bluuebunny/crossref_metadata_2025 huggingface dataset:
The contribution of massive fetomaternal hemorrhage to antepartum stillbirth: a 25‐year cross‐sectional study
Authors: O'Leary Bobby D. , Walsh Colin A. , Fitzgerald Joan M. , Downey Paul , McAuliffe Fionnuala M.
Published: September 2015

Introduction

Fatal antepartum fetomaternal hemorrhage is a relatively uncommon clinical presentation, though one that appears quickly and without warning. The pathophysiology of this disease is unclear, and the incidence does not appear to be decreasing in line with overall antepartum mortality. This study was undertaken to analyse trends in antepartum fetal death from fetomaternal hemorrhage over a 25‐year period in a single maternity hospital in Dublin, Ireland.

Material and methods

A cross‐sectional study of 192 132 nonanomalous infants weighing 500 g or more, delivered in a single tertiary‐referral university institution between 1987 and 2011. Data was compared using Fisher's exact test, univariate analysis, and Cuzick's test for trend.

Results

There was no decrease in the rate of fatal fetomaternal hemorrhage over the past 25 years (p = 0.29), despite a decline in overall antepartum deaths (p = 0.0049). Fetomaternal hemorrhage accounted for 4.1% (34/828) of antepartum stillbirths. A higher proportion of these stillbirths occurred at term gestations (74%; 25/34) compared with other causes (40%; 321/794; p = 0.0003). Female infants were statistically more likely to be involved than males [odds ratio (OR) 2.33, 95% confidence interval (CI) 1.08–5.47, p = 0.02). Multiple gestations were up to six times as likely to be affected as singleton pregnancies (OR 6.52, 95% CI 1.67–18.50, p = 0.005).

Conclusions

Over the past 25 years there has been no reduction in rates of fatal fetomaternal hemorrhage. Female infants and multiple gestations remain at higher risk of antepartum death from fatal fetomaternal hemorrhage.
Multiplex polymerase chain reaction assay developed to diagnose adult bacterial meningitis in Taiwan
Authors: Lee Chi‐Tsung , Hsiao Kuang‐Ming , Chen Jin‐Cherng , Su Cheng‐Chuan
Published: September 2015

Acute bacterial meningitis causes high morbidity and mortality; the associated clinical symptoms often are insensitive or non‐specific; and the pathogenic bacteria are geographically diverse. Clinical diagnosis requires a rapid and accurate methodology. This study aimed to develop a new multiplex polymerase chain reaction (mPCR) assay to detect simultaneously six major bacteria that cause adult bacterial meningitis in Taiwan: Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, and Acinetobacter baumannii. Species‐specific primers for the six bacteria were developed using reference strains. The specificities of the mPCRs for these bacteria were validated, and the sensitivities were evaluated via serial dilutions. The mPCR assay specifically detected all of the six pathogens, particularly with sensitivities of 12 colony forming units (CFU)/mL, 90 CFU/mL, and 390 CFU/mL for E. coli, S. pneumoniae, and K. pneumoniae, respectively. This mPCR assay is a rapid and specific tool to detect the six major bacterial pathogens that cause acute adult meningitis in Taiwan, particularly sensitive for detecting E. coli, S. pneumoniae, and K. pneumoniae. The assay may facilitate early diagnosis and guidance for antimicrobial therapy for adult patients with this deadly disease in Taiwan.
Less is more: The availability heuristic in early childhood
Authors: Geurten Marie , Willems Sylvie , Germain Sophie , Meulemans Thierry
Published: September 2015

This study examined whether young children are influenced by the subjective experience associated with an easy or difficult recall when making memory decisions. Seventy‐one children, aged 4, 6, and 8 years, were asked to generate either a small (easy condition) or large (hard condition) number of first names. Statistical analyses revealed that participants in the hard condition were more likely to infer that they did not know many names than participants in the easy condition, contrary to what would be expected if children based their memory judgement on the objective number of recalled items. Overall, our results support the hypothesis that children as young as 4 years old rely on the subjective experience of ease to regulate their decision‐making processes. Theoretical implications of these findings are discussed.
Patterns of prescription and adherence to European Association of Urology guidelines on androgen deprivation therapy in prostate cancer: an Italian multicentre cross‐sectional analysis from the Choosing Treatment for Prostate Cancer (CHOICE) study
Authors: Morgia Giuseppe , Russo Giorgio Ivan , Tubaro Andrea , Bortolus Roberto , Randone Donato , Gabriele Pietro , Trippa Fabio , Zattoni Filiberto , Porena Massimo , Mirone Vincenzo , Serni Sergio , Del Nero Alberto , Lay Giancarlo , Ricardi Umberto , Rocco Francesco , Terrone Carlo , Pagliarulo Arcangelo , Ludovico Giuseppe , Vespasiani Giuseppe , Brausi Maurizio , Simeone Claudio , Novella Giovanni , Carmignani Giorgio , Leonardi Rosario , Pinnarò Paola , De Paula Ugo , Corvò Renzo , Tenaglia Raffaele , Siracusano Salvatore , Mantini Giovanna , Gontero Paolo , Savoca Gianfranco , Ficarra Vincenzo ,   (Members of the LUNA Foundation, Società Italiana d'Urologia)
Published: September 2015

Objective

To evaluate both the patterns of prescription of androgen deprivation therapy (ADT) in patients with prostate cancer (PCa) and the adherence to European Association of Urology (EAU) guidelines for ADT prescription.

Methods

The Choosing Treatment for Prostate Cancer (CHOICE) study was an Italian multicentre cross‐sectional study conducted between December 2010 and January 2012. A total of 1 386 patients, treated with ADT for PCa (first prescription or renewal of ADT), were selected. With regard to the EAU guidelines on ADT, the cohort was categorized into discordant ADT (Group A) and concordant ADT (Group B).

Results

The final cohort included 1 075 patients with a geographical distribution including North Italy (n = 627, 58.3%), Central Italy (n = 233, 21.7%) and South Italy (n = 215, 20.0%). In the category of patients treated with primary ADT, a total of 125 patients (56.3%) were classified as low risk according to D'Amico classification. With regard to the EAU guidelines, 285 (26.51%) and 790 patients (73.49%) were classified as discordant (Group A) and concordant (Group B), respectively. In Group A, patients were more likely to receive primary ADT (57.5%, 164/285 patients) than radical prostatectomy (RP; 30.9%, 88/285 patients), radiation therapy (RT; 6.7%, 19/285 patients) or RP + RT (17.7%, 14/285 patients; P < 0.01). Multivariate logistic regression analysis, adjusted for clinical and pathological variables, showed that patients from Central Italy (odds ratio [OR] 2.86; P < 0.05) and South Italy (OR 2.65; P < 0.05) were more likely to receive discordant ADT.

Conclusion

EAU guideline adherence for ADT was low in Italy and was influenced by geographic area. Healthcare providers and urologists should consider these results in order to quantify the inadequate use of ADT and to set policy strategies to overcome this risk.
Functional roles of bladder α1‐adrenoceptors in the activation of single‐unit primary bladder afferent activity in rats
Authors: Aizawa Naoki , Sugiyama Rino , Ichihara Koji , Fujimura Tetsuya , Fukuhara Hiroshi , Homma Yukio , Igawa Yasuhiko
Published: September 2015

Objectives

To clarify the involvement of bladder α1‐adrenoceptors (α1‐ARs) in afferent pathways by investigating the effects of silodosin and BMY7378, selective α1A‐ or α1D‐AR antagonists, respectively, on single‐unit afferent nerve fibre activity (SAA) of the primary bladder afferent nerves and their relationship with bladder microcontractions in rats.

Materials and Methods

A total of 63 female Sprague–Dawley rats were anaesthetized with urethane. The SAA of Aδ and C fibres generated from the left L6 dorsal roots was determined using electrical stimulation of the left pelvic nerve and bladder distension. After measuring baseline SAA during constant filling cystometry, the procedure was repeated with i.v. (0.3–30 μg/kg) or intravesical (10 μm) administration of each antagonist. In separate rats, the bladder was filled with saline until the intravesical pressure reached 30 cmH2O, and was kept under isovolumetric conditions, then the recording was performed with i.v.‐administered vehicle and silodosin (0.3 μg/kg).

Results

A total of Aδ fibres and 33 C fibres were isolated from 63 rats. The SAA of Aδ fibres, but not C fibres, were dose‐dependently decreased after both i.v. and intravesical administrations of each of the antagonists. In the experiments under bladder isovolumetric conditions, silodosin administration significantly decreased the SAA of Aδ fibres, but not C fibres, compared with vehicle administration. There were no significant effects on either the mean basal bladder pressure or microcontractions.

Conclusion

The present study suggests that both α1A‐ or α1D‐ARs in the rat bladder are involved in the activation of the bladder mechanosensory Aδ fibres during bladder filling, and that this activation may not be related to bladder microcontractions.
High‐density lipoprotein inhibits human M1 macrophage polarization through redistribution of caveolin‐1
Authors: Lee Man K S , Moore Xiao‐Lei , Fu Yi , Al‐Sharea Annas , Dragoljevic Dragana , Fernandez‐Rojo Manuel A , Parton Robert , Sviridov Dmitri , Murphy Andrew J , Chin‐Dusting Jaye P F
Published: September 2015

Background and Purpose

Monocyte‐derived macrophages are critical in the development of atherosclerosis and can adopt a wide range of functional phenotypes depending on their surrounding milieu. High‐density lipoproteins (HDLs) have many cardio‐protective properties including potent anti‐inflammatory effects. We investigated the effects of HDL on human macrophage phenotype and the mechanisms by which these occur.

Experimental Approach

Human blood monocytes were differentiated into macrophages in the presence or absence of HDL and were then induced to either an inflammatory macrophage (M1) or anti‐inflammatory macrophage (M2) phenotype using LPS and IFN‐γ or IL‐4, respectively.

Key Results

HDL inhibited the induction of macrophages to an M1‐phenotype, as evidenced by a decrease in the expression of M1‐specific cell surface markers CD192 and CD64, as well as M1‐associated inflammatory genes TNF‐α, IL‐6 and MCP‐1 (CCL2). HDL also inhibited M1 function by reducing the production of ROS. In contrast, HDL had no effect on macrophage induction to the M2‐phenotype. Similarly, methyl‐β‐cyclodextrin, a non‐specific cholesterol acceptor also suppressed the induction of M1 suggesting that cholesterol efflux is important in this process. Furthermore, HDL decreased membrane caveolin‐1 in M1 macrophages. We confirmed that caveolin‐1 is required for HDL to inhibit M1 induction as bone marrow‐derived macrophages from caveolin‐1 knockout mice continued to polarize into M1‐phenotype despite the presence of HDL. Moreover, HDL decreased ERK1/2 and STAT3 phosphorylation in M1 macrophages.

Conclusions and Implications

We concluded that HDL reduces the induction of macrophages to the inflammatory M1‐phenotype via redistribution of caveolin‐1, preventing the activation of ERK1/2 and STAT3.

Linked Articles

This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4
Valproic acid protects against haemorrhagic shock‐induced signalling changes via PPARγ activation in an in vitro model
Authors: Zuckermann Alexandra M E , La Ragione Roberto M , Baines Deborah L , Williams Robin S B
Published: September 2015

Background and Purpose

Valproic acid (VPA), a widely used epilepsy and bipolar disorder treatment, provides acute protection against haemorrhagic shock‐induced mortality in a range of in vivo models through an unknown mechanism. In the liver, this effect occurs with a concomitant protection against a decrease in GSK3β‐Ser9 phosphorylation. Here, we developed an in vitro model to investigate this protective effect of VPA and define a molecular mechanism.

Experimental Approach

The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia and hypothermia) to investigate the changes in GSK3β‐Ser9 phosphorylation for a 4 h period following treatment with VPA, related congeners, PPAR agonists, antagonists and siRNA.

Key Results

Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduced the reduced GSK3β‐Ser9 phosphorylation shown in vivo during haemorrhagic shock, and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream β‐catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several VPA‐related compounds with known PPARγ agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPARγ blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPARγ using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock‐like conditions.

Conclusion and Implications

Changes in GSK3β‐Ser9 phosphorylation in in vivo haemorrhagic shock models can be modelled in vitro, and this has identified a role for PPARγ activation in the protective role of VPA.
Mindful Deviation through Combining Causation and Effectuation: A Design Theory‐Based Study of Technology Entrepreneurship
Authors: Agogué Marine , Lundqvist Mats , Middleton Karen Williams
Published: September 2015

Technology entrepreneurship can be seen as building upon, while also deviating from, technological paths. Such deviation has primarily been described as singular events where individuals with prior knowledge discover a new opportunity. In this article, we will instead study deviation as a process of collective decision making, seen more as something mindful than singular. The purpose is to explore mindful deviation as decision making by nascent technology entrepreneurs as they conceptualize an early platform technology. Based on case assignments undertaken by 13 teams in a venture creation programme, C‐K design theory is used to trace how nascent technology entrepreneurs in action combine causal and effectual decision‐making logics. Individually answered questionnaires also offered insights into how the entrepreneurs perceived their decision making in hindsight. The findings break with our received wisdom around how opportunities are recognized as well as how effectual and causal logics occur. As a result, mindful deviation through combinations of effectual and causal logic is suggested as a means to understand early‐stage technology entrepreneurship.
The employment dynamics of less‐educated men in the United States: The role of self‐employment
Authors: Ahn Taehyun
Published: September 2015

Using data from the 1979 National Longitudinal Survey of Youth, I construct a sample of working‐age males and examine the employment dynamics with a particular focus on the role of self‐employment for less‐educated men in the US. I find that men responding they had at some point been self‐employed tend to spend less time in non‐employment than other less‐educated men. The results from the dynamic multinomial logit model reveal positive aspects of self‐employment by indicating that less‐educated men who were self‐employed in the previous year were less likely to be non‐employed in the future as compared to those who were paid workers in the previous year.
What young people with spina bifida want to know about sex and are not being told
Authors: Akre C. , Light A. , Sherman L. , Polvinen J. , Rich M.
Published: September 2015

Objective

The aim of this paper was to examine sexual knowledge, concerns and needs of youth with spina bifida (SB) to inform the medical community on ways to better support their sexual health.

Methods

As part of the Video Intervention/Prevention Assessment (VIA) – transitions, a prospective cohort study, 309 h of video data were collected from 14 participants (13–28 years old) with SB. Participants were loaned a video camcorder for 8–12 weeks to shoot visual narratives about any aspects of their lives. V/A visual narratives were analysed with grounded theory using NVivo.

Results

Out of 14 participants, 11 (six women) addressed issues surrounding romantic relationships and sexuality in their video clips. Analysis revealed shared concerns, questions and challenges regarding sexuality gathered under four main themes: romantic relationships, sexuality, fertility and parenthood, and need for more talk on sexuality.

Conclusions

Youth with SB reported difficulties in finding answers to questions regarding their sexuality, romantic relationships and fertility. This study revealed a need for help from the medical community to inform and empower youth with SB in the area of sexual health. Through sexual and reproductive health education with patients and parents starting at an early age, medical providers can further encourage healthy emotional and physical development in adolescents transitioning into adulthood.
Prenatal exposure to persistent organic pollutants and offspring allergic sensitization and lung function at 20 years of age
Authors: Hansen S. , Strøm M. , Olsen S. F. , Dahl R. , Hoffmann H. J. , Granström C. , Rytter D. , Bech B. H. , Linneberg A. , Maslova E. , Kiviranta H. , Rantakokko P. , Halldorsson T. I.
Published: September 2015

Background

Prenatal exposures to persistent organic pollutants (POPs) have been associated with asthma medication use and self‐reported symptoms, but associations with lung function and allergic sensitization have been minimally explored. The aim of the study was to examine the associations between prenatal exposures to POPs and allergic sensitization and lung function in 20‐year‐old offspring.

Methods

In a Danish cohort of 965 pregnant women established in 1988–1989, six polychlorinated biphenyl (PCB) congeners, hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p’‐DDE) were quantified in archived maternal serum drawn in gestational week 30 (n = 872). Among those with available maternal exposure information, at age 20, 421 offspring attended attended a clinical examination including measurements of allergic sensitization (serum‐specific IgE ≥ 0.35 kUA/L) (n = 418) and lung function [forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)] (n = 414).

Results

There were no associations between maternal concentrations of POPs and offspring allergic sensitization at 20 years of age. Maternal concentrations of POPs were, however, positively associated with offspring airway obstruction (FEV1/FVC < 75%). Compared to offspring in the first tertile of exposure, offspring in the third tertile of dioxin‐like PCB exposure had an OR of 2.96 (95% CI: 1.14–7.70). Similar associations for non‐dioxin‐like PCBs, HCB, and p,p’‐DDE were 2.68 (1.06–6.81), 2.63 (1.07, 6.46), and 2.87 (1.09, 7.57), respectively. No associations were observed with reduced lung function (FEV1% of predicted value < 90%).

Conclusion and Clinical Relevance

Our data indicate that prenatal exposure to POPs appears to be associated with airway obstruction but not allergic sensitization at 20 years of age. The findings support that chronic obstructive lung diseases may have at least part of their origins in early life.
Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults
Authors:   VRC 602 Study Team, Ledgerwood J E , Coates E E , Yamshchikov G , Saunders J G , Holman L , Enama M E , DeZure A , Lynch R M , Gordon I , Plummer S , Hendel C S , Pegu A , Conan-Cibotti M , Sitar S , Bailer R T , Narpala S , McDermott A , Louder M , O'Dell S , Mohan S , Pandey J P , Schwartz R M , Hu Z , Koup R A , Capparelli E , Mascola J R , Graham B S
Published: September 2015

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.
Patients with Pendred syndrome: is cochlear implantation beneficial?
Authors: van Nierop J.W.I. , Huinck W.J. , Pennings R.J.E. , Admiraal R.J.C. , Mylanus E.A.M. , Kunst H.P.M.
Published: September 2015

Objective

To evaluate the benefit of cochlear implantation in patients with Pendred syndrome.

Design

Retrospective study.

Setting

Tertiary centre.

Participants and main outcome measures

Speech perception was measured using a phonetically balanced word list at a sound pressure level of 65 dB. Post‐operative phoneme scores at 12‐month for adults and 36‐month for children with Pendred syndrome were compared to scores of patients with an enlarged vestibular aqueduct (EVA) and a reference group with an unknown cause of hearing impairment. Quality of life was measured with the Nijmegen Cochlear Implant Questionnaire to evaluate the differences between pre‐ and post‐implantation.

Results

The mean post‐operative phoneme scores were as follows: in the Pendred group, 91% (n = 16; SD = 10) for children and 78% (n = 7; SD = 14) for adults; in the reference group, 79% (n = 59; SD = 20) for children and 73% (n = 193; SD = 18) for adults; and in the EVA group, 84% (n = 6; SD = 7) for children and 66% (n = 12; SD = 22) for adults. A significant difference in speech perception was found between the children of the Pendred group and the reference group of 11.4% (SE = 5.2; P = 0.031). Between the adults, a difference of 11.2% (SE = 6.7; P = 0.094) was found. The difference between the Pendred group and the EVA group was 5.7%(SE = 4.5; P = 0.22) for children and 9.9% (SE = 8.7; P = 0.28) for adults. A significant improvement post‐implantation in four of the six subdomains of the quality of life questionnaire was found: basic sound perception (P = 0.002), advanced sound perception (P = 0.004), speech production (P = 0.018) and activity limitations (P = 0.018). The two not significant subdomains were self‐esteem (P = 0.164) and social interaction (P = 0.107).

Conclusions

After cochlear implantation, children with Pendred syndrome performed better than the reference group with respect to speech perception, however, adults performed similar. No significant differences were found between the Pendred and EVA group. Consequently, during pre‐operative counselling, the two groups of patients may be considered comparable in terms of expected speech perception performance after cochlear implantation.
High frequency of contact allergy to implant and bone cement components, in particular gentamicin, in cemented arthroplasty with complications: usefulness of late patch test reading
Authors: Thomas Benjamin , Kulichova Daniela , Wolf Ronald , Summer Burkhard , Mahler Vera , Thomas Peter
Published: September 2015

Background

Arthroplasty patients with complications may be sensitized to implant components.

Objectives

To quantify patch test reactions to implant materials in aseptic cemented arthroplasty patients with complications, and to evaluate the benefit of late patch test reading at D6.

Methods

Analyses of patch test reactions to baseline series and bone cement components and of the questionnaire‐aided histories of 250 consecutive patients with suspected implant allergy were performed. Patch tests were read at D2, D3, and D6.

Results

There were 187 positive reactions to the 29 allergens of the baseline series, and 52 to the seven allergens of the bone cement series. Forty‐nine of 250 patients reacted to the bone cement series. In contrast to ‘early allergens’ such as fragrance mix, late reading at D6 increased the number of positive reactions by 11/32 for nickel, 1/5 for cobalt, and 2/4 for chromium. With bone cement components, most reactions were to gentamicin (25 of 250 patients), and 17 of 25 appeared only at D6.

Conclusion

Late reading is useful for patch tests with metals and bone cement components. With only D2/D3 readings, 32 reactions to nickel, cobalt, chromium and bone cement components would have been missed. This underlines the utility of late reading in general and in complicated cemented arthroplasty patients, given the unexpectedly high number of gentamicin reactions.
The bowel cancer awareness campaign ‘Be Clear on Cancer’: sustained increased pressure on resources and over‐accessed by higher social grades with no increase in cancer detected
Authors: Hall S. J. , Peacock J. D. H. , Cochrane L. A. , Peacock O. , Tierney G. M. , Tou S. I. H. , Lund J. N.
Published: September 2015

Aim

To evaluate the impact of the national ‘Be Clear on Cancer’ bowel cancer reminder campaign on service and diagnosis at a single UK institution. Secondly, to evaluate the socio‐economic background of patients referred before and after the reminder campaign compared with the regional demographic.

Method

Suspected cancer 2‐week wait patients in the 3 months precampaign, postcampaign and after the reminder campaign were included. Demographics, investigations and diagnosis were recorded. The postcode was used to allocate a National Readership Survey social grade.

Results

Three hundred and eighty‐three referrals were received in the 3 months precampaign, 550 postcampaign and 470 postreminder campaign. There were significant increases in the monthly referral rates following the campaign (P < 0.001 in both the post‐ and postreminder periods). Significantly more patients from social grades AB and C1C2 than expected from regional demographics were referred precampaign and after the reminder campaign (P < 0.001 in each case). There were no significant differences between the proportions of patients diagnosed with colorectal cancer in the three study periods (P = 0.710).

Conclusion

The ‘Be Clear on Cancer’ bowel cancer campaign has had a significant sustained impact on resources. It has failed to increase referrals among lower socio‐economic grades, leading to an increase in ‘worried well’ referrals and no change in numbers, or the stage, of colorectal cancers diagnosed.
Faculty Participation in and Needs around Community Engagement within a Large Multiinstitutional Clinical and Translational Science Awardee
Authors: Chung Bowen , Norris Keith , Mangione Carol , del Pino Homero E. , Jones Loretta , Castro Daniel , Wang Christina , Bell Douglas , Vangala Sitaram , Kahn Katherine , Brown Arleen F.
Published: September 2015

Community engagement is recommended to ensure the public health impact of NIH‐funded science. To understand the prevalence of community‐engaged research and faculty interest in and needs around this, from 2012 to 2013, an online survey (n = 3,022) was sent to UCLA Clinical and Translational Science Institute faculty. Among respondents, 45% reported community‐engaged project participation in the last year and 64% an interest in learning about community‐engaged research. Over 50% indicated career development and pilot grants would increase participation in community‐engaged research. A greater percentage of pretenure than tenured faculty (pretenure 54.9%, tenured 42.2%, p = 0008) noted faculty promotion criteria incentivizing community‐engaged research would increase participation. In adjusted analyses, African American (OR 4.06, CI 1.68–9.82, p = 0.002) and Latino (OR 1.91, CI 1.10–3.33, p = 0.022) faculty had higher odds of prior participation in community‐engaged projects than Whites. Female faculty had greater odds of interest (OR 1.40, CI 1.02–1.93, p = 0.038) in learning about community‐engaged research than males. African American (OR 4.31, CI 1.42–13.08, p = 0.010) and Asian/Pacific Islander (OR 2.24, CI 1.52–3.28, p < 0.001) faculty had greater interest in learning about community‐engaged research than Whites. To build community‐engaged faculty research capacity, CTSAs’ may need to focus resources on female and minority faculty development.
Applying Process Improvement Methods to Clinical and Translational Research: Conceptual Framework and Case Examples
Authors: Daudelin Denise H. , Selker Harry P. , Leslie Laurel K.
Published: September 2015

There is growing appreciation that process improvement holds promise for improving quality and efficiency across the translational research continuum but frameworks for such programs are not often described. The purpose of this paper is to present a framework and case examples of a Research Process Improvement Program implemented at Tufts CTSI. To promote research process improvement, we developed online training seminars, workshops, and in‐person consultation models to describe core process improvement principles and methods, demonstrate the use of improvement tools, and illustrate the application of these methods in case examples. We implemented these methods, as well as relational coordination theory, with junior researchers, pilot funding awardees, our CTRC, and CTSI resource and service providers. The program focuses on capacity building to address common process problems and quality gaps that threaten the efficient, timely and successful completion of clinical and translational studies.
The extramedical use and diversion of opioid substitution medications and other medications in prison settings in Australia following the introduction of buprenorphine–naloxone film
Authors: White Nancy , Ali Robert , Larance Briony , Zador Deborah , Mattick Richard P. , Degenhardt Louisa
Published: September 2015

Introduction and Aims

Around 65% of people incarcerated in prisons in Australia, America and Europe have a history of drug dependence, sometimes treated with opioid substitution treatment (OST) medications. Studies report that those in treatment in prison do engage in some level of diversion to others, whether on a voluntary or coerced basis. We aimed to examine the use of prescribed and non‐prescribed OST medications by those in prisons, especially buprenorphine–naloxone film (BNX‐F); the extent of non‐adherence and diversion and reasons for such practices; and the impact of the introduction of BNX‐F into the prison system.

Design and Methods

Mixed methods study drawing on: (i) structured interviews with current OST clients (n = 60) who reported being incarcerated in the 12 months prior to being interviewed and (ii) qualitative interviews with key experts working in corrections and prison (or justice) health settings.

Results

The majority were prescribed OST medications in prison, with 25% removing all or part of their supervised dose on at least one occasion, and 44% reporting use of non‐prescribed medications. Some reported intravenous use (14% injected). One‐third of OST recipients reported selling/sharing OST medications with others in prison. The introduction of BNX‐F into the prison system saw different diversion methods used and removal from dosing within prison.

Discussion and Conclusions

Despite prison being a highly regulated and controlled environment, some level of diversion and sharing of psychoactive medication occurs among prisoners. The buprenorphine formulations used in OST present particular challenges with respect to supervised dosing in this setting. [White N, Ali R, Larance B, Zador D, Mattick RP, Degenhardt L. The extramedical use and diversion of opioid substitution medications and other medications in prison settings in Australia following the introduction of buprenorphine–naloxone film. Drug Alcohol Rev 2015;●●:●●–●●]
Effect of 4 years subcutaneous insulin infusion treatment on albuminuria, kidney function and HbA1c compared with multiple daily injections: a longitudinal follow‐up study
Authors: Rosenlund S. , Hansen T. W. , Andersen S. , Rossing P.
Published: September 2015

Aim

The effect of insulin pump [continuous subcutaneous insulin infusion (CSII)] treatment on diabetes complications in a modern clinical setting is largely unknown. We investigated the effect of 4 years CSII treatment on HbA1c, albuminuria and kidney function compared with multiple daily injections (MDI) in a single‐centre clinical setting.

Methods

All patients initiating CSII treatment from 2004 to 2010 and followed for at least 4 years were included in the study: 193 people with Type 1 diabetes were matched (1 : 2) with 386 patients treated with MDI in the same period. Matching was based on diabetes duration, gender, HbA1c and normo‐, micro‐ or macroalbuminuria at baseline. Urinary albumin/creatinine ratio (UACR) was measured yearly and annual change assessed from linear regression.

Results

CSII‐ vs. MDI‐treated patients were comparable at baseline. After 4 years, HbA1c was 62 ± 11 vs. 68 ± 11 mmol/mol (7.8 ± 1.0 vs. 8.4 ± 1.0%) (P < 0.001). Annual UACR change in CSII‐ vs. MDI‐treated patients was [mean (95% confidence interval)] −10.1 (−13.3; −6.8) vs. −1.2 (−3.6; 0.9)% (P < 0.001). Reduction in UACR was significantly associated with CSII treatment after adjustment for age, gender, diabetes duration, estimated GFR, UACR, mean arterial pressure, HbA1c, cholesterol, renin–angiotensin–aldosterone system inhibition, anti‐hypertensive treatment and smoking (P < 0.001). This remained significant (P < 0.001) when only including patients on stable renin–angiotensin–aldosterone system inhibition during follow‐up (n = 465).

Conclusions

Treatment with CSII over 4 years independently reduced HbA1c and UACR compared with MDI. Reduced UACR may be due to less glycaemic variability because the effect of CSII on HbA1c could only partially explain the effect. This needs confirmation in randomized controlled trials.
Seeing the forest and trees: whole‐body and whole‐brain imaging for circadian biology
Authors: Ode K. L. , Ueda H. R.
Published: September 2015

Recent advances in methods for making mammalian organs translucent have made possible whole‐body fluorescent imaging with single‐cell resolution. Because organ‐clearing methods can be used to image the heterogeneous nature of cell populations, they are powerful tools to investigate the hierarchical organization of the cellular circadian clock, and how the clock synchronizes a variety of physiological activities. In particular, methods compatible with genetically encoded fluorescent reporters have the potential to detect circadian activity in different brain regions and the circadian‐phase distribution across the whole body. In this review, we summarize the current methods and strategy for making organs translucent (removal of lipids, decolourization of haemoglobin and adjusting the refractive index of the specimen). We then discuss possible applications to circadian biology. For example, the coupling of circadian rhythms among different brain regions, brain activity in sleep–wake cycles and the role of migrating cells such as immune cells and cancer cells in chronopharmacology.
The systemic control of circadian gene expression
Authors: Gerber A. , Saini C. , Curie T. , Emmenegger Y. , Rando G. , Gosselin P. , Gotic I. , Gos P. , Franken P. , Schibler U.
Published: September 2015

The mammalian circadian timing system consists of a central pacemaker in the brain's suprachiasmatic nucleus (SCN) and subsidiary oscillators in nearly all body cells. The SCN clock, which is adjusted to geophysical time by the photoperiod, synchronizes peripheral clocks through a wide variety of systemic cues. The latter include signals depending on feeding cycles, glucocorticoid hormones, rhythmic blood‐borne signals eliciting daily changes in actin dynamics and serum response factor (SRF) activity, and sensors of body temperature rhythms, such as heat shock transcription factors and the cold‐inducible RNA‐binding protein CIRP. To study these systemic signalling pathways, we designed and engineered a novel, highly photosensitive apparatus, dubbed RT‐Biolumicorder. This device enables us to record circadian luciferase reporter gene expression in the liver and other organs of freely moving mice over months in real time. Owing to the multitude of systemic signalling pathway involved in the phase resetting of peripheral clocks the disruption of any particular one has only minor effects on the steady state phase of circadian gene expression in organs such as the liver. Nonetheless, the implication of specific pathways in the synchronization of clock gene expression can readily be assessed by monitoring the phase‐shifting kinetics using the RT‐Biolumicorder.
Circadian control of β‐cell function and stress responses
Authors: Lee J. , Liu R. , de Jesus D. , Kim B. S. , Ma K. , Moulik M. , Yechoor V.
Published: September 2015

Circadian disruption is the bane of modern existence and its deleterious effects on health; in particular, diabetes and metabolic syndrome have been well recognized in shift workers. Recent human studies strongly implicate a ‘dose‐dependent’ relationship between circadian disruption and diabetes. Genetic and environmental disruption of the circadian clock in rodents leads to diabetes secondary to β‐cell failure. Deletion of Bmal1, a non‐redundant core clock gene, leads to defects in β‐cell stimulus‐secretion coupling, decreased glucose‐stimulated ATP production, uncoupling of OXPHOS and impaired glucose‐stimulated insulin secretion. Both genetic and environmental circadian disruptions are sufficient to induce oxidative stress and this is mediated by a disruption of the direct transcriptional control of the core molecular clock and Bmal1 on Nrf2, the master antioxidant transcription factor in the β‐cell. In addition, circadian disruption also leads to a dysregulation of the unfolded protein response and leads to endoplasmic reticulum stress in β‐cells. Both the oxidative and endoplasmic reticulum (ER) stress contribute to an impairment of mitochondrial function and β‐cell failure. Understanding the basis of the circadian control of these adaptive stress responses offers hope to target them for pharmacological modulation to prevent and mitigate the deleterious metabolic consequences of circadian disruption.
Circadian rhythm‐related genes: implication in autoimmunity and type 1 diabetes
Authors: Lebailly B. , Boitard C. , Rogner U. C.
Published: September 2015

Recent gene association and functional studies have proven the implication of several circadian rhythm‐related genes in diabetes. Diabetes has been related to variation in central circadian regulation and peripheral oscillation. Different transcriptional regulators have been identified. Circadian genes are clearly implicated in metabolic pathways, pancreatic function and in type 2 diabetes. Much less evidence has been shown for the link between circadian regulation and type 1 diabetes. The hypothesis that circadian genes are involved in type 1 diabetes is reinforced by findings that the immune system undergoes circadian variation and that several autoimmune diseases are associated with circadian genes. Recent findings in the non‐obese diabetic mouse model pinpoint to specific mechanisms controlling type 1 diabetes by the clock‐related geneArntl2in the immune system.
Simultaneous Right and Left Atrial Appendage Thrombus in a Patient with Atrial Fibrillation: A Lesson to Remember
Authors: Davila Carlos D. , Pandian Natesa G.
Published: September 2015

We report a case of simultaneous right and left atrial appendage thrombi in a 76‐year‐old‐man with atrial fibrillation. Although transesophageal echocardiography is considered a routine diagnostic procedure, complete and comprehensive visualization of both atrial appendages is of paramount importance, particularly with the introduction of new therapeutic options like left atrial appendage exclusion devices. We expect to raise awareness among clinicians of the prevalence and implications of bilateral atrial appendage thrombi in common clinical practice.
The topographic specificity of muscle reinnervation predicts function
Authors: O'Daly Andres , Rohde Charles , Brushart Thomas
Published: September 2015

Functional testing has assumed a progressively dominant role in validating the success of experimental nerve repair. Results obtained in one model, however, cannot predict the results in others because they reflect the coordinated interaction of several muscles across multiple joints. As a result, many combinations of topographically correct and incorrect muscle reinnervation could produce the same result. We have developed a binary model in which elbow flexors and extensors are reinnervated, and elbow flexion and extension are the functions tested. The musculocutaneous and radial nerves of Lister‐Hooded rats were subjected to axonotmetic injuries that produced increasing degrees of axonal misdirection at the site of injury ranging from simple crush to transection and rotational offset of proximal and distal stumps. Elbow function was tested with a device that requires coordinated elbow extension to reach sugar pellets and flexion to return them to the mouth. After 12 weeks of regeneration, motoneurons projecting to the distal musculocutaneous nerve were retrogradely labelled with WGA‐Ruby and scored regarding their location within musculocutaneous or radial motoneuron pools. The severity of axonal misdirection resulting from the initial surgery was mirrored by progressive degrees of inappropriate reinnervation of the musculocutaneous nerve by radial nerve axons. The specificity of reinnervation predicted elbow function (r = 0.72), whereas the number of motoneurons regenerating did not. This model is thus well suited to study the interaction of regeneration specificity and function across a single joint, and to produce data that can be generalized more broadly than those obtained from more complex models.
Intrathecal urocortin I in the spinal cord as a murine model of stress hormone‐induced musculoskeletal and tactile hyperalgesia
Authors: Larson Alice A. , Nunez Myra G. , Kissel Casey L. , Kovács Katalin J.
Published: September 2015

Stress is antinociceptive in some models of pain, but enhances musculoskeletal nociceptive responses in mice and muscle pain in patients with fibromyalgia syndrome. To test the hypothesis that urocortins are stress hormones that are sufficient to enhance tactile and musculoskeletal hyperalgesia, von Frey fibre sensitivity and grip force after injection of corticotropin‐releasing factor (CRF), urocortin I and urocortin II were measured in mice. Urocortin I (a CRF1 and CRF2 receptor ligand) produced hyperalgesia in both assays when injected intrathecally (i.t.) but not intracerebroventricularly, and only at a large dose when injected peripherally, suggesting a spinal action. Morphine inhibited urocortin I‐induced changes in nociceptive responses in a dose‐related fashion, confirming that changes in behaviour reflect hyperalgesia rather than weakness. No tolerance developed to the effect of urocortin I (i.t.) when injected repeatedly, consistent with a potential to enhance pain chronically. Tactile hyperalgesia was inhibited by NBI‐35965, a CRF1 receptor antagonist, but not astressin 2B, a CRF2 receptor antagonist. However, while urocortin I‐induced decreases in grip force were not observed when co‐administered i.t. with either NBI‐35965 or astressin 2B, they were even more sensitive to inhibition by astressin, a non‐selective CRF receptor antagonist. Together these data indicate that urocortin I acts at CRF receptors in the mouse spinal cord to elicit a reproducible and persistent tactile (von Frey) and musculoskeletal (grip force) hyperalgesia. Urocortin I‐induced hyperalgesia may serve as a screen for drugs that alleviate painful conditions that are exacerbated by stress.
Impacts of local adaptation of forest trees on associations with herbivorous insects: implications for adaptive forest management
Authors: Sinclair Frazer H. , Stone Graham N. , Nicholls James A. , Cavers Stephen , Gibbs Melanie , Butterill Philip , Wagner Stefanie , Ducousso Alexis , Gerber Sophie , Petit Rémy J. , Kremer Antoine , Schönrogge Karsten
Published: September 2015

Disruption of species interactions is a key issue in climate change biology. Interactions involving forest trees may be particularly vulnerable due to evolutionary rate limitations imposed by long generation times. One mitigation strategy for such impacts is Climate matching – the augmentation of local native tree populations by input from nonlocal populations currently experiencing predicted future climates. This strategy is controversial because of potential cascading impacts on locally adapted animal communities. We explored these impacts using abundance data for local native gallwasp herbivores sampled from 20 provenances of sessile oak (Quercus petraea) planted in a common garden trial. We hypothesized that non‐native provenances would show (i) declining growth performance with increasing distance between provenance origin and trial site, and (ii) phenological differences to local oaks that increased with latitudinal differences between origin and trial site. Under a local adaptation hypothesis, we predicted declining gallwasp abundance with increasing phenological mismatch between native and climate‐matched trees. Both hypotheses for oaks were supported. Provenance explained significant variation in gallwasp abundance, but no gall type showed the relationship between abundance and phenological mismatch predicted by a local adaptation hypothesis. Our results show that climate matching would have complex and variable impacts on oak gall communities.
Inguinal percutaneous ultrasound to locate cryptorchid testes
Authors: Coomer R. P. C. , Gorvy D. A. , McKane S. A. , Wilderjans H.
Published: September 2015

Standing laparoscopic removal of abdominally retained cryptorchid testes may reduce patient morbidity and speed recovery compared with traditional laparotomy because anaesthesia is avoided and skin incisions are smaller. Reliably locating the testis preoperatively is therefore optimal to avoid unnecessary surgical morbidity and expense. We describe and review the results of a simple method of location using ultrasound scanning of the inguinal region, with a negative result indicating abdominal retention. One hundred and twenty‐seven horses with 141 cryptorchid testes were identified. Eighty‐five testes were identified inguinally: 56 abdominal. Two inguinally retained testes were not observed on ultrasound (false negatives) and 2 testes were considered inguinal but subsequently had to be removed from the abdomen (false positives). Sensitivity of inguinal ultrasound to predict the location of cryptorchid testes was therefore 98% and specificity 97%. The technique described herein proved a reliable technique to locate cryptorchid testes prior to surgery, minimising morbidity and cost. Suspect cryptorchids with no external evidence of testes should undergo a screening blood test prior to this ultrasound method of diagnosis.