bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of a combination of gefitinib and methotrexate to treat tubal ectopic pregnancies (GEM II): study protocol
Authors: Horne Andrew W , Skubisz Monika M , Doust Ann , Duncan W Colin , Wallace Euan , Critchley Hilary O D , Johns Terrance G , Norman Jane E , Bhattacharya Siladitya , Mollison Jill , Rassmusen Michael , Tong Stephen
Published: July 2013

Introduction

Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/L

Methods and analysis

We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.

Ethics and dissemination

Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.

Trial registration number

ACTRN12611001056987.
Soft drink intake and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative
Authors: Lu Bing , Ahmad Oneeb , Zhang Fang-Fang , Driban Jeffrey B , Duryea Jeffrey , Lapane Kate L , McAlindon Timothy , Eaton Charles B
Published: July 2013

Objectives

We examine the prospective association of soft drink consumption with radiographic progression of knee osteoarthritis (OA).

Design

Prospective cohort study.

Setting

This study used data from the osteoarthritis initiative (OAI).

Participants

In OAI, 2149 participants with radiographic knee OA and having dietary data at baseline were followed up to 12, 24, 36 and 48 months.

Measures

The soft drink consumption was assessed with a Block Brief Food Frequency Questionnaire completed at baseline. To evaluate knee OA progression, we used quantitative medial tibiofemoral joint space width (JSW) based on plain radiographs. The multivariate linear models for repeated measures were used to test the independent association between soft drink intake and the change in JSW over time, while adjusting for body mass index and other potential confounding factors.

Results

In stratified analyses by gender, we observed a significant dose–response relationship between baseline soft drink intake and adjusted mean change of JSW in men. With increasing levels of soft drink intake (none, ≤1, 2–4 and ≥5 times/week), the mean decreases of JSW were 0.31, 0.39, 0.34 and 0.60 mm, respectively. When we further stratified by obesity, a stronger dose–response relationship was found in non-obese men. In obese men, only the highest soft drink level (≥5 times/week) was associated with increased change in JSW compared with no use. In women, no significant association was observed.

Conclusions

Our results suggest that frequent consumption of soft drinks may be associated with increased OA progression in men. Replication of these novel findings in other studies demonstrating the reduction in soft drink consumption leads to delay in OA progression is needed.
A pilot study on record reviewing with a priori patient selection
Authors: Cihangir Sezgin , Borghans Ine , Hekkert Karin , Muller Hein , Westert Gert , Kool Rudolf B
Published: July 2013

Objectives

To investigate whether a priori selection of patient records using unexpectedly long length of stay (UL-LOS) leads to detection of more records with adverse events (AEs) compared to non-UL-LOS.

Design

To investigate the opportunities of the UL-LOS, we looked for AEs in all records of patients with colorectal cancer. Within this group, we compared the number of AEs found in records of patients with a UL-LOS with the number found in records of patients who did not have a UL-LOS.

Setting

Our study was done at a general hospital in The Netherlands. The hospital is medium sized with approximately 30 000 admissions on an annual basis. The hospital has two major locations in different cities where both primary and secondary care is provided.

Participants

The patient records of 191 patients with colorectal cancer were reviewed.

Primary and secondary outcome measures

Number of triggers and adverse events were the primary outcome measures.

Results

In the records of patients with colorectal cancer who had a UL-LOS, 51% of the records contained one or more AEs compared with 9% in the reference group of non-UL-LOS patients. By reviewing only the UL-LOS group with at least one trigger, we found in 84% (43 out of 51) of these records at least one adverse event.

Conclusions

A priori selection of patient records using the UL-LOS indicator appears to be a powerful selection method which could be an effective way for healthcare professionals to identify opportunities to improve patient safety in their day-to-day work.
Non-communicable diseases, infection and survival in a retrospective cohort of Indigenous and non-Indigenous adults in central Australia
Authors: Einsiedel Lloyd , Fernandes Liselle , Joseph Sheela , Brown Alex , Woodman Richard J
Published: July 2013

Objectives

We hypothesise that rising prevalence rates of non-communicable diseases (NCDs) increase infection risk and worsen outcomes among socially disadvantaged Indigenous Australians undergoing a rapid epidemiological transition.

Design

Available pathology, imaging and discharge morbidity codes were retrospectively reviewed for a period of 5 years prior to admission with a bloodstream infection (BSI), 1 January 2003 to 30 June 2007.

Participants

558 Indigenous and 55 non-Indigenous community residents of central Australia.

Outcome measures

The effects of NCDs on risk of infection and death were determined after stratifying by ethnicity.

Results

The mean annual BSI incidence rates were far higher among Indigenous residents (Indigenous, 937/100 000; non-Indigenous, 64/100 000 person-years; IRR=14.6; 95% CI 14.61 to 14.65, p<0.001). Indigenous patients were also more likely to have previous bacterial infections (68.7% vs 34.6%; respectively, p<0.001), diabetes (44.3% vs 20%; p<0.001), harmful alcohol consumption (37% vs 12.7%; p<0.001) and other communicable diseases (human T-lymphotropic virus type 1, 45.2%; strongyloidiasis, 36.1%; hepatitis B virus, 12.9%). Among Indigenous patients, diabetes increased the odds of currentStaphylococcus aureusBSI (OR=1.6, 95% CI 1.0 to 2.5) and prior skin infections (adjusted OR=2.1, 95% CI 1.4 to 3.3). Harmful alcohol consumption increased the odds of currentStreptococcus pneumoniaeBSI (OR=1.57, 95% CI 1.02 to 2.40) and of previous BSI (OR=1.7, 95% CI 1.1 to 2.5), skin infection (OR=1.7, 95% CI 1.1 to 2.6) or pneumonia (OR=4.3, 95% CI 2.8 to 6.7). Twenty-six per cent of Indigenous patients died at a mean (SD) age of 47±15 years. Complications of diabetes and harmful alcohol consumption predicted 28-day mortality (non-rheumatic heart disease, HR=2.9; 95% CI 1.4 to 6.2; chronic renal failure, HR=2.6, 95%CI 1.0 to 6.5; chronic liver disease, HR=3.3, 95% CI 1.6 to 6.7).

Conclusions

In a socially disadvantaged population undergoing a rapid epidemiological transition, NCDs are associated with an increased risk of infection and BSI-related mortality. Complex interactions between communicable diseases and NCDs demand an integrated approach to management, which must include the empowerment of affected populations to promote behavioural change.
Chronic disease multimorbidity transitions across healthcare interfaces and associated costs: a clinical-linkage database study
Authors: Kadam Umesh T , Uttley John , Jones Peter W , Iqbal Zafar
Published: July 2013

Objective

To investigate multimorbidity transitions from general practice populations across healthcare interfaces and the associated healthcare costs.

Design

Clinical-linkage database study.

Setting

Population (N=60 660) aged 40 years and over registered with 53 general practices in Stoke-on-Trent.

Participants

Population with six specified multimorbidity pairs were identified based on hypertension, diabetes mellitus (DM), coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF) and chronic kidney disease (CKD).

Main outcomes measures

Chronic disease registers were linked to accident and emergency (A&E) and hospital admissions for a 3-year time period (2007–2009), and associated costs measured by Healthcare Resource Groups. Associations between multimorbid groups and direct healthcare costs were compared with their respective single disease groups using linear regression methods, adjusting for age, gender and deprivation.

Results

In the study population, there were 9735 patients with hypertension and diabetes (16%), 3574 with diabetes and CHD (6%), 2894 with diabetes and CKD (5%), 1855 with COPD and CHD (3%), 754 with CHF and COPD (1%) and 1425 with CHF and CKD (2%). Transition, defined as at least one episode in each of the 3-year time periods, was as follows: patients with hypertension and DM had the fewest transitions in the 3-year time period (37% A&E episode and 51% hospital admission), but those with CHF and CKD had the most transitions (67% A&E episode and 79% hospital admission). The average 3-year total costs per multimorbid patient for A&E episodes ranged from £69 to £166 and for hospital admissions ranged from between £2289 and £5344. The adjusted costs were significantly higher for all six multimorbid groups compared with their respective single disease groups.

Conclusions

Specific common multimorbid pairs are associated with higher healthcare transitions and differential costs. Identification of multimorbidity type and linkage of information across interfaces provides opportunities for targeted intervention and delivery of integrated care.
A study protocol for performance evaluation of a new academic intensive care unit facility: impact on patient care
Authors: Ferri Mauricio , Zygun David A , Harrison Alexandra , Stelfox Henry T
Published: July 2013

Background

Healthcare facility construction is increasing because of population demand and the need to replace ageing infrastructure. Research suggests that there may be a relationship between healthcare environment and patient care. To date, most evaluations of new healthcare facilities are derived from techniques used in other industries and focus on physical, financial and architectural performance. However, few studies have evaluated the impact of healthcare facility design on processes and outcomes of patient care.

Study aims

The primary objective of this study was to investigate the impact of relocation to a new intensive care unit (ICU) facility on clinical performance measures. This study also proposes to develop and test a framework for facility performance evaluation using accepted ICU design guidelines and Donabedian's model for healthcare quality.

Methods and analysis

We will utilise a mixed-methods, observational, retrospective, controlled, before-and-after design to take advantage of the quasiexperimental conditions created with the construction of a new ICU facility in Calgary, Canada. For the qualitative substudy, we will conduct individual interviews with end-users to understand their impressions and experiences with the new environment and perform thematic analysis. For the quantitative substudy, we will compare process of care indicators and patient outcomes for the 12-month period before and after relocation to the new facility. Two other local ICU facilities that did not undergo structural change during the study period will serve as controls. We will triangulate qualitative and quantitative results utilising a novel framework.

Ethics and dissemination

The results of this study will contribute in understanding the impact of new ICU facilities on clinical performance measures centred on patients, their families and healthcare providers. The framework will complement existing building performance evaluation techniques and help healthcare administrators plan new ICU facilities. The University of Calgary Research Ethics Board approved this study protocol.
Adherence management for patients with cancer taking capecitabine: a prospective two-arm cohort study
Authors: Krolop Linda , Ko Yon-Dschun , Schwindt Peter Florian , Schumacher Claudia , Fimmers Rolf , Jaehde Ulrich
Published: July 2013

Objective

To develop and evaluate a multiprofessional modular medication management to assure adherence to capecitabine.

Methods

The study was conducted as a prospective, multicentred observational cohort study. All participants received pharmaceutical care consisting of oral and written information. Daily adherence was defined as percentage of days with correctly administered capecitabine doses and assessed using medication event monitoring. According to their daily adherence during the first cycle, patients were identified as initially non-adherent (<90% adherence) or adherent (≥90% adherence). Initially non-adherent patients received additional adherence support.

Results

Seventy-three patients with various tumour entities were enrolled, 58 were initially adherent and 15 non-adherent. Median daily adherence of initially non-adherent patients increased from 85.7% to 97.6% during the observation period of six cycles. Throughout all cycles, median daily adherence of initially adherent patients was 100.0%. Daily adherence was not associated with sociodemographic and disease-related factors. No patient was non-persistent.

Conclusions

An early adherence screening effectively distinguishes between patients adhering and non-adhering to capecitabine. The provision of specific adherence support is associated with enhanced adherence of initially non-adherent patients, whereas initially adherent patients remain adherent for at least six cycles without specific support. Our needs-based approach helps to use available resources for adherence management efficiently.
Explaining the barriers to and tensions in delivering effective healthcare in UK care homes: a qualitative study
Authors: Robbins Isabella , Gordon Adam , Dyas Jane , Logan Philippa , Gladman John
Published: July 2013

Objective

To explain the current delivery of healthcare to residents living in UK care homes.

Design

Qualitative interview study using a grounded theory approach.

Setting

6 UK care homes and primary care professionals serving the homes.

Participants

Of the 32 participants, there were 7 care home managers, 2 care home nurses, 9 care home assistants, 6 general practitioners (GPs), 3 dementia outreach nurses, 2 district nurses, 2 advanced nurse practitioners and 1 occupational therapist.

Results

5 themes were identified: complex health needs and the intrinsic nature of residents’ illness trajectories; a mismatch between healthcare requirements and GP time; reactive or anticipatory healthcare?; a dissonance in healthcare knowledge and ethos; and tensions in the responsibility for the healthcare of residents. Care home managers and staff were pivotal to healthcare delivery for residents despite their perceived role in social care provision. Formal healthcare for residents was primarily provided via one or more GPs, often organised to provide a reactive service that did not meet residents’ complex needs. Deficiencies were identified in training required to meet residents’ needs for both care home staff as well as GPs. Misunderstandings, ambiguities and boundaries around roles and responsibilities of health and social care staff limited the development of constructive relationships.

Conclusions

Healthcare of care home residents is difficult because their needs are complex and unpredictable. Neither GPs nor care home staff have enough time to meet these needs and many lack the prerequisite skills and training. Anticipatory care is generally held to be preferable to reactive care. Attempts to structure care to make it more anticipatory are dependent on effective relationships between GPs and care home staff and their ability to establish common goals. Roles and responsibilities for many aspects of healthcare are not made explicit and this risks poor outcomes for residents.
Electronic health record-based triggers to detect potential delays in cancer diagnosis
Authors: Murphy Daniel R , Laxmisan Archana , Reis Brian A , Thomas Eric J , Esquivel Adol , Forjuoh Samuel N , Parikh Rohan , Khan Myrna M , Singh Hardeep
Published: July 2013

Background

Delayed diagnosis of cancer can lead to patient harm, and strategies are needed to proactively and efficiently detect such delays in care. We aimed to develop and evaluate ‘trigger’ algorithms to electronically flag medical records of patients with potential delays in prostate and colorectal cancer (CRC) diagnosis.

Methods

We mined retrospective data from two large integrated health systems with comprehensive electronic health records (EHR) to iteratively develop triggers. Data mining algorithms identified all patient records with specific demographics and a lack of appropriate and timely follow-up actions on four diagnostic clues that were newly documented in the EHR: abnormal prostate-specific antigen (PSA), positive faecal occult blood test (FOBT), iron-deficiency anaemia (IDA), and haematochezia. Triggers subsequently excluded patients not needing follow-up (eg, terminal illness) or who had already received appropriate and timely care. Each of the four final triggers was applied to a test cohort, and chart reviews of randomly selected records identified by the triggers were used to calculate positive predictive values (PPV).

Results

The PSA trigger was applied to records of 292 587 patients seen between 1 January 2009 and 31 December 2009, and the CRC triggers were applied to 291 773 patients seen between 1 March 2009 and 28 February 2010. Overall, 1564 trigger positive patients were identified (426 PSA, 355 FOBT, 610 IDA and 173 haematochezia). Record reviews revealed PPVs of 70.2%, 66.7%, 67.5%, and 58.3% for the PSA, FOBT, IDA and haematochezia triggers, respectively. Use of all four triggers at the study sites could detect an estimated 1048 instances of delayed or missed follow-up of abnormal findings annually and 47 high-grade cancers.

Conclusions

EHR-based triggers can be used successfully to flag patient records lacking follow-up of abnormal clinical findings suspicious for cancer.
The role of technology in clinician-to-clinician communication
Authors: McElroy Lisa M , Ladner Daniela P , Holl Jane L
Published: July 2013

Incomplete, fragmented and poorly organised communications contribute to more than half the errors that lead to adverse and sentinel events. Meanwhile, communication software and devices with expanding capabilities are rapidly proliferating and being introduced into the healthcare setting. Clinicians face a large communication burden, which has been exacerbated by the additional challenge of selecting a mode of communication. In addition to specific communication devices, some hospitals have implemented advanced technological systems to assist with communication. However, few studies have provided empirical evidence of the specific advantages and disadvantages of the different devices used for communication. Given the increasing quantities of information transmitted to and by clinicians, evaluations of how communication methods and devices can improve the quality, safety and outcomes of healthcare are needed.
An evaluation of the referral process in the emergency department
Authors: Croft Susan J , Barnes Jane , Ginnis Clare , Chatters Robin , Mason Suzanne
Published: July 2013

Introduction

Making an effective telephone referral is an important skill for an emergency department (ED) clinician. It is essential for patient safety that the information is conveyed in a succinct manner to the correct inpatient specialty. The aim of this study was to assess: the impact of grade of staff making the referral; specialty referred to; and condition or patient problem. It also aimed to identify current problems or barriers in the referral process.

Methods

This prospective study took place in one large teaching hospital in the UK. There were two parts: data collection to obtain information on each referral made by ED staff; and questionnaires administered to obtain opinions on the current referral process from both staff making and receiving the referrals.

Results

Data were collected over 6 days and included 362 referrals. The mean evaluation of the referral process (scored 0–4) for all referrals was 3.34 (SD 0.95). 22 ED staff responding (64.7%) felt that some specialties were more difficult to refer to than others. 60.6% of non-ED staff accepting referrals felt they would like some form of senior ED screening process prior to referral compared with 20.6% of ED staff. The most common topics commented on were communication, education and process.

Discussion

There are differences in understanding and opinion between ED and non-ED staff about the referral process. There are also factors which influence ease of referral: specialty referring to and patient problem. More intervention studies are required to identify solutions that can be implemented and sustained in routine practice.
Number of medications and road traffic crashes in senior Swedish drivers: a population-based matched case-control study
Authors: Monárrez-Espino Joel , Laflamme Lucie , Elling Berty , Möller Jette
Published: July 2013

Objective

This study investigated the relationship between the number of different medications dispensed (NDMD) to senior drivers and the risk of injurious road traffic crashes (RTCs).

Design

A matched case-control study with data from various population-based national registers was conducted. Cases were drivers aged 50–80 years involved in a crash in Sweden between 2005 and 2009. Only the first non-alcohol-related RTC was studied. Controls were residents with a valid license who did not crash. Four controls were matched by sex, age (year and month of birth), and place of residence. Exposure to NDMD prior to the crash date was assessed using four time periods: 1–8, 1–15, 1–30 and 1–90 days. Conditional logistic regression was used and analyses adjusted for civil status, occupation and dispensation of medications affecting the cardiovascular or nervous systems (C/N).

Results

ORs (95% CI) increased progressively with the NDMD. For 1–8 days the OR ranged from 1.15 (1.10 to 1.20) for 1–2 medications to 1.27 (1.13 to 1.42) for five or more medications. The magnitude of the effect declined gradually with longer exposure periods, but remained when five or more medications were used. Adjusting for C/N medications resulted in slightly higher effects; for 1–8 days it ranged from 1.16 (1.10 to 1.23) for 1–2 medications to 1.35 (1.17 to 1.56) for five or more, with similar trends by exposure period. The highest effects were seen for single crashes and for drivers aged 66–80 years.

Conclusions

The NDMD was linked to the likelihood of a senior driver being involved in an injurious RTC. The strength of the association steadily increased with increased NDMD, especially when medications were taken closer to the index date, or when more than five medications were dispensed.
Preventing deaths and injuries from house fires: an outcome evaluation of a community-based smoke alarm installation programme
Authors: Istre Gregory R , McCoy Mary A , Moore Billy J , Roper Carey , Stephens-Stidham Shelli , Barnard Jeffrey J , Carlin Debra K , Stowe Martha , Anderson Ron J
Published: July 2013

Background

Few studies have examined the impact of community-based smoke alarm (SA) distribution programmes on the occurrence of house fire-related deaths and injuries (HF-D/I).

Objective

To determine whether the rate of HF-D/I differed for programme houses that had a SA installed through a community-based programme called Operation Installation, versus non-programme houses in the same census tracts that had not received such a SA.

Methods

Teams of volunteers and firefighters canvassed houses in 36 high-risk target census tracts in Dallas, TX, between April 2001 and April 2011, and installed lithium-powered SAs in houses where residents were present and gave permission. We then followed incidence of HF-D/I among residents of the 8134 programme houses versus the 24 346 non-programme houses.

Results

After a mean of 5.2 years of follow-up, the unadjusted HF-D/I rate was 68% lower among residents of programme houses versus non-programme houses (3.1 vs 9.6 per 100 000 population, respectively; rate ratio, 0.32; 95% CI 0.10 to 0.84). Multivariate analysis including several demographic variables showed that the adjusted HF-D/I rate in programme houses was 63% lower than non-programme houses. The programme was most effective in the first 5 years after SA installation, with declining difference in rates after the 6th year, probably due to SAs becoming non-functional during that time.

Conclusions

This collaborative, community-based SA installation programme was effective at preventing deaths and injuries from house fires, but the duration of effectiveness was less than 10 years.
How long do smoke alarms function? A cross-sectional follow-up survey of a smoke alarm installation programme
Authors: McCoy Mary A , Roper Carey , Campa Emily , Stephens-Stidham Shelli , Carlin Debra K , Istre Gregory R
Published: July 2013

Objective

To assess the functionality of lithium-powered smoke alarms that had been installed through a community-based programme called Operation Installation (OI).

Methods

A random sample was chosen of homes that had received smoke alarms through OI, 2, 4, 6, 8 and 10 years previously. Sampled homes were visited, and information collected included functional status of smoke alarms. For homes in the 6-, 8- and 10-year sample, smoke alarms were removed and tested for battery and alarm function.

Results

800 homes were included in the survey results; 1884 smoke alarms had been installed through OI. The proportion of homes that had at least one functioning OI smoke alarm ranged from 91.8% for year 2 sample to 19.8% for year 10. Of the originally installed smoke alarms in year 10 sample, 45.5% had been removed and 59% (64/108) of those that were still installed were not functioning. Multivariate analysis showed that the presence of at least one working alarm in the home was associated positively with the number of smoke alarms that were originally installed and whether the original occupant was still living in the home, and negatively with the length of time since the smoke alarm was installed, and whether there was a smoker in the home. Testing of the smoke alarms revealed that most non-functioning alarms had missing or dead batteries.

Conclusions

Less than a quarter of the originally installed smoke alarms were still present and functioning by year 10. These findings have important implications for smoke alarm installation programmes.
Sex differences in neonatal mortality in Sarlahi, Nepal: the role of biology and environment
Authors: Rosenstock Summer , Katz Joanne , Mullany Luke C , Khatry Subarna K , LeClerq Steven C , Darmstadt Gary L , Tielsch James M
Published: July 2013

Background

Studies in South Asia have documented increased risk of neonatal mortality among girls, despite evidence of a biological survival advantage. Associations between gender preference and mortality are cited as reasons for excess mortality among girls. This has not, however, been tested in statistical models.

Methods

A secondary analysis of data from a population-based randomised controlled trial of newborn infection prevention conducted in rural southern Nepal was used to estimate sex differences in early and late neonatal mortality, with girls as the reference group. The analysis investigated which underlying biological factors (immutable factors specific to the newborn or his/her mother) and environmental factors (mutable external factors) might explain observed sex differences in mortality.

Results

Neonatal mortality was comparable by sex (Ref=girls; OR 1.06, 95% CI 0.92 to 1.22). When stratified by neonatal period, boys were at 20% (OR 1.20, 95% CI 1.02% to 1.42%) greater risk of early and girls at 43% (OR 0.70, 95% CI 0.51% to 0.94%) greater risk of late neonatal mortality. Biological factors, primarily respiratory depression and unconsciousness at birth, explained excess early neonatal mortality among boys. Increased late neonatal mortality among girls was explained by a three-way environmental interaction between ethnicity, sex and prior sibling composition (categorised as primiparous newborns, infants born to families with prior living boys or boys and girls, and infants born to families with only prior living girls).

Conclusions

Risk of neonatal mortality inverted between the early and late neonatal periods. Excess risk of early neonatal death among boys was consistent with biological expectations. Excess risk for late neonatal death among girls was not explained by overarching gender preference or preferential care-seeking for boys as hypothesised, but was driven by increased risk among Madeshi girls born to families with only prior girls.
Deployed antimicrobial stewardship: an audit of antimicrobial use at Role 3
Authors: Fletcher Tom E , Hutley E , Adcock C J , Martin N , Wilson D R
Published: July 2013

Introduction

Infections due to multidrug-resistant organisms are increasingly prevalent, and antimicrobial stewardship has become a priority for many healthcare organisations, including the Defence Medical Services. In military environments, infectious diseases remain a significant burden, and infections complicating the care of modern complex combat injuries are well recognised. A focus on infection prevention and control in the deployed environment is essential, and an important element of this is an antimicrobial formulary and stewardship programme. This audit analyses antimicrobial prescribing practices by military clinicians in patients admitted to UK/US Role 3 medical treatment facility in Camp Bastion, Afghanistan, relative to the UK published guidance.

Methods

Retrospective case note review of all in-patient admissions during two time periods (October 2011 and October 2012). Notes were independently reviewed by an infection specialist not involved in the management of the patients.

Results

475 case notes were reviewed, of which 250 received antimicrobials. Coalition forces represented the most common patient group (131/250), with battle injury the most frequent indication (139/250) for antimicrobial prescription, followed by disease (100/250). A total of 302 antimicrobials were prescribed, with co-amoxiclav being the most frequently used antibiotic in 74% (185/250) of patients. 84.8% (212/250) were prescribed antimicrobials in line with the antimicrobial formulary. In battle injury, 93.5% (130/139) of antimicrobial prescriptions were in line with the formulary compared with 73.9% (82/111) in disease and non-battle injury patients.

Conclusions

Maintaining a strong infection control effort in the deployed setting, even in a stabilised operational environment, is difficult, but our data show good compliance to the antimicrobial formulary superior to that reported in civilian hospitals. To improve this, further innovative strategies are required, combined with a continued focus on infection control basics across the full spectrum of care.
Neuregulin 1-alpha regulates phosphorylation, acetylation, and alternative splicing in lymphoblastoid cells
Authors: Ghahramani Seno Mohammad M. , Gwadry Fuad G. , Hu Pingzhao , Scherer Stephen W.
Published: July 2013

Neuregulins (NRGs) are signaling molecules involved in various cellular and developmental processes. Abnormal expression and (or) genomic variations of some of these molecules, such as NRG1, have been associated with disease conditions such as cancer and schizophrenia. To gain a comprehensive molecular insight into possible pathways/networks regulated by NRG1-alpha, we performed a global expression profiling analysis on lymphoblastoid cell lines exposed to NRG1-alpha. Our data show that this signaling molecule mainly regulates coordinated expression of genes involved in three processes: phosphorylation, acetylation, and alternative splicing. These processes have fundamental roles in proper development and function of various tissues including the central nervous system (CNS)—a fact that may explain conditions associated with NRG1 dysregulations such as schizophrenia. The data also suggest NRG1-alpha regulates genes (FBXO41) and miRNAs (miR-33) involved in cholesterol metabolism. Moreover, RPN2, a gene already shown to be dysregulated in breast cancer cells, is also differentially regulated by NRG1-alpha treatment.
Livestock and the promise of genomics
Authors: Ludu Jagjit S. , Plastow Graham S.
Published: July 2013

The emergence of the middle class in countries such as Brazil, Russia, India, and China is resulting in increasing global demand for animal-based food products. This increase represents a unique opportunity for Canadian livestock producers to export their products to new markets and expand Canada’s reputation as a global provider of safe and highest quality food items. This article has two major themes. First, current Canadian contributions to livestock genomics in the cattle and swine industries are outlined. Second, important future opportunities are discussed, including the high throughput collection of phenotypic data, development of environmentally friendly livestock, emergence of decision support software, and the use of Web 2.0. Through the use of genomic technologies, livestock producers can not only ensure that the nutritional demands of Canada are secured, but also play a pivotal role in ensuring the rest of the world is fed as well. Furthermore, investment through initiatives led by Genome Canada has ensured that Canada is favorably positioned to contribute cutting-edge solutions to meet this global challenge. Ultimately, genomic-based innovations will enable producers to increase efficiency, lower production costs, decrease the use of prophylactics, and limit the expenditure of resources.
Geomorphological evidence of cold-based glacier activity in South Victoria Land, Antarctica
Authors: Atkins C. B.
Published: July 2013

Cold-based glaciers have long been recognized as capable of covering and protecting landscapes. However, recent studies of modern cold-based glaciers in Antarctica show that, in some situations, erosion, deformation and deposition can occur. Recognizing the dual ability of cold-based glaciers to protect and preserve surfaces on the one hand and erode and modify on the other is important for correctly interpreting the often-subtle imprint of cold-based glaciers on landscapes. A range of geomorphological features related to cold-based glacier activity has now been documented along with an improved understanding of cold-based glacier structure, processes and interaction with various substrates. Collectively, this provides an enhanced ability to understand the impact of cold-based glaciers on landscapes and reappraise the geomorphological record. Such insight allows recognition of previously unknown glacial events and better interpretations of the landscape exposure record. This is particularly important at the margins of the Antarctic Ice Sheets, where past fluctuations in ice sheet volume and its contributions to post glacial sea-level rise are poorly constrained. This paper reviews the known geomorphological evidence associated with cold-based glaciers in the South Victoria Land region of the Transantarctic Mountains. It aims to provide progress towards a set of criteria for recognizing cold-based glacier activity in other regions and to highlight the implications of cold-based glacial activity for surface exposure studies and interpreting glacial history.
HIF-1α in heart: Protective mechanisms
Authors: Wu Joe , Chen Ping , Li Ying , Ardell Chris , Der Tatyana , Shohet Ralph , Chen Minghua , Wright Gary L.
Published: July 2013

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that directs many of the cellular responses to hypoxia. In these studies, we have used a mouse model containing a cardiac-specific, oxygen-stabilized, doxycycline (Dox)-off regulated HIF-1α transgene to probe the role of HIF-1α in cardioprotection. Hearts used in these studies were derived from wild-type (WT), noninduced (Non-I), and 2 day (2D) and 6 day (6D) Dox-deprived mice. Whereas HIF-1α protein is undetectable in WT mice, it is present in heart tissue of “noninduced” transgenic mice, presumably because of leakiness of the promoter construct. In mice denied Dox for 2 or 6 days, HIF-1α is overexpressed to a much greater extent than Non-I or WT animals, as expected. WT and HIF-1α-expressing hearts (Non-I, 2D and 6D induced) were subjected to 30 min of ischemia, and functional recovery was measured upon reperfusion. Recovery of preischemic left ventricular developed pressure was 14% for WT, 67% for Non-I hearts, 64% for 2D-induced, and 62% for 6D-induced hearts. 6D-induced HIF hearts have increased preischemic glycogen reserves, higher glycogen synthase protein levels, and significantly higher lactic acid release during ischemia. 6D-induced HIF hearts were also better able to maintain ATP levels during ischemia compared with WT and Non-I hearts. Interestingly, Non-I hearts showed no significant increase in glycogen reserves, glycolytic flux, or greater ATP preservation during ischemia and yet were protected to a similar extent as the 6D-induced hearts. Finally, the mitochondrial membrane potential of isolated adult myocytes was monitored during anoxia or treatments with cyanide and 2-deoxyglucose. HIF-1α expression was shown to protect mitochondrial polarization during both stress treatments. Taken together these data indicate that, while HIF-1α expression in heart does induce increases in compensatory glycolytic capacity, these changes are not necessarily required for cardioprotection, at least in this model of ischemic stress.
Does the combination of hyperkalemia and KATP activation determine excitation rate gradient and electrical failure in the globally ischemic fibrillating heart?
Authors: Taylor Tyson G. , Venable Paul W. , Booth Alicja , Garg Vivek , Shibayama Junko , Zaitsev Alexey V.
Published: July 2013

Ventricular fibrillation (VF) in the globally ischemic heart is characterized by a progressive electrical depression manifested as a decline in the VF excitation rate (VFR) and loss of excitability, which occur first in the subepicardium (Epi) and spread to the subendocardium (Endo). Early electrical failure is detrimental to successful defibrillation and resuscitation during cardiac arrest. Hyperkalemia and/or the activation of ATP-sensitive K+ (KATP) channels have been implicated in electrical failure, but the role of these factors in ischemic VF is poorly understood. We determined the VFR-extracellular K+ concentration ([K+]o) relationship in the Endo and Epi of the left ventricle during VF in globally ischemic hearts (Isch group) and normoxic hearts subjected to hyperkalemia (HighK group) or a combination of hyperkalemia and the KATP channel opener cromakalim (HighK-Crom group). In the Isch group, Endo and Epi values of [K+]o and VFR were compared in the early (0–6 min), middle (7–13 min), and late (14–20 min) phases of ischemic VF. A significant transmural gradient in VFR (Endo > Epi) was observed in all three phases, whereas a significant transmural gradient in [K+]o (Epi > Endo) occurred only in the late phase of ischemic VF. In the Isch group, the VFR decrease and inexcitability started to occur at much lower [K+]o than in the HighK group, especially in the Epi. Combining KATP activation with hyperkalemia only shifted the VFR-[K+]o curve upward (an effect opposite to real ischemia) without changing the [K+]o threshold for asystole. We conclude that hyperkalemia and/or KATP activation cannot adequately explain the heterogeneous electrical depression and electrical failure during ischemic VF.
Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women
Authors: Brunt Vienna E. , Miner Jennifer A. , Kaplan Paul F. , Halliwill John R. , Strycker Lisa A. , Minson Christopher T.
Published: July 2013

The individual effects of estrogen and progesterone on baroreflex function remain poorly understood. We sought to determine how estradiol (E2) and progesterone (P4) independently alter the carotid-cardiac and carotid-vasomotor baroreflexes in young women by using a hormone suppression and exogenous add-back design. Thirty-two young women were divided into two groups and studied under three conditions: 1) after 4 days of endogenous hormone suppression with a gonadotropin releasing hormone antagonist (control condition), 2) after continued suppression and 3 to 4 days of supplementation with either 200 mg/day oral progesterone ( N = 16) or 0.1 to 0.2 mg/day transdermal 17β-estradiol ( N = 16), and 3) after continued suppression and 3 to 4 days of supplementation with both hormones. Changes in heart rate (HR), mean arterial pressure (MAP), and femoral vascular conductance (FVC) were measured in response to 5 s of +50 mmHg external neck pressure to unload the carotid baroreceptors. Significant hormone effects on the change in HR, MAP, and FVC from baseline at the onset of neck pressure were determined using mixed model covariate analyses accounting for P4 and E2 plasma concentrations. Neither P4 ( P = 0.95) nor E2 ( P = 0.95) affected the HR response to neck pressure. Higher P4 concentrations were associated with an attenuated fall in FVC ( P = 0.01), whereas higher E2 concentrations were associated with an augmented fall in FVC ( P = 0.02). Higher E2 was also associated with an augmented rise in MAP ( P = 0.01). We conclude that progesterone blunts whereas estradiol enhances carotid-vasomotor baroreflex sensitivity, perhaps explaining why no differences in sympathetic baroreflex sensitivity are commonly reported between low and high combined hormone phases of the menstrual cycle.
The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium
Authors: Monasky Michelle M. , Taglieri Domenico M. , Henze Marcus , Warren Chad M. , Utter Megan S. , Soergel David G. , Violin Jonathan D. , Solaro R. John
Published: July 2013

In the present study, we compared the cardioprotective effects of TRV120023, a novel angiotensin II (ANG II) type 1 receptor (AT1R) ligand, which blocks G protein coupling but stimulates β-arrestin signaling, against treatment with losartan, a conventional AT1R blocker in the treatment of cardiac hypertrophy and regulation of myofilament activity and phosphorylation. Rats were subjected to 3 wk of treatment with saline, ANG II, ANG II + losartan, ANG II + TRV120023, or TRV120023 alone. ANG II induced increased left ventricular mass compared with rats that received ANG II + losartan or ANG II + TRV120023. Compared with saline controls, ANG II induced a significant increase in pCa50and maximum Ca2+-activated myofilament tension but reduced the Hill coefficient ( nH). TRV120023 increased maximum tension and pCa50, although to lesser extent than ANG II. In contrast to ANG II, TRV120023 increased nH. Losartan blocked the effects of ANG II on pCa50and nHand reduced maximum tension below that of saline controls. ANG II + TRV120023 showed responses similar to those of TRV120023 alone; compared with ANG II + losartan, ANG II + TRV120023 preserved maximum tension and increased both pCa50and cooperativity. Tropomyosin phosphorylation was lower in myofilaments from saline-treated hearts compared with the other groups. Phosphorylation of cardiac troponin I was significantly reduced in ANG II + TRV120023 and TRV120023 groups versus saline controls, and myosin-binding protein C phosphorylation at Ser282was unaffected by ANG II or losartan but significantly reduced with TRV120023 treatment compared with all other groups. Our data indicate that TRV120023-related promotion of β-arrestin signaling and enhanced contractility involves a mechanism promoting the myofilament response to Ca2+via altered protein phosphorylation. Selective activation of β-arrestin-dependent pathways may provide advantages over conventional AT1R blockers.
β3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure
Authors: Masutani Satoshi , Cheng Heng-Jie , Morimoto Atsushi , Hasegawa Hiroshi , Han Qing-Hua , Little William C. , Cheng Che Ping
Published: July 2013

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of β3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. β3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac β3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 μg/kg iv), a selective β3-adrenergic receptor antagonist (β3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after β3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/d tmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, β3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.