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In Alzheimer's disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus 1-3 . However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed "big tau" is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.

We investigated transmission dynamics of a large human immunodeficiency virus (HIV) outbreak among persons who inject drugs (PWID) in KY and OH during 2017-20 by using detailed phylogenetic, network, recombination, and cluster dating analyses. Using polymerase ( pol ) sequences from 193 people associated with the investigation, we document high HIV-1 diversity, including Subtype B (44.6 per cent); numerous circulating recombinant forms (CRFs) including CRF02_AG (2.5 per cent) and CRF02_AG-like (21.8 per cent); and many unique recombinant forms composed of CRFs with major subtypes and sub-subtypes [CRF02_AG/B (24.3 per cent), B/CRF02_AG/B (0.5 per cent), and A6/D/B (6.4 per cent)]. Cluster analysis of sequences using a 1.5 per cent genetic distance identified thirteen clusters, including a seventy-five-member cluster composed of CRF02_AG-like and CRF02_AG/B, an eighteen-member CRF02_AG/B cluster, Subtype B clusters of sizes ranging from two to twenty-three, and a nine-member A6/D and A6/D/B cluster. Recombination and phylogenetic analyses identified CRF02_AG/B variants with ten unique breakpoints likely originating from Subtype B and CRF02_AG-like viruses in the largest clusters. The addition of contact tracing results from OH to the genetic networks identified linkage between persons with Subtype B, CRF02_AG, and CRF02_AG/B sequences in the clusters supporting de novo recombinant generation. Superinfection prevalence was 13.3 per cent (8/60) in persons with multiple specimens and included infection with B and CRF02_AG; B and CRF02_AG/B; or B and A6/D/B. In addition to the presence of multiple, distinct molecular clusters associated with this outbreak, cluster dating inferred transmission associated with the largest molecular cluster occurred as early as 2006, with high transmission rates during 2017-8 in certain other molecular clusters. This outbreak among PWID in KY and OH was likely driven by rapid transmission of multiple HIV-1 variants including de novo viral recombinants from circulating viruses within the community. Our findings documenting the high HIV-1 transmission rate and clustering through partner services and molecular clusters emphasize the importance of leveraging multiple different data sources and analyses, including those from disease intervention specialist investigations, to better understand outbreak dynamics and interrupt HIV spread., Competing Interests: None declared., (Published by Oxford University Press 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Group-based parent training (PT) is an evidence-based approach for strengthening parenting skills and reducing child behavior problems. However, there has been little research on the social connectedness (SC) formed among PT participants, particularly in low-income communities where parents may be more socially isolated. This study describes SC formed among parents in a group-based PT program implemented in their children's school and its association with changes in child behavior. Using a convergent mixed-methods design, data collection occurred between 2020 and 2022. Parents ( n = 97) completed measures of their SC to other parents in their PT group and their child's behavior. Qualitative interviews with a representative subsample of parents ( n = 17) were also conducted to understand parents' perceptions and experiences of SC within their PT group. Parents reported high levels of SC ( M = 4.45 [range = 3.04-5 on scale of 1-5]; SD = 0.4). From baseline to postintervention, the number of children with child behavior problems significantly decreased (32.12%, 37.5% behavior intensity and problems, respectively). The magnitude of decline in child behavior problems was significantly related to parents' SC ( b = -11.52, p = .02, SE = 4.99). Qualitative data confirmed high levels of SC, which parents linked to improvements in their parenting and children's behavior. Themes focused on the building of connections, committing to a safe space with parents who share similar goals, supporting one another, and gaining connections within the school environment and during the COVID-19 pandemic. Results highlight the potential synergistic effects of SC formed in the context of group-based PT with implications for strengthening parenting skills and children's well-being. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Coronavirus Anxiety Scale (CAS) is a widely used measure that captures somatic symptoms of coronavirus-related anxiety. In a large-scale collaboration spanning 60 countries ( N total = 21,513), we examined the CAS's measurement invariance and assessed the convergent validity of CAS scores in relation to the fear of COVID-19 (FCV-19S) and the satisfaction with life (SWLS-3) scales. We utilized both conventional exact invariance tests and alignment procedures, with results revealing that the single-factor model fit the data well in almost all countries. Partial scalar invariance was supported in a subset of 56 countries. To ensure the robustness of results, given the unbalanced samples, we employed resampling techniques both with and without replacement and found the results were more stable in larger samples. The alignment procedure demonstrated a high degree of measurement invariance with 9% of the parameters exhibiting noninvariance. We also conducted simulations of alignment using the parameters estimated in the current model. Findings demonstrated reliability of the means but indicated challenges in estimating the latent variances. Strong positive correlations between CAS and FCV-19S estimated with all three different approaches were found in most countries. Correlations of CAS and SWLS-3 were weak and negative but significantly differed from zero in several countries. Overall, the study provided support for the measurement invariance of the CAS and offered evidence of its convergent validity while also highlighting issues with variance estimation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Immigrant Latinas are at higher risk for postpartum depression (PPD) than the general perinatal population, yet face numerous barriers to accessing mental health services. The goal of this study was to pilot an enhanced virtual group delivery of a PPD prevention program, Mothers and Babies (MB), among immigrant Latinas engaged in early childhood programming., Methods: Forty-nine Spanish-speaking mothers participated in one of four MB virtual groups, facilitated by trained bilingual staff at affiliated early learning centers. MB was enhanced to also target social determinants of health. A mixed-methods design was used to evaluate MB using participant interviews and pre-post surveys measuring depressive symptoms, parenting distress, and self-efficacy to manage emotions., Results: On average, participants attended 69% of MB virtual sessions and rated group cohesiveness at a 4.6 on a 5-point scale. Paired-samples t tests showed significant reductions in depressive symptoms (Cohen's d = 0.29; p = .03) and parenting distress (Cohen's d = 0.31; p = .02), and improved self-efficacy to manage emotions (Cohen's d = -0.58; p < .001). Participants reported both benefits and drawbacks of the virtual format and provided largely favorable feedback on program enhancements., Conclusions: Results provide initial evidence for the acceptability, feasibility, and effectiveness of an enhanced virtual group PPD prevention program for immigrant Latinas, delivered in partnership with local early learning centers. These findings have important implications for extending the reach of preventive interventions among a population that faces many structural and linguistic barriers to traditional forms of mental health service delivery., (Copyright © 2023 Jacobs Institute of Women's Health, George Washington University. Published by Elsevier Inc. All rights reserved.)

Childbearing people in the US have experienced the double burden of increased risks from infection and significant disruptions to access and quality of essential health care services during the COVID pandemic. A single person could face multiple impacts across the course of their reproductive trajectory. We highlight how failure to prioritize this population in the COVID-19 policy response have led to profound disruptions from contraception services to vaccination access, which violate foundational principles of public health, human rights and perpetuate inequities. These disruptions continued through the omicron surge, during which many health systems became overwhelmed and re-imposed earlier restrictions. We argue that an integrated pandemic response that prioritizes the healthcare needs and rights of childbearing people must be implemented to avoid deepening inequities in this and future pandemics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tomori, Penta and Richman.)

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length-dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.

Background: Previous studies suggest the rate of positive surgical margin (PSM) after lumpectomy for breast cancer is approximately 20 %. The risk of PSM at time of resection is often a source of fear for patients, driving some to elect to undergo mastectomy. This study describes rates and predictors of positive margins for invasive breast cancers in the National Cancer Database (NCDB)., Materials and Methods: From 2004 to 2013, patients with non-metastatic invasive breast cancers who underwent breast conservation surgery were identified from the NCDB. Patients' demographic, clinical, and facility of treatment characteristics were collected and compared. Per SSO-ASTRO-ASCO criteria, margin negative is defined as no gross or microscopic disease (i.e. no tumor on ink). Bivariate tests and multivariate logistic regression were conducted to identify independent predictors of patients with PSM at the time of resection., Results: A total of 707,798 patients were identified with non-metastatic invasive breast tumors who underwent lumpectomy. Rate of PSM across the entire cohort was 5.02 %. Over time, the rate of PSM decreased significantly from 6.54 % in 2004 to 3.91 % in 2013 (p < 0.001). Pure lobular histology predicted for the highest rate of PSM compared with IDC (8.63 vs 4.55 %; p < 0.001). In adjusted analysis, high grade, non-ductal histology and HER2 amplification were significantly associated with PSM with breast conservation while estrogen and progesterone status were not., Conclusion: This study demonstrates a 5 % risk of PSM at time of breast conservation surgery using a large, modern national database. Patients with invasive lobular and mixed histology have a nearly two-fold risk of PSM compared to invasive ductal cancers. These results provide important data points to help appropriately counsel patients regarding the risk of PSM., Competing Interests: Declaration of competing interest DHB declares research support, speaker honoraria, and consultant work from Novocure Inc. and Varian Medical Systems. No other authors declare conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous inherited neurodegenerative disorders characterized by progressive ataxia and cerebellar degeneration. Here, we used a mouse model to test a possible connection between SCA and Ronin (Thap11), a polyglutamine-containing transcriptional regulator encoded in a region of human chromosome 16q22.1 that has been genetically linked to SCA type 4. We report that transgenic expression of Ronin in mouse cerebellar Purkinje cells leads to detrimental loss of these cells and the development of severe ataxia as early as 10 weeks after birth. Mechanistically, we find that several SCA-causing genes harbor Ronin DNA-binding motifs and are transcriptionally deregulated in transgenic animals. In addition, ectopic expression of Ronin in embryonic stem cells significantly increases the protein level of Ataxin-1, the protein encoded by Atxn1, alterations of which cause SCA type 1. This increase is also seen in the cerebellum of transgenic animals, although the latter was not statistically significant. Hence, our data provide evidence for a link between Ronin and SCAs, and suggest that Ronin may be involved in the development of other neurodegenerative diseases., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Renal ectopia with stone is a rare case with no specific reported incidence rate. The treatment of kidney stone in ectopic kidneys poses a challenge to urologists. A 48-year-old male presenting with colicky pain on the right flank since one year ago. CT urography revealed an right-crossed renal ectopia and hyperdense lesions (25 × 20 mm and 10 × 10 mm) in the ureteropelvic junction of the right kidney. Under general anesthesia, we performed open pyelolithotomy for the patient and removed two stones completely. Open surgery could be the choice for patients with complex stone burden and associated renal anomalies such as ectopic kidney., (© 2020 The Authors. Published by Elsevier Inc.)

Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3's other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.

α-Synuclein (α-Syn) accumulation is a pathological hallmark of Parkinson's disease. Duplications and triplications of SNCA , the gene coding for α-Syn, cause genetic forms of the disease, which suggests that increased α-Syn dosage can drive PD. To identify the proteins that regulate α-Syn, we previously performed a screen of potentially druggable genes that led to the identification of 60 modifiers. Among them, Doublecortin-like kinase 1 (DCLK1), a microtubule binding serine threonine kinase, emerged as a promising target due to its potent effect on α-Syn and potential druggability as a neuron-expressed kinase. In this study, we explore the relationship between DCLK1 and α-Syn in human cellular and mouse models of PD. First, we show that DCLK1 regulates α-Syn levels post-transcriptionally. Second, we demonstrate that knockdown of Dclk1 reduces phosphorylated species of α-Syn and α-Syn-induced neurotoxicity in the SNc in two distinct mouse models of synucleinopathy. Last, silencing DCLK1 in human neurons derived from individuals with SNCA triplications reduces phosphorylated and total α-Syn, thereby highlighting DCLK1 as a potential therapeutic target to reduce pathological α-Syn in disease. SIGNIFICANCE STATEMENT DCLK1 regulates α-Syn protein levels, and Dclk1 knockdown rescues α-Syn toxicity in mice. This study provides evidence for a novel function for DCLK1 in the mature brain, and for its potential as a new therapeutic target for synucleinopathies., (Copyright © 2020 the authors.)

RNA splicing entails the coordinated interaction of more than 150 proteins in the spliceosome, one of the most complex of the cell's molecular machines. We previously discovered that the RNA-binding motif protein 17 (RBM17), a component of the spliceosome, is essential for survival and cell maintenance. Here, we find that it interacts with the spliceosomal factors U2SURP and CHERP and that they reciprocally regulate each other's stability, both in mouse and in human cells. Individual knockdown of each of the three proteins induces overlapping changes in splicing and gene expression of transcripts enriched for RNA-processing factors. Our results elucidate the function of RBM17, U2SURP, and CHERP and link the activity of the spliceosome to the regulation of downstream RNA-binding proteins. These data support the hypothesis that, beyond driving constitutive splicing, spliceosomal factors can regulate alternative splicing of specific targets., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chikungunya virus (CHIKV) originated in a sylvatic cycle of transmission between non-human animal hosts and vector mosquitoes in the forests of Africa. Subsequently the virus jumped out of this ancestral cycle into a human-endemic transmission cycle vectored by anthropophilic mosquitoes. Sylvatic CHIKV cycles persist in Africa and continue to spill over into humans, creating the potential for new CHIKV strains to enter human-endemic transmission. To mitigate such spillover, it is first necessary to delineate the distributions of the sylvatic mosquito vectors of CHIKV, to identify the environmental factors that shape these distributions, and to determine the association of mosquito presence with key drivers of virus spillover, including mosquito and CHIKV abundance. We therefore modeled the distribution of seven CHIKV mosquito vectors over two sequential rainy seasons in Kédougou, Senegal using Maxent., Methods: Mosquito data were collected in fifty sites distributed in five land cover classes across the study area. Environmental data representing land cover, topographic, and climatic factors were included in the models. Models were compared and evaluated using area under the receiver operating characteristic curve (AUROC) statistics. The correlation of model outputs with abundance of individual mosquito species as well as CHIKV-positive mosquito pools was tested., Results: Fourteen models were produced and evaluated; the environmental variables most strongly associated with mosquito distributions were distance to large patches of forest, landscape patch size, rainfall, and the normalized difference vegetation index (NDVI). Seven models were positively correlated with mosquito abundance and one (Aedes taylori) was consistently, positively correlated with CHIKV-positive mosquito pools. Eight models predicted high relative occurrence rates of mosquitoes near the villages of Tenkoto and Ngary, the areas with the highest frequency of CHIKV-positive mosquito pools., Conclusions: Of the environmental factors considered here, landscape fragmentation and configuration had the strongest influence on mosquito distributions. Of the mosquito species modeled, the distribution of Ae. taylori correlated most strongly with abundance of CHIKV, suggesting that presence of this species will be a useful predictor of sylvatic CHIKV presence.

Ongoing improvements in digital data acquisition and storage has led to the phenomenon of e(lectronic)-mortality, where digital data can now exist for a potentially infinite period. Globally, many countries are facilitating the acquisition and researcher-led access to large-scale, population-based digitised healthcare data sets. Their utilisation has led to numerous positive advances in healthcare. New Zealand's medical record system is becoming increasingly digitised, and as a consequence there will be an ever-increasing resource of posthumous healthcare data stored digitally, including genomic information. Such data could be utilised for research purposes, and developing such a consolidated resource could improve healthcare outcomes in our own nation and allow us to parallel global progress in healthcare research trends. This viewpoint article explores the issues surrounding, and potential for utilisation of, a national resource of posthumous digital healthcare data. Currently, there appear to be no legal barriers to the large-scale acquisition and utilisation of posthumous healthcare data in New Zealand, however, previous legislation may not have been developed with developments in technology or e-mortality in mind. Ethically, culturally and socially there are many challenges to address, including issues surrounding obtaining consent, respecting privacy, management of incidental findings, maintaining anonymity and ensuring community support for such a resource. Despite the potential for widespread health benefits that utilisation of posthumous healthcare data in this country may facilitate, wide and ongoing consultation is required to examine how such a precious resource can be enabled for the downstream benefit of all New Zealanders., Competing Interests: Miss Hoeksema reports grants from University of Otago Centre for Society, Governance and Science during the conduct of the study.

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

Aim: to learn the role of docetaxel in non-castrate resistant prostate cancer patient., Methods: literature search was conducted to find relevant study comparing the combination of docetaxel and androgen deprivation therapy (ADT) to ADT alone in non-castrate resistant prostate cancer using PubMed, Cohrane Library, Proquest, EBSCO, and Scopus database. Quality assessment of studies was done using Bond University Rapid Critical Appraisal of a Systematic Review., Results: we found 494 studies from literature search, but only two studies were included in final selection. Based on validity assessment, we chose one study to be discussed further. This study showed that combination of docetaxel and ADT is better than ADT alone in regards of overall survival (HR 0.64; 95% CI 0.55, 0.75; p<0.0001; NNT=3), biochemical progression free survival (HR 0.63; 95% CI 0.57, 0.69; p<0.0001; NNT=2) and clinical progression free survival (HR 0.73; 95% CI 0.64, 0.84; p<0.0001; NNT=2). Benefit of docetaxel and ADT combination was especially seen in high volume disease (HR 0.67; 95% CI 0.54, 0.83; p=0.0003; NNT=3)., Conclusion: addition of docetaxel into ADT has beneficial effects in terms of overall survival and progression free survival in patients with non-castrate resistant metastatic prostate cancer.

Body donor programs rely on the generosity and trust of the public to facilitate the provision of cadaver resources for anatomical education and research. The uptake and adoption of emerging technologies, including those allowing the acquisition and distribution of images, are becoming more widespread, including within anatomical science education. Images of cadavers are useful for research and education, and their supply and distribution have commercial potential for textbooks and online education. It is unclear whether the utilization of images of donated cadavers are congruent with donor expectations, societal norms and boundaries of established public understanding. Presently, no global "best practices" or standards exist, nor is there a common model requiring specific image-related consent from body donors. As ongoing success of body donation programs relies upon the ethical and institutional governance of body utilization to maintain trust and a positive relationship with potential donors and the community, discussions considering the potential impact of image misuse are important. This paper discusses the subject of images of donated cadavers, commenting on images in non-specific use, education, research, and commercial applications. It explores the role and significance of such images in the context of anatomical science and society, and discusses how misuse - including unconsented use - of images has the potential to affect donor program success, suggesting that informed consent is currently necessary for all images arising from donated cadavers. Its purpose is to encourage discussion to guide responsible utilization of cadaver images, while protecting the interests of body donors and the public., (© 2015 Wiley Periodicals, Inc.)

Previously, we reported that ATXN1 oligomers are the primary drivers of toxicity in Spinocerebellar ataxia type 1 (SCA1; Lasagna-Reeves et al., 2015). Here we report that polyQ ATXN1 oligomers can propagate locally in vivo in mice predisposed to SCA1 following intracerebral oligomeric tissue inoculation. Our data also show that targeting these oligomers with passive immunotherapy leads to some improvement in motor coordination in SCA1 mice and to a modest increase in their life span. These findings provide evidence that oligomer propagation is regionally limited in SCA1 and that immunotherapy targeting extracellular oligomers can mildly modify disease phenotypes.

Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded ATAXIN-1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1(154Q/+) mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.

Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized Cyfip2-mutant (Cyfip2(+/-)) mice. We found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1(-/y)) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in Cyfip2(+/-) hippocampus. However, dendritic spines were altered in Cyfip2(+/-) cortex, and the dendritic spine phenotype of Fmr1(-/y) cortex was aggravated in Fmr1(-/y); Cyfip2(+/-) double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Electromagnetic fields (EMF) permeate the built environment in different forms and come from a number of sources including electrical wiring and devices, wireless communication, 'energy-efficient' lighting, and appliances. It can be present in the indoor environment directly from indoor sources, or can be transmitted through building materials from outside sources. Scientists have identified it as an indoor environmental pollutant or toxin that has ubiquitously plagued developed nations causing a variety of adverse health effects such as sick-building syndrome symptoms, asthma, diabetes, multiple sclerosis, leukemia, electro-hypersensitivity (EHS), behavior disorders, and more. There is currently no international consensus on guidelines and exposure limits. This paper presents the results of 29 EMF field audits in single family residential dwellings located within an urban neighborhood in Toronto (Canada). The following EMF spectra were evaluated: radio frequency, power frequency electric fields, power frequency magnetic fields and high frequency voltage transients. The field audits were conducted in order to provide initial baseline statistics to be used in future studies and in order to be compared to a low-cost EMF reduction design incorporated within the Renovation2050 research house - located within the test neighborhood. The results show the low-cost reduction strategy to be effective, on average reducing exposure by 80% for high-intensity EMF metrics. Research of this nature has not been conducted with relation to the built environment and can be used to spark an industry movement to design for low-exposure to EMF in a residential context., (© 2013.)

Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis.

Background: Children with impulsive behavior and poor self regulation have been shown to have low parasympathetic tone. High vagal tone is associated with attention to novel stimuli., Objective: To study if Heart Rate Variability, an index of vagal tone, is a mediator of attention., Method: 77 children who performed a Continuous Performance test (TOVA test) had their EKG recorded for Heart Rate Variability Measurements. Subjects were assigned to groups according to their performance on the TOVA test and a general linear model for repeated measures applied. Pearson Correlations were applied for TOVA scores and HRV Values at four epochs., Results: No individual correlations were found between Attention Scores and HRV. However, there was a significant group difference showing that good performers had a higher "vagal" tone than poor performers., Conclusion: The parasympathetic system as measured through HRV is not a mediator of attention. HRV may be an indicator of better health and ability to self regulate.

Objective: There have been no objective assessments to determine whether boys with MECP2 duplication have autism or whether female carriers manifest phenotypes. This study characterizes the clinical and neuropsychiatric phenotypes of affected boys and carrier females., Methods: Eight families (9 males and 9 females) with MECP2 duplication participated. A detailed history, physical examination, electroencephalogram, developmental evaluation, Autism Diagnostic Observation Schedule, and Autism Diagnostic Interview-Revised were performed for each boy. Carrier females completed the Symptom Checklist-90-R, Wechsler Abbreviated Scale of Intelligence, Broad Autism Phenotype Questionnaire, and detailed medical and mental health histories. Size and gene content of each duplication were determined by array comparative genome hybridization. X-chromosome inactivation patterns were analyzed using leukocyte DNA. MECP2 and IRAK1 RNA levels were quantified from lymphoblast cell lines, and western blots were performed to assess MeCP2 protein levels., Results: All of the boys demonstrated mental retardation and autism. Poor expressive language, gaze avoidance, repetitive behaviors, anxiety, and atypical socialization were prevalent. Female carriers had psychiatric symptoms, including generalized anxiety, depression, and compulsions that preceded the birth of their children. The majority exhibited features of the broad autism phenotype and had higher nonverbal compared to verbal reasoning skills., Interpretation: Autism is a defining feature of the MECP2 duplication syndrome in boys. Females manifest phenotypes despite 100% skewing of X-inactivation and normal MECP2 RNA levels in peripheral blood. Analysis of the duplication size, MECP2 and IRAK1 RNA levels, and MeCP2 protein levels revealed that most of the traits in affected boys are likely due to the genomic region spanning of MECP2 and IRAK1. The phenotypes observed in carrier females may be secondary to tissue-specific dosage alterations and require further study. Ann Neurol 2009;66:771-782.

Porosities in the outer table of the cranial vault (porotic hyperostosis) and orbital roof (cribra orbitalia) are among the most frequent pathological lesions seen in ancient human skeletal collections. Since the 1950s, chronic iron-deficiency anemia has been widely accepted as the probable cause of both conditions. Based on this proposed etiology, bioarchaeologists use the prevalence of these conditions to infer living conditions conducive to dietary iron deficiency, iron malabsorption, and iron loss from both diarrheal disease and intestinal parasites in earlier human populations. This iron-deficiency-anemia hypothesis is inconsistent with recent hematological research that shows iron deficiency per se cannot sustain the massive red blood cell production that causes the marrow expansion responsible for these lesions. Several lines of evidence suggest that the accelerated loss and compensatory over-production of red blood cells seen in hemolytic and megaloblastic anemias is the most likely proximate cause of porotic hyperostosis. Although cranial vault and orbital roof porosities are sometimes conflated under the term porotic hyperostosis, paleopathological and clinical evidence suggests they often have different etiologies. Reconsidering the etiology of these skeletal conditions has important implications for current interpretations of malnutrition and infectious disease in earlier human populations., (Copyright 2009 Wiley-Liss, Inc.)

Purpose and Method: The authors surveyed U.S. and Canadian medical school deans regarding organizational climate for faculty, policies affecting faculty, processes deans use for developing faculty leadership, and the impact of the Executive Leadership in Academic Medicine (ELAM) Program for Women., Results: The usable response rate was 58% (n = 83/142). Deans perceived gender equity in organizational climate as neutral, improving, or attained on most items and deficient on four. Only three family-friendly policies/benefits were available at more than 68% of medical schools; several policies specifically designed to increase gender equity were available at fewer than 14%. Women deans reported significantly more frequent use than men (P = .032) of practices used to develop faculty leadership. Deans' impressions regarding the impact of ELAM alumnae on their schools was positive (M = 5.62 out of 7), with those having more fellows reporting greater benefit (P = .01). The deans felt the ELAM program had a very positive influence on its alumnae (M = 6.27) and increased their eligibility for promotion (M = 5.7)., Conclusions: This study provides a unique window into the perceptions of medical school deans, important policy leaders at their institutions. Their opinion adds to previous studies of organizational climate focused on faculty perceptions. Deans perceive the organizational climate for women to be improving, but they believe that certain interventions are still needed. Women deans seem more proactive in their use of practices to develop leadership. Finally, deans provide an important third-party judgment for program evaluation of the ELAM leadership intervention, reporting a positive impact on its alumnae and their schools.

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

As circumstances of conquest change, leaders of empires must adapt their colonial strategies in order to be successful. One example of such modification in approach is the shift from Middle Kingdom to New Kingdom Egyptian colonial activities in Nubia. During the Middle Kingdom (2050-1650 BC) Egypt used aggressive military campaigns to subdue the strong Nubian polity at Kerma, resulting in the construction of fortresses and many victory stelae. In the subsequent New Kingdom period (1550-1050 BC) during which the Egyptian administration succeeded in occupying nearly all of Nubia, changes were necessary in conquest strategies. Diplomacy and cooperation may have replaced military action as mechanisms of control. This article investigates changes in imperial policy through the examination of traumatic injuries in human skeletal remains. Patterns of injuries in a sample from the site of Tombos, an Egyptian colonial cemetery in Nubia dating to the New Kingdom period, are compared with data on the patterns of injuries from Kerma, a cemetery dating to the Middle Kingdom period, published by Judd (2004). Analysis indicates a decrease in the level of traumatic injuries from Kerma to Tombos supporting the idea that through time the Egyptian administration modified their colonial strategy toward more nonviolent means. This article presents data on differences in the patterns of injury at Tombos and Kerma and explores possible explanations for this variation.

Background: Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1(154Q/2Q) mice) that replicates many features of the human disease., Methods and Findings: Sca1(154Q/2Q) mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1(154Q/2Q) mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity., Conclusions: The effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.

A team of academic researchers, clinicians, prison administrators and undergraduate and graduate students came together to conduct an evaluation of a pre-release discharge planning program in a women's prison facility. This paper describes differences between academic and corrections systems, adaptations needed in order to work within the correctional system, pragmatic and ethical issues addressed by our team, and the joys and benefits we experienced doing the project. Team members who had not previously worked in a prison setting found it an extraordinary, transformative learning experience in spite of the challenges.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions.

Since the mid-1990s, the protection of human subjects through institutional review boards (IRBs) has progressively broadened in scope. In this case study, the authors describe their challenges in effectively handling IRB processes to conduct educational and social sciences research within academic health centers, particularly (1) complications in conducting longitudinal interinstitutional research that involves multiple IRBs, each with different procedures that changed over ten years; and (2) factors affecting consent form and survey response rates when applying the biomedical IRB process to obtain the consent of human subjects for participation in social and educational research. The authors had a unique opportunity to follow the effect of changes in consent forms (from no form to a one-page form to a three-page form requiring signature of a witness), ways of administration (in person or by mail), and time of administration (at the time of the program or years later) on consent form and survey response rates among medical and dental school faculty members. The authors explore the extended timelines required for data collection and increased costs in dealing with these issues, as well as the effects on response rates of consent form language and administration procedures. The authors recommend strategies to lessen adverse effects of dealing with multiple IRBs at different institutions for social science and educational research, and discuss policy implications for funders, institutions and investigators.

The origin and geographic distribution of syphilis, a form of treponemal infection, have long been regarded as among the most important medical riddles of prehistoric and historic disease evolution. In this study, we expand on previous discussions of the origin, evolution, and relationship of treponemal infections as they occur in the prehistoric southeastern United States. Individuals from 25 skeletal series (n = 2,410 individuals) were examined for cranial and dental lesions characteristic of treponemal infection. They lived between the Archaic period (8000-1000 BC) and protohistoric period (AD 1500-1600), and in physiographic zones from the coast to the mountains of Alabama, Florida, North Carolina, and Tennessee. Radial cranial scars were found for 47 individuals, but none of the four cases of dental lesions could be attributed to congenital syphilis. Differences in frequency of cranial lesions by region were minimal, with the least number of cases found for the mountains, but the frequency of positive cases tended to increase through time. It is suggested that increasing population density and changing behaviors, rather than novel strains of the treponemal pathogen, are responsible for the chronological increase in the frequency of positive cases., (Copyright 2006 Wiley-Liss, Inc.)

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.

Objective: To assess the effect of a 3 month behaviour modification weight management programme on self-efficacy and anthropometric variables among obese women seeking treatment at an obesity management clinic and to compare self-efficacy among these obese women to non-obese women., Design: Cross sectional., Subjects: A total of 161 non-obese (BMI 22.6+/-2.9 kg/m(2)) and 138 obese (BMI 37.7+/-5.8 kg/m(2)) women of similar age., Measurements: Self-efficacy in relation to eating was assessed by the Weight Efficacy Lifestyle (WEL) questionnaire. Demographic information was obtained by interview and questionnaire in the obese and by questionnaire in the non-obese. Anthropometric measurements were obtained by direct measure in the obese and BMI was calculated from self-reported weight and height in the non-obese., Results: At entry to the programme obese women scored significantly less (P<0.0001) than non-obese women on the WEL (99.4+/-34.1 vs 139.0+/-24.9). Women who completed the programme (n=65) demonstrated a decrease in waist circumference of 3.9+/-5.3 cm, a 10.0+/-11.5% loss of excess weight and a significant improvement in total WEL score from 106.0+/-30.3 to 126.5+/-28.4., Conclusion: Improvements in some dimensions of self-efficacy among obese women were of sufficient magnitude to attain scores similar to women of a normal weight. The WEL questionnaire may provide an additional measure of success as well as provide positive feedback and encouragement to the client.

A prospective study was made of scintimammographic findings obtained in 75 patients with minimal mammographic or physical examination findings. Patients included those with a new mammographic nodule or density (n = 33), indeterminate calcifications (n = 15), a palpable abnormality with normal mammographic findings and normal or inconclusive ultrasonographic findings (n = 13), or a new lump or mammographic change at the site of prior surgery (n = 14). A positive scintimammographic focus was defined as a discrete, rounded lesion with increased uptake and could have an intensity ranging from low to very high. Of the 30 cancers diagnosed, 27 demonstrated a positive scintimammographic focus. Eight of these foci represented occult cancers that were not identified at mammography or physical examination, and 11 were smaller than 1 cm (down to 4 mm). The overall sensitivity and specificity of scintimammography were 90% and 93.8%, respectively, which suggests that this modality may be useful in the early detection of breast cancer. It can also help distinguish postsurgical and post-radiation therapy changes from carcinoma and may be of value in certain high-risk patients. Scintimammography is a useful, noninvasive method of evaluating patients with low-suspicion or indeterminate mammographic or palpable findings and can help detect additional small tumors.

Women are persistently underrepresented in the higher levels of academic administration despite the fact that they have been entering the medical profession in increasing numbers for at least 20 years and now make up a large proportion of the medical student body and fill a similar proportion of entry level positions in medical schools. Although there are no easy remedies for gender inequities in medical schools, strategies have been proposed and implemented both within academic institutions and more broadly to achieve and sustain the advancement of women faculty to senior level positions. Substantial, sustained efforts to increase programs and activities addressing the major obstacles to advancement of women must be put in place so that the contributions of women can be fully realized and their skills fittingly applied in meeting the medical education and healthcare needs of all people in the 21st century.

Previous studies have used conventional electron microscopy and freeze fracture to identify the morphological equivalents of the blood-aqueous barrier in the mammalian eye. These equivalents are the tight junctions that form a part of the apicolateral junctional complex between adjacent non-pigmented ciliary epithelial cells and the tight junctions present between endothelial cells of the iris vasculature. Recent investigations have begun to unravel the molecular assembly of the tight junction and some variability has been found. Our goal in the present study was to probe the ciliary epithelium and iris vascular endothelium of the rabbit eye to determine if certain molecular constituents associated with tight junctions in other tissues are also present as parts of the blood-aqueous barrier. The selected constituents were occludin, ZO-1, and a representative, adherens junction-related cadherin. Immunohistochemical and immunoelectron microscopic methods were used. The results showed that occludin was distributed exclusively at known locations of tight junctions. ZO-1 was also expressed at these locations but its distribution extended beyond that of occludin, along the adjacent membranes. Pan-cadherin was expressed ubiquitously within the ciliary epithelium and negligibly in iris vascular endothelium. Our results demonstrate that occludin and ZO-1 are integral components of the blood-aqueous barrier of the normal rabbit eye.

Clinical practice guidelines have been available to clinicians for almost two decades, but the consistency of their implementation in practice remains highly variable. This paper describes the various processes and mechanisms used by one managed care organization to develop clinical guidelines and promote their adoption. Some of these mechanisms include provision of individual physician report cards, financial incentives, and various documentation tools that serve as reminders of guideline recommendations and provide an easy format to document recommended services. There have been measurement challenges in evaluating the effectiveness of selected interventions designed to enhance guideline compliance. Most of these challenges relate to reliability and validity concerns regarding the three primary data sources used in the evaluation process: medical records, administrative claims data, and member survey data. Some of the interventions the health plan has implemented to address these measurement challenges include using hybrid methods of data collection and developing collaborative partnerships with outside organizations to enhance the accuracy and completeness of the available data. Outcomes of these efforts are described, as are physician response and recommendations for future enhancement of practice guidelines.

Koreans are a recent but relatively small ethnic minority group in Australia. This descriptive cross-sectional, comparative intercountry study examines the effect of Australian acculturation among elderly Koreans on cardiovascular disease (CVD) risk factors, compared with their counterparts in Korea. Fifty-one (72.4 ± 8.7 years) Australian Koreans (AK) and 48 (75.7 ± 6.9 years) Koreans (K) living in Seoul participated in the study. Diabetes was reported by 10.2% of AK and 17.4% of K and hypertension by 38.8 and 29.8% of AK and K, respectively. Significantly, more AK (85.7%) than K (53.2%) reported undertaking physical activity (P = 0.0005) and fewer AK were current smokers (6% vs 26.1%; P = 0.0077). After controlling for age, body mass index and waist-to-hip ratio no differences were found in lipid profiles between AK and K men or women. The effect of acculturation may be reflected among Australian Koreans by increased physical activity and reduced smoking levels and increased levels of abdominal obesity.