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The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis-regulatory elements (CREs) of the receptor tyrosine kinase gene RET, which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce RET gene expression, and dysregulate other ENS and HSCR genes in the RET–EDNRB gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate RET CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect RET gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on RET gene expression. These, coupled with our prior results, show that common sequence variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting RET gene expression, extending the known RET–EDNRB GRN to reveal an extensive regulatory code modulating disease risk at a single gene.

A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.

Hirschsprung disease (HSCR) is associated with deficiency of the receptor tyrosine kinase RET, resulting in loss of cells of the enteric nervous system (ENS) during fetal gut development. The major contribution to HSCR risk is from common sequence variants in RET enhancers with additional risk from rare coding variants in many genes. Here, we demonstrate that these RET enhancer variants specifically alter the human fetal gut development program through significant decreases in gene expression of RET, members of the RET-EDNRB gene regulatory network (GRN), other HSCR genes, and an altered transcriptome with 2,382 differentially expressed genes with diverse neuronal and mesenchymal functions. A parsimonious hypothesis for these results is that beyond RET’s direct effect on its GRN, it also has a major role in enteric neural crest derived cell (ENCDC) precursor proliferation, its deficiency reducing ENCDCs with relative expansion of non-ENCDC cells. Thus, genes reducing RET proliferative activity can potentially cause HSCR. One such class is the 23 RET-dependent transcription factors enriched in early gut development. We show that their knockdown in human neuroblastoma SK-N-SH cells reduces RET and/or EDNRB gene expression, expanding the RET-EDNRB GRN. The human embryos we studied had major remodeling of the gut transcriptional but were unlikely to have had HSCR: thus, genetic changes in addition to those in RET are required for a significant enough reduction in ENCDCs to cause aganglionosis.

SARS-CoV-2 prevention measures impact the circulation of other respiratory viruses. Surveillance in the network of general practitioners is hampered by widespread testing for SARS-CoV-2 in public testing facilities.To evaluate integrated community surveillance of SARS-CoV-2 and other respiratory viruses and describe epidemiological trends.Respiratory surveillance was set up within an existing SARS-CoV-2 public testing facility. Community-dwelling (a)symptomatic persons provided consent for completion of a questionnaire and additional testing on residual material from swabs taken for SARS-CoV-2 RT-PCR (Allplex Seegene). Daily, a random subset was tested for sixteen respiratory viruses by multiplex realtime PCRs (Seegene).Between October 6th (week 40) 2021 and April 22nd (week 16) 2022, 3,969 subjects were tested. The weekly median age ranged from 23 to 39 years. The prevalence of respiratory symptoms ranged from 98.5% (week 40) to 27.4% (week 1). The prevalence of detection of any respiratory virus (including SARS-CoV-2), ranged from 19.6% in week 49 to 75.3% in week 14. SARS-CoV-2 prevalence ranged from 2.2% (week 40) to 63.3% (week 14). Overall, SARS-CoV-2 was detected most frequently (27.3%), followed by rhinoviruses (14.6%, range 3.5-47.8%) and seasonal coronaviruses (3.7%, range 0-10.4%, mostly 229E and OC43). Influenzavirus was detected in 3.0% of participants from week 6 onwards.Integrated respiratory viral surveillance within public testing facilities is feasible and informative. Prevalences may be affected by changes in SARS-CoV-2 prevention and testing policies. Population characteristics help to interpret trends over time. Integrated surveillance may inform policymakers and hospitals for adequate response measures during respiratory seasons.

Background: Hand washing continues to be the number one most effective way to prevent the spread of germs. This quality improvement project examines whether a hands-on soap and water hand washing tutorial increases the quality of hand washing technique. Method: The Glow Team developed and presented an evidence-based hands-on teaching tutorial demonstrating proper hand washing technique as recommended by the World Health Organization to 100 emergency department health care workers. The efficacy of the technique was evaluated by applying black light–sensitive lotion. Participants washed their hands before and after the education session. Participants completed a posttest to evaluate their gained knowledge of hand washing. Results: Hand washing efficacy improved from 60% preeducation to 82% posteducation. Each individual step noted improvement posteducation. Conclusion: Of 100 participants, 98 reported this education was helpful and suggested yearly competencies, posted fliers, and repeated demonstrations to improve compliance among self and peers. [ J Contin Educ Nurs . 2020;51(10):453–456.]

BackgroundIn order to optimize interventions and services in the community, it is important to identify the profile of persons who are able to stay at home and of those who are being admitted into residential care. Understanding their needs and their use of resources is essential. The main objective of the study is to identify persons who are likely to enter residential care based upon their needs and resource utilization, so that care providers can plan interventions effectively and optimize services and resources to meet the persons’ needs.MethodsThis is a longitudinal quasi-experimental study. The data consists of primary data from the community setting collected every six months during the period of 2010–2016. Interventions had the goal of keeping older people longer at home. Participants were at least 65 years old and were living in the community. The interRAI Resource Utilization Group system (RUG-III) was used to calculate the case-mix indexes (CMI) of all participants. Comparisons were made between the case-mix of those who were still living at home and those who were admitted into residential care at follow-up.ResultsA total of 10,289 older persons participated in the study (81.2 ± 7.1 yrs., 69.1% female). From this population, 853 participants (8.3%) were admitted into residential care. The CMI of the persons receiving night care at home were the highest (1.6 at baseline and 1.7 at the entry point of residential care), followed by persons receiving occupational therapy (1.5 at baseline and 1.6 at the entry point of residential care) and persons enrolled in case management interventions with rehabilitation (1.4 at baseline and 1.6 at the entry point of residential care). The CMIs at follow-up were significantly higher than at baseline and the linear regression model showed that admission to residential care was a significant factor in the model.ConclusionsThe study showed that the RUG-III system offers possibilities for identifying persons at risk of institutionalization. Interventions designed to avoid early nursing home admission can make use of the RUG-III system to optimize care planning and the allocation of services and resources. Based on the RUG-III case-mix, resources can be allocated to keep older persons at home longer, bearing in mind the complexity of care and the availability of services in the community.

The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within

Limited funding across health and social service programs presents a challenge regarding how to best match resources to the needs of the population. There is increasing consensus that differences in individual characteristics and care needs should be reflected in variations in service costs, which has led to the development of case-mix systems. The present study sought to develop a new approach to allocate resources among children and youth with intellectual and developmental disabilities (IDD) as part of a system-wide Medicaid payment reform initiative in Arkansas. To develop the system, assessment data collected using the interRAI Child and Youth Mental Health-Developmental Disability instrument was matched to paid service claims. The sample consisted of 346 children and youth with developmental disabilities in the home setting. Using automatic interactions detection, individuals were sorted into unique, clinically relevant groups (ie, based on similar resource use) and a standardized relative measure of the cost of services provided to each group was calculated. The resulting case-mix system has 8 distinct, final groups and explains 30% of the variance in per diem costs. Our analyses indicate that this case-mix classification system could provide the foundation for a future prospective payment system that is centered around stability and equitability in the allocation of limited resources within this vulnerable population.

Author(s): Padhi, Evin M; Hayeck, Tristan J; Mannion, Brandon; Chatterjee, Sumantra; Byrska-Bishop, Marta; Musunuri, Rajeeva; Narzisi, Giuseppe; Abhyankar, Avinash; Cheng, Zhang; Hunter, Riana D; Akiyama, Jennifer; Fries, Lauren E; Ng, Jeffrey; Stong, Nick; Allen, Andrew S; Dickel, Diane E; Bernier, Raphael A; Gorkin, David U; Pennacchio, Len A; Zody, Michael C; Turner, Tychele N | Abstract: AbstractPrevious research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of de novo protein-coding variants within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2,671 families with autism, with a specific focus on de novo variation in enhancers with previously characterized in vivo activity. We identified three independent de novo mutations limited to individuals with autism in the enhancer hs737. These mutations result in similar phenotypic characteristics, affect enhancer activity in vitro, and preferentially occur in AAT motifs in the enhancer with predicted disruptions of transcription factor binding. We also find that hs737 is enriched for copy number variation in individuals with NDDs, is dosage sensitive in the human population, is brain-specific, and targets the NDD gene EBF3 that is genome-wide significant for protein coding de novo variants, demonstrating the importance of understanding all forms of variation in the genome.One Sentence SummaryWhole-genome sequencing in thousands of families reveals variants relevant to simplex autism in a brain enhancer of the well-established neurodevelopmental disorder gene EBF3.

Background Down syndrome (DS) is characterised by premature ageing that affects selected organ systems, and persons with this condition can present patterns of co-morbidities and deficits often observed in the older population without DS. However, information on the characteristics of adult persons with DS is limited. The objective of the study is to describe characteristics of adults with DS collected with a standardised, comprehensive assessment instrument. Methods Cross-sectional study. Four hundred thirty adults with DS (age range 18/75 years) from three countries (Italy, n = 95; USA, n = 175; and Canada, n = 160). A standardised assessment instrument (interRAI intellectual disability) was used to assess sample characteristics. Results Mean age ranged from 35.2 (standard deviation 12.0) years in the US sample to 48.8 (standard deviation 9.0) years in the Canadian sample. Most participants in the Italian and US sample were living in private homes, while more than half of those in the Canadian sample were institutionalised. Prevalences of geriatric conditions, including cognitive deficits, disability in the common activities of daily living, symptoms of withdrawal or anhedonia, aggressive behaviour, communication problems, falls and hearing problems were high in the study sample. Gastrointestinal symptoms, skin and dental problems and obesity were also frequently observed. Conclusions Adults with DS present with a high level of complexity, which may suggest the need for an approach based on a comprehensive assessment and management that can provide adequate care. Further research is needed to understand better the effectiveness of such an approach in the DS population.

Recent studies have indicated that urban streets can be hotspots for emissions of methane (CH(4)) from leaky natural gas lines, particularly in cities with older natural gas distribution systems. The objective of the current study was to determine whether leaking sewer pipes could also be a source of street-level CH(4) as well as nitrous oxide (N(2)O) in Cincinnati, Ohio, a city with a relatively new gas pipeline network. To do this, we measured the carbon (δ(13)C) and hydrogen (δ(2)H) stable isotopic composition of CH(4) to distinguish between biogenic CH(4) from sewer gas and thermogenic CH(4) from leaking natural gas pipelines and measured CH(4) and N(2)O flux rates and concentrations at sites from a previous study of street-level CH(4) enhancements (77 out of 104 sites) as well as additional sites found through surveying sewer grates and utility manholes (27 out of 104 sites). The average isotopic signatures for δ(13)C-CH(4) and δ(2)H-CH(4) were −48.5‰ ± 6.0‰ and −302‰ ± 142‰. The measured flux rates ranged from 0.0 to 282.5 mg CH(4) day(−1) and 0.0 to 14.1 mg N(2)O day(−1) (n = 43). The average CH(4) and N(2)O concentrations measured in our study were 4.0 ± 7.6 ppm and 392 ± 158 ppb, respectively (n = 104). 72% of sites where fluxes were measured were a source of biogenic CH(4). Overall, 47% of the sampled sites had biogenic CH(4), while only 13% of our sites had solely thermogenic CH(4). The other sites were either a source of both biogenic and thermogenic CH(4) (13%), and a relatively large portion of sites had an unresolved source (29%). Overall, this survey of emissions across a large urban area indicates that production and emission of biogenic CH(4) and N(2)O is considerable, although CH(4) fluxes are lower than those reported for cities with leaky natural gas distribution systems.

Engineered silver nanoparticles (Ag ENP) enter the environment and lead to concerns about their environmental effects. Clay-sized particles are assumed to govern the environmental mobility and bioavailability of ENP, although little is known about their interaction with pedogenic minerals. The interactions of sterically (AgNM–300k, OECD standard) and electrosterically (AgCN30) stabilized Ag ENP with iron and clay minerals were investigated at a range of pH values from 4 to 7. The Ag ENP were separated from mineral suspensions by filtration at

Recent work indicates that oil and gas methane (CH4) inventories for the United States are underestimated. Here we present results from direct measurements of CH4 emissions from 138 abandoned oil and gas wells, a source currently missing from inventories. Most abandoned wells do not emit CH4, but 6.5% of wells had measurable CH4 emissions. Twenty-five percent of wells we visited that had not been plugged emitted > 5 g CH4 h−1. Stable isotopes indicate that wells emit natural gas and/or coalbed CH4. We estimate that abandoned wells make a small contribution (

The RUG-III case-mix system is a method of grouping patients in long-term and post-acute care settings. RUG-III groups patients by relative per diem resource consumption and may be used as the basis for prospective payment systems to ensure that facility reimbursement is commensurate with patient acuity. Since RUG-III’s development in 1994, more than a dozen international staff time measurement studies have been published to evaluate the utility of the case-mix system in a variety of diverse health care environments around the world. This overview of the literature summarizes the results of these RUG-III validation studies and compares the performance of the algorithm across countries, patient populations, and health care environments. Limitations of the RUG-III validation literature are discussed for the benefit of health system administrators who are considering implementing RUG-III and next-generation resource utilization group case-mix systems.

Cognitive decline impacts older adults, particularly their independence. The goal of this project was to increase understanding of how short-term, everyday lifestyle options, including physical activity, help an older adult sustain cognitive independence. Using a secondary analysis of lifestyle choices, we drew on a dataset of 4,620 community-dwelling elders in the US, assessed at baseline and one year later using 2 valid and reliable tools, the interRAI Community Health Assessment and the interRAI Wellness tool. Decline or no decline on the Cognitive Performance Scale was the dependent variable. We examined sustaining one’s status on this measure over a one-year period in relation to key dimensions of wellness through intellectual, physical, emotional, social, and spiritual variables. Engaging in physical activity, formal exercise, and specific recreational activities had a favorable effect on short-term cognitive decline. Involvement with computers, crossword puzzles, handicrafts, and formal education courses also were protective factors. The physical and intellectual domains of wellness are prominent aspects in protection from cognitive decline. Inherent in these two domains are mutable factors suitable for targeted efforts to promote older adult health and well-being.

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.

Objectives interRAI launched this study to introduce a set of standardized self-report measures through which residents of long-term care facilities (LTCFs) could describe their quality of life and services. This article reports on the international development effort, describing measures relative to privacy, food, security, comfort, autonomy, respect, staff responsiveness, relationships with staff, friendships, and activities. First, we evaluated these items individually and then combined them in summary scales. Second, we examined how the summary scales related to whether the residents did or did not say that the LTCFs in which they lived felt like home. Design Cross-sectional self-report surveys by residents of LTCFs regarding their quality of life and services. Setting/Participants Resident self-report data came from 16,017 individuals who resided in 355 LTCFs. Of this total, 7113 were from the Flanders region of Belgium, 5143 residents were from Canada, and 3358 residents were from the eastern and mid-western United States. Smaller data sets were collected from facilities in Australia (20), the Czech Republic (72), Estonia (103), Poland (118), and South Africa (87). Measurements The interRAI Self-Report Quality of Life Survey for LTCFs was used to assess residents' quality of life and services. It includes 49 items. Each area of inquiry (eg, autonomy) is represented by multiple items; the item sets have been designed to elicit resident responses that could range from highly positive to highly negative. Each item has a 5-item response set that ranges from “never” to “always.” Results Typically, we scored individual items scored based on the 2 most positive categories: “sometimes” and “always.” When these 2 categories were aggregated, among the more positive items were: being alone when wished (83%); decide what clothes to wear (85%); get needed services (87%); and treated with dignity by staff (88%). Areas with a less positive response included: staff knows resident's life story (30%); resident has enjoyable things to do on weekends (32%); resident has people to do things with (33%); and resident has friendly conversation with staff (45%). We identified 5 reliable scales; these scales were positively associated with the resident statement that the LTCF felt like home. Finally, international score standards were established for the items and scales. Conclusions This study establishes a set of standardized, self-report items and scales with which to assess the quality of life and services for residents in LTCFs. The study also demonstrates that these scales are significantly related to resident perception of the home-like quality of the facilities.

This study measured the prevalence of current, severe symptoms of a mental health problem in an adult population of inmates in Ontario, Canada. The Resident Assessment Instrument–Mental Health was used to measure the prevalence of symptoms among a sample of 522 inmates. Propensity score weighting was used to adjust for nonrandom selection into the sample. Prevalence estimates were derived for the total inmate population, remand and sentenced, males and females, and Aboriginal and non-Aboriginal inmates. It is estimated that 41.1% of Ontario inmates will have at least one current, severe symptom of a mental health problem; of this group, 13.0%, will evidence two or more symptoms. The number of symptoms is strongly associated with presence of a psychiatric diagnosis and level of mental health care needs. Female (35.1%) and Aboriginal (18.7%) inmates are more likely to demonstrate two or more current, severe symptoms. Greater efforts must be made to bridge the gap between correctional and mental health care systems to ensure inmates in correctional facilities can access and receive appropriate mental health care services.

Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.

Few studies have examined the effects of smoking on nursing home utilization, generally using poor data on smoking status. No previous study has distinguished utilization for recent from long-term quitters.Using the Health and Retirement Study, we assessed nursing home utilization by never-smokers, long-term quitters (quit3 years), recent quitters (quit ≤3 years), and current smokers. We used logistic regression to evaluate the likelihood of a nursing home admission. For those with an admission, we used negative binomial regression on the number of nursing home nights. Finally, we employed zero-inflated negative binomial regression to estimate nights for the full sample.Controlling for other variables, compared with never-smokers, long-term quitters have an odds ratio (OR) for nursing home admission of 1.18 (95% CI: 1.07-1.2), current smokers 1.39 (1.23-1.57), and recent quitters 1.55 (1.29-1.87). The probability of admission rises rapidly with age and is lower for African Americans and Hispanics, more affluent respondents, respondents with a spouse present in the home, and respondents with a living child. Given admission, smoking status is not associated with length of stay (LOS). LOS is longer for older respondents and women and shorter for more affluent respondents and those with spouses present.Compared with otherwise identical never-smokers, former and current smokers have a significantly increased risk of nursing home admission. That recent quitters are at greatest risk of admission is consistent with evidence that many stop smoking because they are sick, often due to smoking.

1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.

This study reports on a representative sample of prisoners in Michigan correctional facilities to determine the prevalence of psychiatric illness and the delivery of mental health (MH) services. Mental health assessments were conducted with 618 incarcerated subjects using the interRAI Correctional Facilities (interRAI CF). Subjects were randomly sampled based on four strata: males in the general population, males in administrative segregation, males in special units, and females. The interRAI CF assessments were merged with secondary data provided by the Michigan Department of Corrections (MDOC) containing information on MH diagnoses or services that the subjects were receiving within the facilities, demographics, and sentencing. Study results show that 20.1% of men and 24.8% of women in Michigan prisons have a substantial level of MH symptoms and that 16.5% and 28.9%, respectively, are receiving MH services. However, when compared with Michigan Department of Corrections MH care records, 65.0% of prisoners who are experiencing symptoms of mental illness are not currently receiving any psychiatric services. The mis-match between symptoms and service delivery suggests the need for improved procedures for identifying and measuring psychiatric symptoms within Michigan correctional facilities to ensure that appropriate individuals receive needed care. It is recommended that a standardized assessment process be implemented and conducted at regular intervals for targeting and improving psychiatric care in the prison system.

To determine functional status and mortality rates after colon cancer surgery in older nursing home residents.Retrospective cohort study.Nursing homes in the United States.Six thousand eight hundred twenty-two nursing home residents aged 65 and older who underwent surgery for colon cancer in the United States between 1999 and 2005.Changes in functional status were assessed before and after surgery using the Minimum Data Set Activity of Daily Living (MDS-ADL) summary scale, a 28-point scale in which score increases as functional dependence increases. Regression techniques were used to identify patient characteristics associated with mortality and functional decline 1 year after surgery.On average, residents who underwent colectomy had a 3.9-point worsening in MDS-ADL score at 1 year. One year after surgery, rates of mortality and sustained functional decline were 53% and 24%, respectively. In multivariate analysis, older age (≥ 80 vs 65-69, adjusted relative risk (ARR) = 1.53, 95% confidence interval (CI) = 1.15-2.04, P.001), readmission after surgical hospitalization (ARR = 1.15, 95% CI = 1.03-1.29, P = .02), surgical complications (ARR = 1.11, 95% CI = 1.02-1.21, P = .01), and functional decline before surgery (ARR = 1.21, 95% CI = 1.11-1.32, P.001) were associated with functional decline at 1 year.Mortality and sustained functional decline are common after colon cancer surgery in nursing home residents. Initiatives aimed at improving surgical outcomes are needed in this vulnerable population.

The aim of this study was to assess the association between overweight and school performance among primary school children prospectively and including a broad range of potential confounding factors. In addition it was investigated what factors mediate this association. For this purpose, data of 2,159 12-year-old children who participated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study were used. Two indicators of school performance were parental reported when children were 12 years of age and included (i): the score on a standardized achievement test that Dutch children have to complete at the end of their primary education (Cito)-test and (ii): the teacher's advice regarding a child's potential performance level in secondary education. Children's height and weight were measured by a trained research assistant at the age of 8 and by their parents at the age of 12. Overweight was defined using age and gender specific cut-off points. Multivariate regression analyses were performed to assess the association between overweight and school performance. Besides, both confounder and mediation analyses were conducted. Results showed lower Cito-test scores and lower teacher's school-level advice among overweight children. These associations were no longer significant when adjusting for parental educational level, skipping breakfast, and screen time. This study found no independent association between overweight and school performance among primary school children. Results showed strong confounding by parental educational level.

To better understand the problems associated with diagnosis of bipolar disorder, especially problems related to race and ethnicity, this study compared whites, African Americans, and Latinos with bipolar I disorder in the presentation of manic symptoms, depressive episodes, functional impairments (Short Form-12), and self-reports of schizophrenia diagnosis. Data for this study were derived from the 2001 National Epidemiologic Survey on Alcohol and Related Conditions, which are nationally representative of United States households. African Americans and Latinos expressed similar rates in presentation of 14 out of 16 manic symptoms compared with whites, with the exception of grandiosity/self-esteem, in which they were more likely to exhibit this symptom compared with whites. Higher rates of depressive episodes were observed among whites, and these episodes occurred significantly earlier compared with African Americans and Latinos. Latinos had slightly higher vitality scores on the SF-12 measures after adjusting for sociodemographic and clinical factors, but no other differences across the groups were observed. Overall, these data show that the expression and functional impairments of bipolar I disorder is very similar across racial ethnic groups using this community-based sample. This is the first community-based study making such comparisons, with results suggesting that provider biases are more likely to explain problems in misdiagnosis than fundamental differences in the presentation of bipolar disorder across racial/ethnic groups.

Purpose: When government funding for long-term care is reduced, participant outcomes may be adversely affected. We investigated the effect of program resources on individuals enrolled in the Michigan Home- and Community-Based Services (HCBS) waiver program for elderly and disabled adults. Design and Methods: Using dates of major policy and budget changes, we defi ned 4 distinct time periods between October 2001 and December 2005. Minimum Data Set for Home Care assessment records for HCBS participants ( n = 112,182) were used to examine temporal trends in formal care hours and 6 outcomes: emergency room (ER) use, hospitalization, caregiver burden, death, nursing facility (NF) use, and permanent NF placement. Controlling for demographics, functional status, and cognitive status, adjusted odds of outcomes were obtained using discrete-time survival analysis. Results: As resources diminished, mean formal care hours decreased, declining most for persons with moderate functional or cognitive impairment, for up to an approximately 30% decrease. In the most fi nancially restricted period, 3 adverse outcomes increased relative to baseline: hospitalization (odds ratio [OR] = 1.10; 95% confi dence interval [CI] = 1.03 – 1.18), ER use (OR = 1.13; 95% CI = 1.03 – 1.24), and permanent NF placement (OR = 1.20; 95% CI = 1.00 – 1.42). Implications: Reductions in resources for home care were associated with increased probability of adverse outcomes. Cutting funds to home care programs can increase utilization of other more costly services, thus offsetting potential health care savings. Policymakers must consider all ways in which budget reductions and policy changes can affect participants.

Background and purpose: The recent development of the UT ligand palosuran (1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl- quinolin-4-yl)-urea sulphate salt) has led to the proposition that urotensin-II (U-II) plays a significant pathological role in acute and chronic renal injury in the rat. Experimental approach: In the present study, the pharmacological properties of palosuran were investigated further using a series of radioligand binding and functional bioassays. Key results: Palosuran functioned as a ‘primate-selective’ UT ligand in recombinant cell membranes (monkey and human UT Ki values of 4±1 and 5±1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline Ki values >1 μM). Paradoxically, however, palosuran lost significant (10- to 54-fold) affinity for native and recombinant human UT when radioligand binding was performed in intact cells (Ki values of 50±3 and 276±67 nM). In accordance, palosuran also exhibited diminished activity in hUT (human urotensin-II receptor)-CHO (Chinese hamster ovary) cells (IC50 323±67 nM) and isolated arteries (Kb>10 μM in rat aorta; Kb>8.5 μM in cat arteries; Kb>1.6 μM in monkey arteries; Kb 2.2±0.6 μM in hUT transgenic mouse aorta). Relative to recombinant binding Ki values, palosuran was subjected to a 392- to 690-fold reduction in functional activity in monkey isolated arteries. Such phenomena were peculiar to palosuran and were not apparent with an alternative chemotype, SB-657510 (2-bromo-N-[4-chloro-3-((R)-1-methyl- pyrrolidin-3-yloxy)-phenyl]-4,5-dimethoxybenzenesulphonamide HCl). Conclusions and implications: Collectively, such findings suggest that caution should be taken when interpreting data generated using palosuran. The loss of UT affinity/activity observed in intact cells and tissues cf. membranes offers a potential explanation for the disappointing clinical efficacy reported with palosuran in diabetic nephropathy patients. As such, the (patho)physiological significance of U-II in diabetic renal dysfunction remains uncertain. British Journal of Pharmacology (2008) 155, 374–386; doi:10.1038/bjp.2008.266; published online 30 June 2008

This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.