were triangulated to explore, compare, and validate findings. Athletes' perceptions of within-field variability generally corresponded with measured surface properties. Athletes perceived within-field variations of turfgrass coverage and surface evenness to be most important. They expressed awareness of potential influences the variations could have, but not all athletes made behavior changes. Those who reported changing did so with regard to athletic maneuvers and/or strategy, primarily for safety or context of play. Spatial maps of surface properties that athletes identified could be used for Precision Turfgrass Management to potentially improve perceptions by mitigating within-field variability. [ABSTRACT FROM AUTHOR]

Purpose: Mutation of the CLN3 gene, associated with juvenile neuronal ceroid lipofuscinosis, has recently been associated with late-onset, non-syndromic retinal dystrophy. Herein we describe the multimodal imaging, immunological and systemic features of an adult with compound heterozygous CLN3 mutations.Methods: A 50-year-old female with non-syndromic retinal dystrophy from the age of 36 years underwent multimodal retinal imaging, electroretinography, neuroimaging, immunological studies and genetic testing. CLN3 transcripts were amplified from patient leukocytes by reverse transcriptase polymerase chain reaction and characterized by Sanger sequencing.Results: Visual acuity declined to 6/12 and 6/76 due to asymmetrical central scotoma. ERG responses became electronegative and patient's serum contained anti-retinal antibodies. Final visual acuity stabilized at 6/60 bilaterally 3 years after peri-ocular steroid and rituximab infusion. Genetic testing revealed compound heterozygous CLN3 mutations: the 1.02 kb deletion and a novel missense mutation (c.175G>A). In silico, analyses predicted the c.175G>A mutation disrupted an exonic splice enhancer site in exon 3. In patient leukocytes, CLN3 expression was reduced and novel CLN3 transcripts lacking exon 3 were detected.Conclusions: Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene. Overall, we provide comprehensive clinical characterization of a patient with non-syndromic CLN3 disease. [ABSTRACT FROM AUTHOR]

Purpose: Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood-brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge.Methods: We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E-selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants' global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates.Results: Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P = 0.008; P = 0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P = 0.02). Higher E-selectin was associated with worse global cognition (P = 0.006 at 3 months; P = 0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P = 0.05) and E-selectin (P = 0.02) were associated with increased disability in ADLs at 3 months.Conclusions: S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury. [ABSTRACT FROM AUTHOR]

Farm to School (FTS) programs aim to connect school children with local foods, to promote a synergistic relationship between local farmers, child nutrition and education goals, and community development. Drawing from 18 months of ethnographic research with a regional FTS project and interviews with child nutrition program operators (POs) implementing FTS across Georgia, we identify perceptions of food safety as an emerging barrier in efforts to bring local foods into schools. Conducting a thematic analysis of data related to food safety, we find that FTS participation may be hindered by discourses and perceptions of safety risks attributed to local foods-and to local produce in particular. We argue that this results, paradoxically, from a core tenant of FTS and other local food movements: forging personal relationships with farmers, through which POs confront the transparency of local food production, in contrast to the opacity of food procured through standard supply chains. Faced with unfamiliar production practices, and responsibilized to protect students as 'at risk' subjects, POs may decide that buying local food is 'not worth the risk.' [ABSTRACT FROM AUTHOR]

The Genetic Counseling Pre-Conference Workshop (GCPCW) was held on September 16, 2015, in Hanoi, Vietnam. We report the GCPCW outcomes obtained from pre- and post-conference questionnaires, case-review breakout session, and an open discussion of needs for genetic counseling services in the Asia region. The GCPCW participants completed questionnaires with closed- and open-ended questions regarding the status and needs of providing genetic counseling services in Asia. Utilizing thematic content analysis, common themes shared during the case-review breakout session are summarized and survey results are tabulated. Of the 71 participants, pre- and post-conference questionnaires were returned by 57 (80%) and 44 (62%) individuals, respectively. Of the 42 participants who did not identify themselves as students in training, 36 (86%) stated they are currently providing genetic counseling services. Participants cited that the most useful information obtained during the GCPCW related to the status of genetic counseling services in the region, discovery of shared challenges, professional networking, and the need to establish genetic counseling training programs and its accreditation. The GCPCW provided a collaborative forum to address current challenges and needs of genetic counseling services in the region. Strategies were identified to foster genetic counseling training and clinical service opportunities. [ABSTRACT FROM AUTHOR]

This publication presents the combination of the one-loop matrix-element generator Recola with the multipurpose Monte Carlo program Sherpa. Since both programs are highly automated, the resulting Sherpa + Recola framework allows for the computation of - in principle - any Standard Model process at both NLO QCD and EW accuracy. To illustrate this, three representative LHC processes have been computed at NLO QCD and EW: vector-boson production in association with jets, off-shell $$\mathrm{Z}$$ -boson pair production, and the production of a top-quark pair in association with a Higgs boson. In addition to fixed-order computations, when considering QCD corrections, all functionalities of Sherpa, i.e. particle decays, QCD parton showers, hadronisation, underlying events, etc. can be used in combination with Recola. This is demonstrated by the merging and matching of one-loop QCD matrix elements for Drell-Yan production in association with jets to the parton shower. The implementation is fully automatised, thus making it a perfect tool for both experimentalists and theorists who want to use state-of-the-art predictions at NLO accuracy. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: To assess the differences in patient-reported, catheter-specific satisfaction and quality of life with either suprapubic or transurethral postoperative bladder drainage following reconstructive pelvic surgery. Methods: This was a prospective study of all eligible women who were scheduled to undergo reconstructive surgery requiring bladder drainage during the study period November 2013 to March 2015. Women who did not undergo the planned procedure(s) or did not require bladder drainage were excluded. The primary outcome was patient-reported quality of life using catheter-specific instruments including the Catheter-related Quality of Life (CIQOL) instrument, and a modified version of the Intermittent Self-Catheterization Questionnaire (ISC-Q), designed to evaluate aspects of catheter-related quality of life and satisfaction specific to the needs of the individual. Results: A total of 178 women were analyzed, 108 in the transurethral catheter group and 70 in the suprapubic group. Women with suprapubic bladder drainage had higher quality of life and satisfaction scores than women with transurethral bladder drainage as measured by the ISC-Q (68.31 ± 16.87 vs. 54.04 ± 16.95, mean difference 14.27, 95 % CI 9.15 - 19.39). There was no difference in quality of life by the CIQOL. After regression analysis, women with suprapubic bladder drainage were more satisfied with their catheter-specific needs despite longer duration of catheter use, more concurrent continence surgery, and higher trait anxiety. Conclusions: Differences in catheter-specific quality of life and patient satisfaction scores favoring suprapubic bladder drainage support its continued use in appropriately selected women for treatment of temporary postoperative urinary retention after reconstructive pelvic surgery. [ABSTRACT FROM AUTHOR]

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Passage of the DSHEA in 1994 created a new "liminal" category for the FDA: dietary supplements are regulated as neither food nor drugs. However, there appears to be a significant disconnect between the "official" discourse surrounding dietary supplements and supplement users' actual practices. Despite this discrepancy, and the inadequacy of surveys to capture the dynamics of pharmaceutical practice, there is little ethnographic information available on the ways that Americans think about or use dietary supplements. We offer some preliminary observations from a pilot ethnographic study of Americans' use of dietary supplements in which we consider not only the reasons why people are using supplements, but how they are using them, and how their experimentation has been influenced by the information they seek and receive from a variety of sources. We illustrate how anthropological studies of supplement related practice can help us better understand Americans' attraction to and use of dietary supplements, and suggest that anthropology can contribute to a more balanced perspective on supplement use-one that moves the study of supplements beyond surveys and randomized controlled studies of efficacy to considerations of patterns of use in context, user expectations, and measures of perceived effectiveness. [ABSTRACT FROM AUTHOR]

The assignment of pathogenicity to variants suspected of causing an inherited retinal disease and the subsequent creation of molecular genetic reports sent to clinical geneticists and ophthalmologists has traditionally been time-consuming and subject to error and ambiguity. The purpose of this paper is to describe a computer-assisted method we have developed for (1) assessment of the predicted pathogenicity of genetic variants identified in patients diagnosed with an inherited retinal disease and (2) the incorporation of these results into the Australian Inherited Retinal Disease Register and DNA Bank's databases, for the production of molecular genetics reports. This method has significantly accelerated the assessment of variant pathogenicity prediction and subsequent patient report generation for the Australian Inherited Retinal Disease Register and DNA Bank, and has reduced the potential for human error. The principles described in this paper may be applied in any situation where genetic variants and patient information are stored in a well-organised database. [ABSTRACT FROM AUTHOR]

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22 % at entry ( N = 1,251) and was associated ( p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17 % by week 96 ( p = 0.0002) following similar trends in all study groups ( p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29 % ( p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB ( p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment. [ABSTRACT FROM AUTHOR]

Aim: Rho-associated kinase (ROCK) signaling regulates numerous fundamental developmental processes during embryogenesis, primarily by controlling actin-cytoskeleton assembly and cell contractility. ROCK knockout mice exhibit a ventral body wall defect (VBWD) phenotype due to disorganization of actin filaments at the umbilical ring. However, the exact molecular mechanisms leading to VBWD still remain unclear. Improper somitogenesis has been hypothesized to contribute to failure of VBW closure. We designed this study to investigate the hypothesis that administration of ROCK inhibitor (Y-27632) disrupts cytoskeletal arrangements in morphology during early chick embryogenesis, which may contribute to the development of VBWD.Methods: At 60 h incubation, chick embryos were explanted into shell-less culture and treated with 50 µL of vehicle for controls (n = 33) or 50 µL of 500 µM of Y-27632 for the experimental group (Y-27, n = 56). At 8 h post-treatment, RT-PCR was performed to evaluate mRNA levels of N-cadherin, E-cadherin and connexin43. Immunofluorescence confocal microscopy was performed to analyze the expression and distribution of actin, vinculin and microtubules in the neural tube and somites. A further cohort of embryos was treated in ovo by dropping 50 µL of vehicle or 50 µL of different concentrations of Y-27632 onto the embryo and allowing development to 12 and 14 days for further assessment.Results: Gene expression levels of N-cadherin, E-cadherin and connexin43 were significantly decreased in treated embryos compared with controls (p < 0.05). Thickened actin filament bundles were recorded in the neural tube of Y-27 embryos. In somites, cells were dissociated with reduced actin distribution in affected embryos. Clumping of vinculin expression was found in the neural tube and somites, whereas reduced expression of microtubules was observed in Y-27 embryos compared with controls. At 12 and 14 days of development, affected embryos presented with an enlarged umbilical ring and herniation of abdominal contents through the defect.Conclusion: ROCK inhibition alters cytoskeletal arrangement during early chick embryogenesis, which may contribute to failure of anterior body wall closure causing VBWD at later stages of development. [ABSTRACT FROM AUTHOR]

Cognitive impairment is common in patients with the neurodegenerative tauopathy progressive supranuclear palsy (PSP). Although a pattern of 'subcortical' cognitive impairment is considered prototypical in PSP, pathological and clinical observations suggest an overlap with frontotemporal dementia (FTD). Our objective was to evaluate behavioural and cognitive symptoms in a retrospective study of patients with PSP syndrome (PSPS) and their relationship to features seen in behavioural variant FTD. We reviewed the records of 62 patients (29 male, 33 female, median age 65.5 years) evaluated at a tertiary cognitive clinic who met NINDS-SPSP criteria for probable or possible PSP, and collected clinical details of their presenting history, cognitive and behavioural features. We also evaluated the proportion of patients fulfilling FTD Consensus criteria. Cognitive and behavioural symptoms were a predominant presenting feature in 58 % of patients evaluated. Cognitive slowing, executive impairments, and inefficient memory recall, consistent with 'subcortical' impairment, were identified in the majority of patients. Twenty patients (32 %) fulfilled cognitive and behavioural criteria for possible FTD at initial assessment, whereas behavioural changes not meeting formal diagnostic criteria were present in a greater proportion of the patients. Our findings support the existence of a spectrum of cognitive-behavioural features in PSPS, with significant clinical overlap with behavioural variant FTD. Cognitive and behavioural profiling should be an integral part of the assessment of patients with PSPS. [ABSTRACT FROM AUTHOR]

Purpose: When implementing affirmative action programs involving race and gender, human resource practitioners must balance efforts to increase workforce diversity against the need to avoid illegal reverse discrimination. The tension between non-discrimination law and preferential treatment is explored. In reverse discrimination case law, affirmative action plans are evaluated by judges along two dimensions: remedial need and limiting harm. The legal literature specifies certain factors such as statistical imbalance, employee qualification, and duration of plan that are usually examined within these two dimensions. Methodology: A content analysis of 80 federal court cases was conducted to quantitatively analyze the weight and importance of these factors within judicial rulings as well as contextual factors (e.g., judge’s political affiliation, beneficiary of program) that may influence the outcome of affirmative action lawsuits. Results: It was found that remedial need can be demonstrated by large statistical disparities in the workforce, and was also more likely to be found by Democratic than Republican judges. Limiting harm is more likely to be supported by plans that are of limited duration and do not use reserved slots, or quotas. Implications: The study provides empirically based recommendations for the design of legally defensible affirmative action plans that involve preferential treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hospital discharge planning is required as a Medicare Condition of Participation (CoP), and is essential to the health and safety for all patients. However, there have been no studies examining specific hospital discharge processes, such as patient education and communication with primary care providers, in relation to hospital 30-day risk standardized mortality rates (RSMRs) for patients with acute myocardial infarction (AMI). OBJECTIVE: To identify hospital discharge processes that may be associated with better performance in hospital AMI care as measured by RSMR. DESIGN: We conducted a qualitative study of U.S. Hospitals, which were selected based on their RSMR reported by the Centers for Medicare & Medicaid Services (CMS) Hospital Compare website for the most recent data available (January 1, 2005 - December 31, 2007). We selected hospitals that ranked in the top 5 % and the bottom 5 % of RSMR for the two consecutive years. We focused on hospitals at the extreme ends of the range in RSMR, known as deviant case sampling. We excluded hospitals that did not have the ability to perform percutaneous coronary intervention in order to decrease the heterogeneity in our sample. PARTICIPANTS: Participants included key hospital clinical and administrative staff most involved in discharge planning for patients admitted with AMI. METHODS: We conducted 14 site visits and 57 in-depth interviews using a standard discussion guide. We employed a grounded theory approach and used the constant comparative method to generate recurrent and unifying themes. KEY RESULTS: We identified five broad discharge processes that distinguished higher and lower performing hospitals: 1) initiating discharge planning upon patient admission; 2) using multidisciplinary case management services; 3) ensuring that a follow-up plan is in place prior to discharge; 4) providing focused education sessions for both the patient and family; and 5) contacting the primary care physician regarding the patient's hospitalization and follow-up care plan. CONCLUSION: Comprehensive and more intense discharge processes that start on admission continue during the patient's hospital stay, and follow up with the primary care physician within 2 days post-discharge, may be critical in reducing hospital RSMR for patients with AMI. [ABSTRACT FROM AUTHOR]

Introduction: Administration of cadmium (Cd) after 60 h (H) incubation induces ventral body wall defect (VBWD) similar to the omphalocele phenotype in the chick embryo. In this model, the earliest histological changes have been observed in somites commencing at 4-h post-treatment (4H). The molecular mechanism by which Cd acts in this critical period of embryogenesis still remains unclear. Sonic hedgehog (SHH) signalling plays an important role in vertebrate development, including somitogenesis and thus ventral body wall formation. Patched (PTCH), a cell membrane receptor for SHH, is expressed in somites and Patched knockout mice display somite dysfunction. Another transmembrane receptor, Smoothened (SMO), is also expressed in somites and transduces the SHH signal regulated by PTCH. We designed this study to test the hypothesis that SHH signalling is downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model. Methods: After 60 h of incubation, chicks were exposed to either chick saline or 50 μL of 50 μM cadmium acetate and divided into two groups: control and Cd ( n = 24 for each group). Chicks were harvested 1, 4, and 8 h post-treatment. Real-time RT-PCR was performed to evaluate the relative mRNA expression level of SHH, PTCH and SMO. Immunofluorescence confocal microscopy was then performed to evaluate protein expression/distribution of SHH, PTCH and SMO. Results: The relative mRNA expression levels of SHH, PTCH and SMO were significantly downregulated in the Cd group compared to controls at 4H post treatment, whereas, there were no significant differences at the other time points. Immunohistochemistry revealed that the intensity of SHH, PTCH and SMO was markedly diminished at 4 h in Cd-treated embryos compared to controls. Conclusion: Disturbance of the SHH signalling pathway as evidenced by SHH, PTCH and SMO downregulation during the narrow window of early embryogenesis may result in somite maldevelopment, contributing to the omphalocele phenotype in the Cd chick model. [ABSTRACT FROM AUTHOR]

Aim: In chick embryos, administration of cadmium (Cd) induces ventral body wall defects (VBWD) similar to human omphalocele. It has been shown that failure of proper VBW formation may be due to disruption of somite development during early embryogenesis. In the VBWD chick model, Cd causes abnormal cell death in the somitic region resulting in improperly developed somites and tortuosity of the neural tube. However, the exact molecular mechanisms leading to VBWD still remain unclear. Wnt signaling is crucial during embryogenesis and plays a key role in normal somite formation. The Rho-associated coiled-coil containing protein kinase (ROCK) is involved in the non-canonical Wnt pathway which controls actin cytoskeleton assembly and cell contractility, and contributes to several developmental processes including somitogenesis. ROCK gene expression levels have recently been reported to be significantly decreased in the Cd-induced VBWD chick model. We designed this study to investigate the hypothesis that administration of ROCK inhibitor (Y-27632) in the absence of Cd disrupts somitogenesis and could contribute to the development of VBWD during early embryogenesis. Methods: After 60 h of incubation chick embryos were transferred from eggs to culture dishes containing 20 μM of Y-27632 for experimental group (Y-27, n = 22) or chick saline for controls ( n = 14). Following 24 h in the incubator they were assessed for stage development and gross abnormalities in morphology using the dissecting microscope. Western blot was performed to confirm Y-27632 inhibition of ROCK downstream signaling using an antibody against phosphorylated cofilin-2. Results: 20 (90.9 %) embryos from Y-27 group and all controls were alive at examination. Morphological abnormalities were detected in 14 (70 %) Y-27 embryos. Somites appeared improperly developed, flattened in the cranio-caudal direction, and elongated in transverse direction in relation to controls. Chick embryos in Y-27 also presented with tortuosity of the neural tube in the lumbosacral region. Western blot analysis showed inhibition of cofilin-2 phosphorylation in affected embryos in comparison to controls. Conclusion: Our study provides evidence that ROCK inhibitor results in the disruption of normal somitogenesis in chick embryos which may contribute to the failure of fusion of the anterior abdominal wall causing VBWD. [ABSTRACT FROM AUTHOR]

Purpose: To assess the associations between a priori-selected markers of inflammation and coagulation and delirium during critical illness. Methods: In this prospective cohort study, we collected blood from mechanically ventilated medical intensive care unit (ICU) patients and measured nine plasma markers of inflammation and coagulation. We assessed patients daily for delirium using the Confusion Assessment Method for the ICU and used multivariable regression to analyze the associations between plasma markers and subsequent delirium, after adjusting for age, severity of illness, and sepsis. Results: Among the 138 patients studied, with median age of 66 years and median Acute Physiology and Chronic Health Evaluation (APACHE) II of 27, 107 (78 %) were delirious at some point during the study. Two markers of inflammation and one of coagulation were significantly associated with delirium. After adjusting for covariates, lower plasma concentrations of matrix metalloproteinase-9 (MMP-9) and protein C were associated with increased probability of delirium ( p = 0.04 and 0.01, respectively), and higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were associated with increased probability of delirium ( p < 0.01). Concentrations of C-reactive protein ( p = 0.82), myeloperoxidase ( p = 0.11), neutrophil gelatinase-associated lipocalin ( p = 0.70), D-dimer ( p = 0.83), plasminogen activator inhibitor type 1 ( p = 0.98), and Von Willebrand factor antigen ( p = 0.65) were not associated with delirium. Conclusions: In this study, MMP-9, protein C, and sTNFR1 were independently associated with subsequent ICU delirium. These results suggest that specific aspects of inflammation and coagulation may play a role in the evolution of delirium during critical illness and that these markers should be examined in larger studies of ICU patients. [ABSTRACT FROM AUTHOR]

This article identifies activity-related changes to, traumatic injuries on, and pathological conditions of the human remains of the Chinese immigrants from Carlin, Nevada, who were interred between 1885 and 1923. Chinese males came to the Americas to work as railroad laborers and miners, and when the railroad was completed many went home, but some found work in small towns. In Carlin, Chinese immigrants were employed as merchants, shopkeepers, cooks, laundry workers, and a variety of other occupations. Within this immigrant group, there were differences in the degree of physical labor each individual experienced. According to historical records, this was a time of increasing anti-Chinese sentiments, and there are accounts of intergroup conflict with the politically dominant settlers. However, little is known about the biological correlates of this sociopolitical inequality. An analysis of these correlates is assessed as a means for understanding patterns of social, economic, and political inequality between these immigrants and the local population. The findings demonstrate that socioeconomic and political inequality experienced by the Carlin individuals resulted in high rates of activity-induced changes, trauma, and pathological conditions. Furthermore, examination of the relationship between cranial trauma and other types of skeletal injuries supports research that has shown trauma to the head can predispose people to other types of trauma (accidental or deliberate). The results support the historical accounts of the time that indicate hard physical labor, accidental or deliberate trauma, and interpersonal conflict were part of the life history of this group of Chinese immigrants. [ABSTRACT FROM AUTHOR]

Purpose: Although the precise pathogenesis of ventral body wall (VBW) defects is not clearly understood, it has recently postulated that disruption of somite development during early embryogenesis may cause failure of proper VBW formation. The administration of cadmium (Cd) after 60 h of incubation induces omphalocele spectrum in the chick embryo. Previous studies have shown that one of the earliest histological changes seen in this model is abnormal cell death in the somite, occurring at 4 h post treatment (4H). However, the molecular mechanism by which Cd acts in this critical period of embryogenesis still remains unclear. Presenilins are expressed in somites and play an important role in vertebrate development, including somitogenesis and thus VBW formation. We designed this study to test the hypothesis that gene expression levels of presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele in the chick model. Methods: After 60 h of incubation, chick embryos were exposed to either saline or 50 μM cadmium and divided into two groups: control and Cd ( n = 8 at each time point for each group). Real-time RT-PCR was performed to evaluate the relative mRNA expression levels of PSEN1 and PSEN2 in the Cd-induced omphalocele chick model. Differences between two groups at each time point were analysed statistically and the significance was accepted at p < 0.05. Immunofluorescence confocal microscopy was performed to evaluate the protein expression/distribution of presenilins in the somite of chick embryo. Results: The relative mRNA expression levels of PSEN1 and PSEN2 were significantly downregulated in the Cd group at 4H compared with controls ( p < 0.005) (Table). However, there were no significant differences at the other time points. At 4H, immunofluorescence of presenilins (green) was markedly diminished in the Cd-treated embryos, whereas strong immunofluorescence of them was seen in the somite (dermomyotome) in controls (Fig. 1).[Figure not available: see fulltext.] Conclusion: We provide evidence, for the first time, that gene expression of presenilins is downregulated during the narrow window of very early embryogenesis in the Cd chick model. Decreased expression of presenilins may contribute to omphalocele phenotype in Cd chick model, by disrupting somite development. [ABSTRACT FROM AUTHOR]

TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common ( p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without ( p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation ( p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present. [ABSTRACT FROM AUTHOR]

This study aimed to determine the effect of varying degrees of intermittent umbilical cord occlusion (UCO) on arterial elastin composition. Over 4 days, chronically catheterized late gestation fetal sheep received 5 total UCO per day lasting 1 min/h (mild group: n = 6), 2 min/h (moderate group: n = 4), 3 min/h (severe group; n = 6); or no occlusion (control group: n = 7). Each group was evaluated for elastin content of the carotid and superior mesenteric artery (SMA), the arterial pressure response to UCO, and plasma cortisol concentration. Elastin content of the carotid artery was significantly increased by severe UCO (9.5 µg/mg versus 6.4 µg/mg; P < .05) and insignificantly increased in mild and moderate groups, whereas UCO had no effect on elastin content of the SMA. This dose- and site-dependent response of the vasculature appears attributable to the hemodynamic changes that accompany UCO. [ABSTRACT FROM PUBLISHER]

The evolution of modern human life history has involved substantial changes in the overall length of the subadult period, the introduction of a novel early childhood stage, and many changes in the initiation, termination, and character of the other stages. The fossil record is explored for evidence of this evolutionary process, with a special emphasis on middle childhood, which many argue is equivalent to the juvenile stage of African apes. Although the 'juvenile' and 'middle childhood' stages appear to be the same from a broad comparative perspective, in that they begin with the eruption of the first molar and the achievement of the majority of adult brain size and end with sexual maturity, the detailed differences in the expression of these two stages, and how they relate to the preceding and following stages, suggest that a distinction should be maintained between them to avoid blurring subtle, but important, differences. [ABSTRACT FROM AUTHOR]

Purpose: In the chick embryo, administration of cadmium (Cd) induces omphalocele phenotype. The earliest histological changes in this model are observed commencing at 4-h post treatment (4H). The molecular mechanisms by which Cd acts during the critical period of embryogenesis remain unclear. Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) regulate many fundamental biological processes and are involved in various embryonic morphogenesis, including ventral body wall (VBW) formation. Homozygous BMP1 mutant mice cause VBW defects. It has been reported that BMPR1A conditional knockouts also exhibit omphalocele phenotype. We designed this study to test the hypothesis that gene expression levels of BMP1 and BMPR1A are downregulated during the critical period of embryogenesis in the Cd chick model.Methods: After 60-h incubation, chick embryos were exposed to either Cd or saline and then harvested 1H, 4H and 8H. Chicks were divided into control (n = 24) and Cd (n = 24). RT-PCR was performed and differences between the two groups were tested statistically (significance was accepted at p < 0.05). Immunohistochemical study was also performed to evaluate those proteins expression/distribution.Results: The gene expression levels of BMP1 and BMPR1A at 4H were significantly downregulated in Cd group compared to controls. Immunoreactivity of BMP1 and BMPR1A was also markedly decreased in Cd-treated embryos compared to controls.Conclusion: Disruption of BMPR1A-mediated BMP1 signalling during the narrow window of early embryogenesis may interfere with normal VBW formation, causing omphalocele phenotype in the Cd chick model. [ABSTRACT FROM AUTHOR]

Purpose: Although, recent studies have suggested that disruption of somitogenesis may be involved in ventral body wall (VBW) defects; the molecular mechanisms of VBW defects remain unclear. In the chick embryo, the administration of cadmium (Cd) induces VBW defects similar to the human omphalocele. In this model, the earliest histological change in the somite occurs commencing at 4 h post-Cd treatment (4 h). PITX2 is expressed in somites, and PITX2 mutants have been shown to display VBW defects. PITX2 interacts with lymphoid enhancer factor-1 (LEF1) to regulate somite myogenesis. We designed this study to investigate the hypothesis that PITX2 and LEF1 genes are downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model.Materials and Methods: Chick embryos were exposed to Cd or saline after 60 h incubation and harvested at 1, 4, and 8 h posttreatment. Chicks were then divided into two groups: control (n = 24), and Cd (n = 24). RT-PCR was performed and analyzed statistically (significant difference was accepted at p < 0.05). Immunohistochemistry was also performed to evaluate expression/distribution of those proteins.Results: The mRNA expression levels of PITX2 and LEF1 at 4 h were significantly decreased in the Cd group compared with controls, whereas there were no differences at the other time points. Immunoreactivity of those proteins at 4 h was also markedly decreased in somites in the Cd-treated embryos compared with controls.Conclusions: Downregulation of PITX2 and LEF1 genes may interfere with ventral body wall formation in Cd chick model causing omphalocele by disrupting somite myogenesis. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) is generally recognised as a disorder with presenile onset (that is before 65 years of age) with only occasional cases presenting later than this. We set out to determine what proportion of cases of FTLD had late onset of disease and whether such cases of FTLD had distinctive clinical and neuropathological features as compared to cases with presenile onset. Within a combined Manchester and Newcastle autopsy series of 117 cases with pathologically confirmed FTLD (109/117 cases also met Lund Manchester clinical criteria for FTLD), we identified 30 cases (onset age range 65-86 years), comprising 25% of all FTLD cases ascertained in these two centres over a 25-year period. Neuropathologically, the 30 elderly cases presented features of several FTLD histological subgroups [FTLD-TDP (types 1, 2 and 3, 19 cases (63%)], FLTD-tau [ MAPT, PiD and CBD, 10 cases (33%)] and FTLD-UPS (1 case), similar in range of phenotypes to that seen in the presenile group, though patients with MAPT, but not PGRN, mutation, or FUS pathology, were notably absent or fewer in the elderly group. Hippocampal sclerosis (HS) was present in 13/30 of the elderly FTLD cases (43%) compared with 14/79 (18%) ( P = 0.012) in the presenile FTLD patients. Lobar atrophy present in most of the younger patients was prominent in only 25% of the elderly subjects. Prospective and retrospective psychiatric and medical case note analysis showed that the majority of the elderly FTLD patients, like their younger counterparts, had behavioural features consistent with frontotemporal dementia. FTLD is common amongst elderly persons and all or most of the major clinical and histological subtypes present in younger individuals can be seen in the older group. [ABSTRACT FROM AUTHOR]

Purpose: Administration of heavy metal cadmium (Cd) after 60-h incubation induces omphalocele spectrum in the chick embryo. Although previous studies have shown that the earliest detectable histological changes in the chick Cd model occurs commencing at 4-h post-treatment (4H). However, the molecular mechanism by which Cd acts in the critical period of early embryogenesis still remains unclear. Zic3, a Gli superfamily transcription factor, is expressed in somites and plays an important role in vertebrate development, including somitogenesis and thus ventral body wall formation. Gli3 is also expressed in somites and interacts with Zic3 physically and functionally. It has been reported that Gli3 homozygous double mutants display omphalocele. Zic3 mutant mice have also been known to result in omphalocele phenotype. We designed this study to test the hypothesis that Gli3 and Zic3 gene expression is downregulated during the critical period of very early embryogenesis in the Cd-induced omphalocele in the chick model.Methods: After 60-h incubation, chick embryos were exposed to either saline or 50 μM cadmium and divided into two groups: control and Cd (n = 24 for each group). Real-time reverse transcription polymerase chain reaction was performed to evaluate the relative mRNA expression levels of Gli3 and Zic3 in the Cd-induced omphalocele chick model. Differences between the two groups at each time point were analyzed statistically and the significance was accepted at p < 0.05. Immunohistochemistry was also performed to evaluate the expression/distribution of those proteins in chick embryo.Results: The relative mRNA expression level of Gli3 and Zic3 was significantly decreased in the Cd group at 4H when compared with controls (p < 0.05). However, there were no significant differences at the other time points. At 4H, immunoreactivity of GLI3 and ZIC3 was also markedly decreased in Cd-treated embryos, whereas strong expression of them was seen in the somite in controls.Conclusion: We provide evidence, for the first time, that Gli3 and Zic3 gene expression is downregulated during the narrow window of very early embryogenesis in Cd chick model. Disruption of Gli3-Zic3 interaction in the critical period for ventral body wall formation may contribute to omphalocele phenotype in Cd chick model. [ABSTRACT FROM AUTHOR]

Purpose: In the chick embryo, administration of the heavy metal Cadmium (Cd) induces omphalocele phenotype. Cd is a potent inhibitor of antioxidant enzymes and causes accumulation of reactive oxygen species (ROSs) such as hydrogen peroxide. Previous work with the Cd chick model has demonstrated that increased levels of MDA, as a marker for oxidative stress, 24 h post Cd treatment (24H) are identical in chick embryos exposed to Cd. Furthermore, of the several antioxidants assessed, only N-acetylcysteine (NAC) has been shown to reduce MDA levels to control values in the Cd-treated chick embryo. However, the molecular mechanisms by which NAC acts to maintain oxidative stress in the Cd-induced ventral body wall defect chick model remains to be unclear. We designed this study to investigate the hypothesis that gene expression levels of antioxidant enzymes are downregulated in malformed embryos exposed to Cd compared to controls and to determine the effect of pre-treatment with NAC on the expression levels of genes encoding antioxidant enzymes.Methods: After 60 h incubation, chick embryos were pre-treated with NAC and exposed to either chick saline or Cd. Chicks were then harvested at 24H and divided into five groups: control, Cd group without malformation [Cd(-)], Cd group with malformation [Cd(+)], NAC + Cd(-) and NAC + Cd(+). Real-time PCR was performed to evaluate the relative mRNA expression levels of antioxidant enzymes, including superoxide dismutase (SOD)-1, SOD2, catalase (CAT) and glutathione peroxidase (GPX)-4. Differences between five groups were tested by Tukey-Kramer post-hoc test following one-way ANOVA. Statistical significance was accepted at p < 0.05. Immunohistochemistry was also performed to evaluate protein expression.Results: The mRNA expression levels of SOD2 and CAT were significantly decreased in Cd(+) as compared to controls, whereas there was no significant difference between controls and Cd(-) (p < 0.05 vs. controls). In addition, gene expression levels of SOD2 and CAT were significantly increased in NAC + Cd(-) as compared to Cd(+) and NAC + Cd(+) (p < 0.05 vs. controls). However, there were no significant differences in the expression levels of SOD1 and GPX4 among any groups. Increased immunoreactivity of SOD2 and CAT was also observed in NAC + Cd(-) as compared to Cd(+) and NAC + Cd(+).Conclusion: Our results suggest that SOD2 and CAT may play an important role in preventing Cd-induced teratogenesis. Prenatal treatment with drugs which can upregulate SOD2 and CAT transcripts may have a therapeutic potential in preventing omphalocele phenotype. [ABSTRACT FROM AUTHOR]

Purpose: In the chick embryo, administration of cadmium (Cd) induces omphalocele phenotype. HoxB2 and HoxB4, expressed in cell types that contribute to ventral body wall (VBW) formation, act together to mediate proper closure of the VBW, involving a key downstream transcription factor, Alx4. HoxB2 and HoxB4 knockout mice display VBW defects with specific downregulation of Alx4 gene expression, while homozygous Alx4 knockouts show omphalocele phenotype. Although the earliest histological changes in the Cd chick model occur commencing at 4H post treatment, the exact timing and molecular mechanism by which Cd acts is still unclear. We hypothesized that HoxB2, HoxB4 and Alx4 genes are downregulated during the critical timing of very early embryogenesis in the Cd-induced omphalocele chick model.Methods: After 60H incubation, chick embryos were harvested at 1H, 4H and 8H after treatment with saline or Cd and divided into controls and Cd group (n = 24 for each group). RT-PCR was performed to investigate the gene expression of HoxB2, HoxB4 and Alx4 and statistically analyzed (significance was accepted at p < 0.05). Immunohistochemical staining was also performed to evaluate the protein expression/distribution of HoxB2, HoxB4 and Alx4 in the chick embryo.Results: The expression levels of HoxB2, HoxB4 and Alx4 gene at 4H were significantly downregulated in the Cd group as compared to controls, whereas there were no significant differences at the other time points. Immunoreactivity of HoxB2, HoxB4 and Alx4 at 4H is also markedly decreased in the ectoderm and the dermomyotome in the Cd chick model as compared to controls.Conclusion: Downregulation of HoxB2, HoxB4 and Alx4 expression during the narrow window of early embryogenesis may cause omphalocele in the Cd chick model by interfering with molecular signaling required for proper VBW formation. Furthermore, these results support the concept that HoxB2, HoxB4 and Alx4 genes work together to mediate proper VBW formation. [ABSTRACT FROM AUTHOR]

The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs—one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma—by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance. [ABSTRACT FROM AUTHOR]