The chemical synthesis of a series of mucin-type oligosaccharide fragments 1–7 containing an α-linked aminopropyl spacer ready for glycoarray attachment is reported. A highly convergent and stereoselective strategy that employs two different orthogonal protected galactosamine building blocks was used to access all of the targets. A tandem deprotection sequence, that did not require chromatography-based purification between steps, was employed to globally unmask all protecting groups and all final targets were isolated in good to excellent yields.
glycosylation; mucin-type oligosaccharides; O-glycans; oligosaccharide synthesis
ACASI; handheld computers; HIV prevention in urban women; soap opera videos for health promotion
Current policies encourage healthcare institutions to acquire clinical information systems (CIS) so that captured data can be used for secondary purposes, including clinical process improvement. Such policies do not account for the extra work required to repurpose data for uses other than direct clinical care, making their implementation problematic. This paper aims to analyze the strategies employed by clinical units to use data effectively for both direct clinical care and clinical process improvement.
Ethnographic methods were employed. A total of 54 contextual interviews with health professionals spanning various disciplines and 18 hours of observation were carried out in 5 intensive care units in England using an advanced CIS. Case studies of how the extra work was achieved in each unit were derived from the data and then compared.
We found that extra work is required to repurpose CIS data for clinical process improvement. Health professionals must enter data not required for clinical care and manipulation of this data into a machine-readable form is often necessary. Ambiguity over who should be responsible for this extra work hindered CIS data usage for clinical process improvement. We describe 11 strategies employed by units to accommodate this extra work, distributing it across roles. Seven of these motivated data entry by health professionals and four addressed the machine readability of data. Many of the strategies relied heavily on the skill and leadership of local clinical customizers.
To realize the expected clinical process improvements by the use of CIS data, clinical leaders and policy makers need to recognize and support the redistribution of the extra work that is involved in data repurposing. Adequate time, funding, and appropriate motivation are needed to enable units to acquire and deliver the necessary skills in CIS customization.
Clinical information system; Clinical process improvement; Computerized medical records systems; Intensive care; Qualitative research; Secondary use of data; User-customization
Lay abstract: It has been proposed that autistic-like traits in the general population lie on a continuum, with clinical Autism Spectrum Disorder (ASD), representing the extreme end of this distribution. The current study undertook a genome-wide association (GWA) scan of 965 young Western Australian adults to identify novel risk variants associated with autistic-like traits. No associations reached genome-wide significance; however, a review of nominally associated single nucleotide polymorphisms (SNPs) indicated two positional candidate loci that have been previously implicated in autistic-like trait etiology.
Scientific abstract: Research has proposed that autistic-like traits in the general population lie on a continuum, with clinical ASD representing the extreme end of this distribution. Inherent in this proposal is that biological mechanisms associated with clinical ASD may also underpin variation in autistic-like traits within the general population. A GWA study using 2,462,046 SNPs was undertaken for ASD in 965 individuals from the Western Australian Pregnancy Cohort (Raine) Study. No SNP associations reached genome-wide significance (p < 5.0 × 10−8). However, investigations into nominal observed SNP associations (p < 1.0 × 10−5) add support to two positional candidate genes previously implicated in ASD etiology, PRKCB1, and CBLN1. The rs198198 SNP (p = 9.587 × 10−6), is located within an intron of the protein kinase C, beta 1 (PRKCB1) gene on chromosome 16p11. The PRKCB1 gene has been previously reported in linkage and association studies for ASD, and its mRNA expression has been shown to be significantly down regulated in ASD cases compared with controls. The rs16946931 SNP (p = 1.78 × 10−6) is located in a region flanking the Cerebellin 1 (CBLN1) gene on chromosome 16q12.1. The CBLN1 gene is involved with synaptogenesis and is part of a gene family previously implicated in ASD. This GWA study is only the second to examine SNPs associated with autistic-like traits in the general population, and provides evidence to support roles for the PRKCB1 and CBLN1 genes in risk of clinical ASD.
autistic-like traits; genome-wide association; PRKCB1; autism spectrum disorder; autism spectrum quotient; CBLN1
Little is known about patterns of sedentary behavior (SB) and physical activity among preschoolers. Therefore, in this observational study patterns of SB and moderate-to-vigorous physical activity (MVPA) were examined in detail throughout the week in preschool-aged boys and girls.
A sample of 703 Melbourne preschool children (387 boys; 4.6 ± 0.7 y) were included in data analysis. SB and MVPA data were collected using accelerometry over an eight-day period. Percentage of time per hour in SB and in MVPA between 08:00 h and 20:00 h was calculated. Multi-level logistic regression models were created to examine the hour-by-hour variability in SB and MVPA for boys and girls across weekdays and weekend days. Odds ratios (OR) were calculated to interpret differences in hour-by-hour SB and MVPA levels between boys and girls, and between weekdays and weekend days.
The highest SB levels co-occurred with the lowest MVPA levels from the morning till the early afternoon on weekdays, and during the morning and around midday on weekends. Besides, participation in SB was the lowest and participation in MVPA was the highest from the mid afternoon till the evening on weekdays and weekend days. The variability across the hours in SB and, especially, in MVPA was rather small throughout weekdays and weekends. These patterns were found in both boys and girls. During some hours, girls were found to be more likely than boys to demonstrate higher SB levels (OR from 1.08 to 1.16; all p < 0.05) and lower MVPA levels (OR from 0.75 to 0.88; all p < 0.05), but differences were small. During weekends, hour-by-hour SB levels were more likely to be lower (OR from 0.74 to 0.98; all p < 0.05) and hour-by-hour MVPA levels were more likely to be higher (OR from 1.15 to 1.50; all p < 0.05), than during weekdays, in boys and girls.
Entire weekdays, especially from the morning till the early afternoon, and entire weekend days are opportunities to reduce SB and to promote MVPA in preschool-aged boys and girls. Particularly weekdays hold the greatest promise for improving SB and MVPA. No particular time of the week was found where one sex should be targeted.
Accelerometry; Physical activity; Sedentary behavior; Variability; Hour-by-hour; Young children
Over the last 30 years the number of people who drink alcohol at harmful levels has increased in many countries. There have also been large increases in rates of sexually transmitted infections. Available evidence suggests that excessive alcohol consumption and poor sexual health may be linked. The prevalence of harmful alcohol use is higher among people attending sexual health clinics than in the general population, and a third of those attending clinics state that alcohol use affects whether they have unprotected sex. Previous research has demonstrated that brief intervention for alcohol misuse in other medical settings can lead to behavioral change, but the clinical- and cost-effectiveness of this intervention on sexual behavior have not been examined.
We will conduct a two parallel-arm, randomized trial. A consecutive sample of people attending three sexual health clinics in London and willing to participate in the study will be screened for excessive alcohol consumption. Participants identified as drinking excessively will then be allocated to either active treatment (Brief Advice and referral for Brief Intervention) or control treatment (a leaflet on healthy living). Randomization will be via an independent and remote telephone randomization service and will be stratified by study clinic. Brief Advice will comprise feedback on the possible health consequences of excessive alcohol consumption, written information about alcohol and the offer of an appointment for further assessment and Brief Intervention. Follow-up data on alcohol use, sexual behavior, health related quality of life and service use will be collected by a researcher masked to allocation status six months later. The primary outcome for the study is mean weekly alcohol consumption during the previous three months, and the main secondary outcome is the proportion of participants who report unprotected sex during this period.
Opportunistic intervention for excessive alcohol use has been shown to be effective in a range of medical settings. The SHEAR study will examine whether delivering such interventions in sexual health clinics results in reductions in alcohol consumption and will explore whether this is associated with changes in sexual behavior.
Alcohol misuse; Intervention; Randomized controlled trial; Sexual health; Effectiveness
Autoantibodies to neutrophil cytoplasmic antigen-associated vasculitis (AAV) is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed AAV from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity. There is, however, a high unmet need in the treatment of AAV. A proportion of patients are refractory to current therapies; 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte-targeted and cytokine-targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.
Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population.
Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data.
The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman’s rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have ‘high’ scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females.
These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD.
Autism; Testosterone; Prenatal; Perinatal; Autistic-like traits
Dipsticks are one of the most commonly used near-patient tests in primary care, but few clinical or dipstick algorithms have been rigorously developed.
To confirm whether previously documented clinical and dipstick variables and algorithms predict laboratory diagnosis of urinary tract infection (UTI).
Design of study
A total of 434 adult females with suspected lower UTI had bacteriuria assessed using the European Urinalysis Guidelines.
Sixty-six per cent of patients had confirmed UTI. The predictive values of nitrite, leucocyte esterase (+ or greater), and blood (haemolysed trace or greater) were confirmed (independent multivariate odds ratios = 5.6, 3.5, and 2.1 respectively). The previously developed dipstick rule — based on presence of nitrite, or both leucocytes and blood — was moderately sensitive (75%) but less specific (66%; positive predictive value [PPV] 81%, negative predictive value [NPV] 57%). Predictive values were improved by varying the cut-off point: NPV was 76% for all three dipstick results being negative; the PPV was 92% for having nitrite and either blood or leucocyte esterase. Urine offensive smell was not found to be predictive in this sample; for a clinical score using the remaining three predictive clinical features (urine cloudiness, dysuria, and nocturia), NPV was 67% for none of the features, and PPV was 82% for three features.
A clinical score is of limited value in increasing diagnostic precision. Dipstick results can modestly improve diagnostic precision but poorly rule out infection. Clinicians need strategies to take account of poor NPVs.
algorithms, clinical scoring; diagnosis, urinary tract infection; primary care; urinalysis
Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability.
This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure.
Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an “inappropriate” phase when conditioning stimuli were absent and reward presentation would be delayed.
Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase.
Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.
Schizophrenia; Dual diagnosis; Substance use disorders; Addiction; Impulsivity; Prefrontal cortex; Nucleus accumbens; Hippocampus; Conditioned learning
Sexual pressure among young urban women represents adherence to gender stereotypical expectations to engage in sex. Revision of the original 5-factor Sexual Pressure Scale was undertaken in two studies to improve reliabilities in two of the five factors. In Study 1 the reliability of the Sexual Pressure Scale for Women-Revised (SPSW-R) was tested, and principal components analysis was performed in a sample of 325 young, urban women. A parsimonious 18-item, 4-factor model explained 61% of the variance. In Study 2 the theory underlying sexual pressure was supported by confirmatory factor analysis using structural equation modeling in a sample of 181 women. Reliabilities of the SPSW-R total and subscales were very satisfactory, suggesting it may be used in intervention research.
Sexual pressure; women; gender; sex scripts; HIV risk; SEM; ACASI
Discontinuation of contraceptive use that is not immediately followed by resumption of use of another method while a woman is at risk is a common cause of unintended pregnancy.
We provide new estimates of discontinuation for the pill, injectable, male condom, withdrawal, and fertility-awareness-based methods, and identify socioeconomic characteristics associated with discontinuation for the pill, male condom, and withdrawal. We provide new estimates of resumption of use by prior method used and identify socioeconomic characteristics associated with resumption of use. Estimates are obtained using the 2002 National Survey of Family Growth, supplemented by the 2001 Abortion Patient Survey to correct for underreporting of abortion.
The fraction of method use segments discontinued for method-related reasons within one year was highest for the male condom (57%), withdrawal (54%) and fertility-awareness-based methods (53%) and lowest for the pill (33%), with the injectable in-between (44%). However, contraception was abandoned altogether in only 25% of cases. The probability of resuming use of a contraceptive was 72% in the initial month of exposure to the risk of an unintended pregnancy; this rose to 76% by the third month.
The risk of discontinuation of use of reversible methods of contraception for method-related reasons, including a change of method is very high, but fortunately the risk of abandoning use of contraception altogether is far lower, and most spells of exposure to risk of an unintended pregnancy following discontinuation are protected from the start by a switch to another method.
Contraception; Discontinuation; Method switching; Resumption of use of contraception; National Survey of Family Growth; NSFG
Messenger RNA (mRNA) export adaptors play an important role in the transport of mRNA from the nucleus to the cytoplasm. They couple early mRNA processing events such as 5′ capping and 3′ end formation with loading of the TAP/NXF1 export receptor onto mRNA. The canonical adaptor REF/ALY/Yra1 is recruited to mRNA via UAP56 and subsequently delivers the mRNA to NXF1 . Knockdown of UAP56 [2, 3] and NXF1 [4–7] in higher eukaryotes efficiently blocks mRNA export, whereas knockdown of REF only causes a modest reduction, suggesting the existence of additional adaptors [8–10]. Here we identify a new UAP56-interacting factor, UIF, which functions as an export adaptor, binding NXF1 and delivering mRNA to the nuclear pore. REF and UIF are simultaneously found on the same mRNA molecules, and both proteins are required for efficient export of mRNA. We show that the histone chaperone FACT specifically binds UIF, but not REF, via the SSRP1 subunit, and this interaction is required for recruitment of UIF to mRNA. Together the results indicate that REF and UIF represent key human adaptors for the export of cellular mRNAs via the UAP56-NXF1 pathway.
This study explored reasons women engaged in unprotected sex with male partners they distrusted and perceived to engage in HIV risk behaviors. Seven focus groups were held in public housing and neighborhood centers in the urban Northeast with 43 African American and Latina women. Content analysis was conducted by open and axial coding. Barrett’s theory of power as knowing participation in change and sex script theory guided interpretation. Results indicated that Patterns of Unprotected Sex is a usual practice to maintain hope, sensuality, intimacy, strategic gain, and stability with a male partner. In low power sex scripts the salient risks of HIV were buried under an awareness of oneself as having to satisfy a man and accept cheating. High power sex scripts involved women’s awareness of themselves as worthy of self care with diverse choices. High power scripts can be integrated into normative sex scripts as exemplars of more powerful ways of being and acting to reduce HIV risk.
Women; HIV sexual risk; Focus groups; Power; Sex scripts; Sexual pressure; Trust