bluuebunny/crossref_metadata_2025 huggingface dataset:
Extending CRISPR-Cas9 Technology from Genome Editing to Transcriptional Engineering in the Genus Clostridium
Authors: Bruder Mark R. , Pyne Michael E. , Moo-Young Murray , Chung Duane A. , Chou C. Perry
Published: August 2016

The discovery and exploitation of the prokaryotic adaptive immunity system based on clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins have revolutionized genetic engineering. CRISPR-Cas tools have enabled extensive genome editing as well as efficient modulation of the transcriptional program in a multitude of organisms. Progress in the development of genetic engineering tools for the genus
Clostridium
has lagged behind that of many other prokaryotes, presenting the CRISPR-Cas technology an opportunity to resolve a long-existing issue. Here, we applied the
Streptococcus pyogenes
type II CRISPR-Cas9 (SpCRISPR-Cas9) system for genome editing in
Clostridium acetobutylicum
DSM792. We further explored the utility of the SpCRISPR-Cas9 machinery for gene-specific transcriptional repression. For proof-of-concept demonstration, a plasmid-encoded fluorescent protein gene was used for transcriptional repression in
C. acetobutylicum
. Subsequently, we targeted the carbon catabolite repression (CCR) system of
C. acetobutylicum
through transcriptional repression of the
hprK
gene encoding HPr kinase/phosphorylase, leading to the coutilization of glucose and xylose, which are two abundant carbon sources from lignocellulosic feedstocks. Similar approaches based on SpCRISPR-Cas9 for genome editing and transcriptional repression were also demonstrated in
Clostridium pasteurianum
ATCC 6013. As such, this work lays a foundation for the derivation of clostridial strains for industrial purposes.

IMPORTANCE
After recognizing the industrial potential of
Clostridium
for decades, methods for the genetic manipulation of these anaerobic bacteria are still underdeveloped. This study reports the implementation of CRISPR-Cas technology for genome editing and transcriptional regulation in
Clostridium acetobutylicum
, which is arguably the most common industrial clostridial strain. The developed genetic tools enable simpler, more reliable, and more extensive derivation of
C. acetobutylicum
mutant strains for industrial purposes. Similar approaches were also demonstrated in
Clostridium pasteurianum
, another clostridial strain that is capable of utilizing glycerol as the carbon source for butanol fermentation, and therefore can be arguably applied in other clostridial strains.
Disparity in maternal, newborn and child health services in high focus states in India: a district-level cross-sectional analysis
Authors: Awasthi Ashish , Pandey C M , Chauhan Rajesh K , Singh Uttam
Published: August 2016

Objectives

To examine the level and trend in the coverage gap of a set of interventions of maternal and child health services using a summary index and to assess the disparity in usage of maternal and child health services in the districts of high focus states of India.

Design

Data for the present study are taken from the Annual Health Survey (AHS), 2010–2013 and Census of India, 2011.

Settings

This study used secondary data from states having higher mortality and fertility rates, termed as high focus states in India.

Participants

District-level information regarding children aged 12–23 months and ever married women aged 15–49 years has been extracted from the AHS (2010–2013), and household amenities, female literacy and main workforce information has been obtained from the Census of India 2011.

Measures

2 summary indexes were calculated first for maternal and child health services and another for socioeconomic and development status, using data from AHS and Census. Cronbach's α was used to assess the internal consistency of the items used in the index.

Results

The result shows that the coverage gap is highest in Uttar Pradesh (37%) and lowest in Madhya Pradesh (21%). Converge gap and socioeconomic development are negatively correlated (r=−0.49, p=0.01). The average coverage gap was highest in the lowest quintile of socioeconomic development. There was an absolute change of 1.5% per year in coverage gap during 2009–2013. In regression analysis, the coefficient of determination was 0.24, β=−30.05, p=0.01 for a negative relationship between socioeconomic development and coverage gap.

Conclusions

There is a significant disparity in the usage of maternal and child healthcare services in the districts of India. Resource-rich people (urban residents and richest quintile) are way ahead of marginalised people (rural residents and poorest quintile) in the usage of healthcare services.
Systematic review of validated case definitions for diabetes in ICD-9-coded and ICD-10-coded data in adult populations
Authors: Khokhar Bushra , Jette Nathalie , Metcalfe Amy , Cunningham Ceara Tess , Quan Hude , Kaplan Gilaad G , Butalia Sonia , Rabi Doreen
Published: August 2016

Objectives

With steady increases in ‘big data’ and data analytics over the past two decades, administrative health databases have become more accessible and are now used regularly for diabetes surveillance. The objective of this study is to systematically review validated International Classification of Diseases (ICD)-based case definitions for diabetes in the adult population.

Setting, participants and outcome measures

Electronic databases, MEDLINE and Embase, were searched for validation studies where an administrative case definition (using ICD codes) for diabetes in adults was validated against a reference and statistical measures of the performance reported.

Results

The search yielded 2895 abstracts, and of the 193 potentially relevant studies, 16 met criteria. Diabetes definition for adults varied by data source, including physician claims (sensitivity ranged from 26.9% to 97%, specificity ranged from 94.3% to 99.4%, positive predictive value (PPV) ranged from 71.4% to 96.2%, negative predictive value (NPV) ranged from 95% to 99.6% and κ ranged from 0.8 to 0.9), hospital discharge data (sensitivity ranged from 59.1% to 92.6%, specificity ranged from 95.5% to 99%, PPV ranged from 62.5% to 96%, NPV ranged from 90.8% to 99% and κ ranged from 0.6 to 0.9) and a combination of both (sensitivity ranged from 57% to 95.6%, specificity ranged from 88% to 98.5%, PPV ranged from 54% to 80%, NPV ranged from 98% to 99.6% and κ ranged from 0.7 to 0.8).

Conclusions

Overall, administrative health databases are useful for undertaking diabetes surveillance, but an awareness of the variation in performance being affected by case definition is essential. The performance characteristics of these case definitions depend on the variations in the definition of primary diagnosis in ICD-coded discharge data and/or the methodology adopted by the healthcare facility to extract information from patient records.
Usage, adherence and attrition: how new mothers engage with a nurse-moderated web-based intervention to support maternal and infant health. A 9-month observational study
Authors: Sawyer Michael G , Reece Christy E , Bowering Kerrie , Jeffs Debra , Sawyer Alyssa C P , Peters Jacqueline D , Mpundu-Kaambwa Christine , Clark Jennifer J , McDonald Denise , Mittinty Murthy N , Lynch John W
Published: August 2016

Objectives

To identify factors predicting use, adherence and attrition with a nurse-moderated web-based group intervention designed to support mothers of infants aged 0–6 months.

Design

9-Month observational study.

Setting

Community maternal and child health service.

Participants

240 mothers attending initial postnatal health checks at community clinics who were randomly assigned to the intervention arm of a pragmatic preference randomised trial (total randomised controlled trial, n=819; response rate=45%).

Intervention

In the first week (phase I), mothers were assisted with their first website login by a research assistant. In weeks 2–7 (phase II), mothers participated in the web-based intervention with an expectation of weekly logins. The web-based intervention was comparable to traditional face-to-face new mothers’ groups. During weeks 8–26 (phase III), mothers participated in an extended programme at a frequency of their choosing.

Primary outcome measures

Number of logins and posted messages. Standard self-report measures assessed maternal demographic and psychosocial characteristics.

Results

In phase II, the median number of logins was 9 logins (IQR=1–25), and in phase III, it was 10 logins (IQR=0–39). Incident risk ratios from multivariable analyses indicated that compared to mothers with the lowest third of logins in phase I, those with the highest third had 6.43 times as many logins in phase II and 7.14 times in phase III. Fifty per cent of mothers logged-in at least once every 30 days for 147 days after phase I and 44% logged-in at least once in the last 30 days of the intervention. Frequency of logins during phase I was a stronger predictor of mothers’ level of engagement with the intervention than their demographic and psychosocial characteristics.

Conclusions

Mothers’ early use of web-based interventions could be employed to customise engagement protocols to the circumstances of individual mothers with the aim of improving adherence and reducing attrition with web-based interventions.

Trial registration number

ACTRN12613000204741; Results.
Exploring unintended consequences of policy initiatives in mental health: the example of Child and Adolescent Mental Health Services (CAMHS) in England
Authors: Foreman David M
Published: August 2016

Objectives

The impact of policy and funding on Child and Adolescent Mental Health Service (CAMHS) activity and capacity, from 2003 to 2012, was assessed. The focus was on preschool children (aged 0–4 years), as current and 2003 policy initiatives stressed the importance of ‘early intervention’.

Settings

National service capacity from English CAMHS mapping was obtained from 2003 to 2008 inclusive. English Hospital Episode Statistics (HES) for English CAMHS was obtained from 2003 to 2012. The Child and Adolescent Faculty of the Royal College of Psychiatrists surveyed its members about comparative 0–4-year service activity and attitudes in 2012.

Participants

CAMHS services in England provided HES and CAMHS mapping data. The Child and Adolescent Faculty of the Royal College of Psychiatrists are child psychiatrists, including trainees.

Outcome measures

CAMHS mapping data provided national estimates of total numbers of CAMHS patients, whereas HES data counted appointments or episodes of inpatient care. The survey reported on Child Psychiatrists' informal estimates of service activity and attitudes towards children aged 0–4 years.

Results

The association between service capacity and service activity was moderated by an interaction between specified funding and age, the youngest children benefiting least from specified funding and suffering most when it was withdrawn (Pr=0.005). Policy review and significant differences between age-specific HES trends (Pr<0.001) suggested this reflected prioritisation of older children. Clinicians were unaware of this effect at local level, though it significantly influenced their attitudes to prioritising this group (Pr=0.02).

Conclusions

If the new policy initiative for CAMHS is to succeed, it will need to have time-limited priorities attached to sustained, specified funding, with planning for limits as well as expansion. Data collection for policy evaluation should include measures of capacity and activity.
Semi-individualised Chinese medicine treatment as an adjuvant management for diabetic nephropathy: a pilot add-on, randomised, controlled, multicentre, open-label pragmatic clinical trial
Authors: Chan Kam Wa , Ip Tai Pang , Kwong Alfred Siu Kei , Lui Sing Leung , Chan Gary Chi Wang , Cowling Benjamin John , Yiu Wai Han , Wong Dickson Wai Leong , Liu Yang , Feng Yibin , Tan Kathryn Choon Beng , Chan Loretta Yuk Yee , Leung Joseph Chi Kam , Lai Kar Neng , Tang Sydney Chi Wai
Published: August 2016

Introduction

Diabetes mellitus and diabetic nephropathy (DN) are prevalent and costly to manage. DN is the leading cause of end-stage kidney disease. Conventional therapy blocking the renin–angiotensin system has only achieved limited effect in preserving renal function. Recent observational data show that the use of Chinese medicine (CM), a major form of traditional medicine used extensively in Asia, could reduce the risk of end-stage kidney disease. However, existing clinical practice guidelines are weakly evidence-based and the effect of CM remains unclear. This trial explores the effect of an existing integrative Chinese–Western medicine protocol for the management of DN.

Objective

To optimise parameters and assess the feasibility for a subsequent phase III randomised controlled trial through preliminary evaluation on the effect of an adjuvant semi-individualised CM treatment protocol on patients with type 2 diabetes with stages 2–3 chronic kidney disease and macroalbuminuria.

Methods and analysis

This is an assessor-blind, add-on, randomised, controlled, parallel, multicentre, open-label pilot pragmatic clinical trial. 148 patients diagnosed with DN will be recruited and randomised 1:1 to a 48-week additional semi-individualised CM treatment programme or standard medical care. Primary end points are the changes in estimated glomerular filtration rate and spot urine albumin-to-creatinine ratio between baseline and treatment end point. Secondary end points include fasting blood glucose, glycated haemoglobin, brain natriuretic peptide, fasting insulin, C peptide, fibroblast growth factor 23, urinary monocyte chemotactic protein-1, cystatin C, nephrin, transforming growth factor-β1 and vascular endothelial growth factor. Adverse events are monitored through self-completed questionnaire and clinical visits. Outcomes will be analysed by regression models. Enrolment started in July 2015.

Ethics and registration

This protocol is approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (reference number UW 14-301).

Trial registration number

NCT02488252.
Hypertensive disorders of pregnancy and risk of diabetes in Indian women: a cross-sectional study
Authors: Agrawal Sutapa , Fledderjohann Jasmine
Published: August 2016

Background

Epidemiological data from high-income countries suggest that women with hypertensive disorders of pregnancy (HDP) are more likely to develop diabetes later in life.

Objective

We investigated the association between pre-eclampsia and eclampsia (PE&E) during pregnancy and the risk of diabetes in Indian women.

Design

Cross-sectional study.

Setting

India.

Methods

Data from India's third National Family Health Survey (NFHS-3, 2005–2006), a cross-sectional survey of women aged 15–49 years, are used. Self-reported symptoms suggestive of PE&E were obtained from 39 657 women who had a live birth in the 5 years preceding the survey. The association between PE&E and self-reported diabetes status was assessed using multivariable logistic regression models adjusting for dietary intake, body mass index (BMI), tobacco smoking, alcohol drinking, frequency of TV watching, sociodemographic characteristics and geographic region.

Results

The prevalence of symptoms suggestive of PE&E in women with diabetes was 1.8% (n=207; 95% CI 1.5 to 2.0; p<0.0001) and 2.1% (n=85; 95% CI 1.8 to 2.3; p<0.0001), respectively, compared with 1.1% (n=304; 95% CI 1.0 to 1.4) and 1.2% (n=426; 95% CI 1.1 to 1.5) in women who did not report any PE&E symptoms. In the multivariable analysis, PE&E was associated with 1.6 times (OR=1.59; 95% CI 1.31 to 1.94; p<0.0001) and 1.4 times (OR=1.36; 95% CI 1.05 to 1.77; p=0.001) higher risk for self-reported diabetes even after controlling for dietary intake, BMI and sociodemographic characteristics.

Conclusions

HDP is strongly associated with the risk of diabetes in a large nationally representative sample of Indian women. These findings are important for a country which is already tackling the burden of young onset of diabetes in the population. However, longitudinal medical histories and a clinical measurement of diabetes are needed in this low-resource setting.
Patient safety priorities in mental healthcare in Switzerland: a modified Delphi study
Authors: Mascherek Anna C , Schwappach David L B
Published: August 2016

Objective

Identifying patient safety priorities in mental healthcare is an emerging issue. A variety of aspects of patient safety in medical care apply for patient safety in mental care as well. However, specific aspects may be different as a consequence of special characteristics of patients, setting and treatment. The aim of the present study was to combine knowledge from the field and research and bundle existing initiatives and projects to define patient safety priorities in mental healthcare in Switzerland. The present study draws on national expert panels, namely, round-table discussion and modified Delphi consensus method.

Design

As preparation for the modified Delphi questionnaire, two round-table discussions and one semistructured questionnaire were conducted. Preparative work was conducted between May 2015 and October 2015. The modified Delphi was conducted to gauge experts' opinion on priorities in patient safety in mental healthcare in Switzerland. In two independent rating rounds, experts made private ratings. The modified Delphi was conducted in winter 2015.

Results

Nine topics were defined along the treatment pathway: diagnostic errors, non-drug treatment errors, medication errors, errors related to coercive measures, errors related to aggression management against self and others, errors in treatment of suicidal patients, communication errors, errors at interfaces of care and structural errors.

Conclusions

Patient safety is considered as an important topic of quality in mental healthcare among experts, but it has been seriously neglected up until now. Activities in research and in practice are needed. Structural errors and diagnostics were given highest priority. From the topics identified, some are overlapping with important aspects of patient safety in medical care; however, some core aspects are unique.
Feasibility of repeated self-measurements of maximum step length and gait speed by community-dwelling older persons
Authors: Bongers Kim T J , Schoon Yvonne , Olde Rikkert Marcel G M
Published: August 2016

Objectives

Self-management of mobility and fall risk can be important in fall prevention; however, it remains unstudied. Therefore, the current study assessed whether community-dwelling older persons were able to repeatedly self-assess maximum step length (MSL) and gait speed (GS) in their own home for a 6-month period, how these tests changed during this period and if these changes were related to falling.

Design

This is a prospective study.

Setting

This study was conducted at home.

Participants

A total of 56 community-dwelling older adults (24 women (43%), mean age 76.2 (SD 3.9) years) entered the study; of which, 45 completed the study.

Methods

Participants performed MSL and GS once a week in their own home during a 6-month period.

Primary and secondary outcomes

Repeated MSL and GS measurements were the primary outcomes. Falls, self-management and mobility were the secondary outcomes.

Results

Self-assessment of MSL and GS by older persons is feasible. Compliance of repeatedly self-measuring MSL and GS was good; the median number of weekly measurements was 23.0 (88%) and 21.0 (81%) for MSL and GS, respectively. Drop-outs showed less self-management abilities compared to the participants who completed the study (p=0.049). Linear mixed models showed a small significant improvement in MSL and GS over time (p<0.001), without an influence on falling.

Conclusions

Most community-dwelling older persons are able and willing to repeatedly assess their MSL and GS. Self-managing mobility and fall risk did not increase fall occurrence. The fact that older persons can be actively involved in their own healthcare is clinically relevant. Further studies are needed to examine the (cost-)effectiveness of self-management in fall prevention interventions.
Estimating the economic burden of cardiovascular events in patients receiving lipid-modifying therapy in the UK
Authors: Danese Mark D , Gleeson Michelle , Kutikova Lucie , Griffiths Robert I , Azough Ali , Khunti Kamlesh , Seshasai Sreenivasa Rao Kondapally , Ray Kausik K
Published: August 2016

Objectives

To characterise the costs to the UK National Health Service of cardiovascular (CV) events among individuals receiving lipid-modifying therapy.

Design

Retrospective cohort study using Clinical Practice Research Datalink records from 2006 to 2012 to identify individuals with their first and second CV-related hospitalisations (first event and second event cohorts). Within-person differences were used to estimate CV-related outcomes.

Setting

Patients in the UK who had their first CV event between January 2006 and March 2012.

Participants

Patients ≥18 years who had a CV event and received at least 2 lipid-modifying therapy prescriptions within 180 days beforehand.

Primary and secondary outcome measures

Direct medical costs (2014 £) were estimated in 3 periods: baseline (pre-event), acute (6 months afterwards) and long-term (subsequent 30 months). Primary outcomes included incremental costs, resource usage and total costs per period.

Results

There were 24 093 patients in the first event cohort of whom 5274 were included in the second event cohort. The mean incremental acute CV event costs for the first event and second event cohorts were: coronary artery bypass graft/percutaneous transluminal coronary angioplasty (CABG/PTCA) £5635 and £5823, myocardial infarction £4275 and £4301, ischaemic stroke £3512 and £4572, heart failure £2444 and £3461, unstable angina £2179 and £2489 and transient ischaemic attack £1537 and £1814. The mean incremental long-term costs were: heart failure £848 and £2829, myocardial infarction £922 and £1385, ischaemic stroke £973 and £682, transient ischaemic attack £705 and £1692, unstable angina £328 and £677, and CABG/PTCA £−368 and £599. Hospitalisation accounted for 95% of acute and 61% of long-term incremental costs. Higher comorbidity was associated with higher long-term costs.

Conclusions

Revascularisation and myocardial infarction were associated with the highest incremental costs following a CV event. On the basis of real-world data, the economic burden of CV events in the UK is substantial, particularly among those with greater comorbidity burden.
Nutritional route in oesophageal resection trial II (NUTRIENT II): study protocol for a multicentre open-label randomised controlled trial
Authors: Berkelmans Gijs H K , Wilts Bas J W , Kouwenhoven Ewout A , Kumagai Koshi , Nilsson Magnus , Weijs Teus J , Nieuwenhuijzen Grard A P , van Det Marc J , Luyer Misha D P
Published: August 2016

Introduction

Early start of an oral diet is safe and beneficial in most types of gastrointestinal surgery and is a crucial part of fast track or enhanced recovery protocols. However, the feasibility and safety of oral intake directly following oesophagectomy remain unclear. The aim of this study is to investigate the effects of early versus delayed start of oral intake on postoperative recovery following oesophagectomy.

Methods and analysis

This is an open-label multicentre randomised controlled trial. Patients undergoing elective minimally invasive or hybrid oesophagectomy for cancer are eligible. Further inclusion criteria are intrathoracic anastomosis, written informed consent and age 18 years or older. Inability for oral intake, inability to place a feeding jejunostomy, inability to provide written consent, swallowing disorder, achalasia, Karnofsky Performance Status <80 and malnutrition are exclusion criteria. Patients will be randomised using online randomisation software. The intervention group (direct oral feeding) will receive a liquid oral diet for 2 weeks with gradually expanding daily maximums. The control group (delayed oral feeding) will receive enteral feeding via a jejunostomy during 5 days and then start the same liquid oral diet. The primary outcome measure is functional recovery. Secondary outcome measures are 30-day surgical complications; nutritional status; need for artificial nutrition; need for additional interventions; health-related quality of life. We aim to recruit 148 patients. Statistical analysis will be performed according to an intention to treat principle. Results are presented as risk ratios with corresponding 95% CIs. A two-tailed p<0.05 is considered statistically significant.

Ethics and dissemination

Our study protocol has received ethical approval from the Medical research Ethics Committees United (MEC-U). This study is conducted according to the principles of Good Clinical Practice. Verbal and written informed consent is required before randomisation. All data will be collected using an online database with adequate security measures.

Trial registration numbers

NCT02378948 and Dutch trial registry: NTR4972; Pre-results.
Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways
Authors: Hill Jonathan C , Kang Sujin , Benedetto Elena , Myers Helen , Blackburn Steven , Smith Stephanie , Dunn Kate M , Hay Elaine , Rees Jonathan , Beard David , Glyn-Jones Sion , Barker Karen , Ellis Benjamin , Fitzpatrick Ray , Price Andrew
Published: August 2016

Objectives

Current musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ).

Setting

A consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics.

Participants

Stakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients).

Outcome measures

Outcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test–retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM).

Results

Musculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be ‘highly relevant’ and ‘easy to understand’. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test–retest reliability was excellent, and convergent validity was strong (correlations 0.81–0.88).

Conclusions

A new musculoskeletal outcome measure has been developed through a coproduction process with patients to capture prioritised outcomes for use throughout the pathway and with different musculoskeletal conditions. Four validation cohorts found that the MSK-HQ had high completion rates, excellent test–retest reliability and strong convergent validity with reference standards. Further validation studies are ongoing, including a cohort with rheumatoid/inflammatory arthritis.
Comprehensive evidence-based review on European antitussives
Authors: Morice Alyn , Kardos Peter
Published: August 2016

Acute cough caused by viral respiratory tract infections is probably the most common illness to afflict mankind. Despite the widespread but ineffective prescribing of antibiotics, there is no specific therapy. Home remedies and over-the-counter medicines are the mainstay for treatment of this short-lived but debilitating condition where cough is a major troublesome symptom. Across Europe, there are large variations in the recommendations made by healthcare professionals for the treatment of acute cough. This has arisen through custom and practice based on the evidence of historical studies performed to standards well short of what would be considered legitimate today. Acute cough is particularly difficult to study in a controlled setting because of the high rate of spontaneous remission and a large placebo effect. Here we detail the validated modern methodology used to assess the efficacy of antitussives and review the drugs commonly used in Europe against these standards.
Avoiding costly hospitalisation at end of life: findings from a specialist palliative care pilot in residential care for older adults
Authors: Chapman Michael , Johnston Nikki , Lovell Clare , Forbat Liz , Liu Wai-Man
Published: August 2016

Objectives

Specialist palliative care is not a standardised component of service delivery in nursing home care in Australia. Specialist palliative care services can increase rates of advance care planning, decrease hospital admissions and improve symptom management in such facilities. New approaches are required to support nursing home residents in avoiding unnecessary hospitalisation and improving rates of dying in documented preferred place of death. This study examined whether the addition of a proactive model of specialist palliative care reduced resident transfer to the acute care setting, and achieved a reduction in hospital deaths.

Methods

A quasi-experimental design was adopted, with participants at 4 residential care facilities. The intervention involved a palliative care nurse practitioner leading ‘Palliative Care Needs Rounds’ to support clinical decision-making, education and training. Participants were matched with historical decedents using propensity scores based on age, sex, primary diagnosis, comorbidities and the Aged Care Funding Instrument rating. Outcome measures included participants’ hospitalisation in the past 3 months of life and the location of death.

Results

The data demonstrate that the intervention is associated with a substantial reduction in the length of hospital stays and a lower incidence of death in the acute care setting. While rates of hospitalisation were unchanged on average, length of admission was reduced by an average of 3.22 days (p<0.01 and 95% CI −5.05 to −1.41), a 67% decrease in admitted days.

Conclusions

The findings have significant implications for promoting quality outcomes through models of palliative care service delivery in residential facilities.
The transition to clinical expert: enhanced decision making for children aged less than 5 years attending the paediatric ED with acute respiratory conditions
Authors: Bowen Leah , Shaw Alison , Lyttle Mark D , Purdy Sarah
Published: August 2016

Background

Rates of unplanned paediatric admissions are persistently high. Many admissions are short-stay events, lasting less than 48 hours.

Objective

This qualitative research explores factors that influence clinical decision making in the paediatric ED (PED) for children under 5 attending with acute respiratory conditions, focusing on how management decisions adapt with increasing experience.

Method

Semi-structured interviews were conducted with 15 PED clinicians (doctors, emergency nurse practitioners and registered nurses) with varying levels of experience in paediatric emergency medicine (PEM), emergency medicine or paediatrics. Audio-recorded interviews were transcribed and analysed thematically.

Results

There were clear differences in decision-making approaches between experienced clinicians and junior staff. The latter were more risk adverse, relying heavily on guidelines, set admission criteria, clinical theory and second opinions. This was particularly true for doctors. ‘Informal’ learning was apparent in accounts from less-experienced doctors and nurses, whereby tacit knowledge and risk management played an increasing role in the development of clinical intuition that permitted rapid assessment and treatment of young patients.

Conclusions

The emergence of intuition entwined with approaches to risk management and the role of these skills in clinical decision making, carry implications for the development of training programmes for clinicians working in PEM. Enhanced training for such groups to permit development of the supplementary skills described in this study could have the ability to improve care delivery and even reduce paediatric admissions.
Relative risk for cardiovascular morbidity in hemodialysis patients regarding gene polymorphism for IL-10, IL-6, and TNF
Authors: Tosic Dragovic J. , Popovic J. , Djuric P. , Jankovic A. , Bulatovic A. , Barovic M. , Pravica V. , Marinkovic J. , Dimkovic N.
Published: August 2016

Uremia-related inflammation is prone to be a key factor to explain high cardiovascular morbidity in hemodialysis patients. Genetic susceptibility may be of importance, including IL-10, IL-6, and TNF. The aim was to analyze IL-10, IL-6, and TNF gene polymorphisms in a group of hemodialysis patients and to correlate the findings with cardiovascular morbidity. This study included 169 patients on regular hemodialysis at Zvezdara University Medical Center. Gene polymorphisms for IL-10, IL-6 and TNF were determined using PCR. These findings were correlated with the cardiovascular morbidity data from patient histories. Heterozygots for IL-10 gene showed significantly lower incidence of cardiovascular events (p = 0.05) and twice lower risk for development of myocardial infarction, but experienced twice higher risk for left ventricular hypertrophy. Regarding TNF gene polymorphism, patients with A allele had 1.5-fold higher risk for cerebrovascular accident and cardiovascular events and 2-fold higher risk for hypertension and peripheral vascular disease. Patients with G allele of IL-6 gene experienced 1.5-fold higher risks for cerebrovascular accident. We need studies with larger number of patients for definitive conclusion about the influence of gene polymorphisms on cardiovascular morbidity in hemodialysis patients and its importance in everyday clinical practice.
Zinc supplementation alleviates hyperglycemia and associated metabolic abnormalities in streptozotocin-induced diabetic rats
Authors: Barman Susmita , Srinivasan Krishnapura
Published: August 2016

The cause and effect relationship between diabetes and zinc is complex and unclear. This animal study has examined the potential of zinc supplementation in beneficial modulating hyperglycemia, insulin secretion, and metabolic abnormalities associated with diabetes. The study was conducted in streptozotocin-induced diabetic rats. Groups of hyperglycemic rats were subjected to dietary interventions for 6 weeks with zinc supplementation (5 times and 10 times the normal level). Supplemental-zinc-fed diabetic groups showed significant control on hyperglycemia and hypoinsulinemia. There was a significant reduction in protein glycosylation, glucosuria, and urinary excretion of proteins and urea in diabetic animals maintained on a zinc-supplemented diet. Diabetic rats showed significantly higher plasma albumin and lower plasma urea and creatinine levels upon zinc supplementation. Significant alterations in insulin sensitivity indices HOMA-IR, HOMA-B, and QUICKI were also indicated by zinc supplementation. The pathological abnormalities in pancreatic islets of diabetic animals were significantly alleviated by dietary zinc intervention. This study provides the first evidence that zinc supplementation can partially ameliorate the severity of diabetic hyperglycemia and associated metabolic abnormalities, hypoinsulinemia, insulin resistance, and altered pancreatic morphology. Thus, zinc supplementation may offer a significant potential for clinical application in managing diabetic hyperglycemia and related metabolic complications.
Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling
Authors: Zhu Baoling , Liu Kai , Yang Chengzhi , Qiao Yuhui , Li Zijian
Published: August 2016

Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro–Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.
Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats
Authors: Ghiassy Bentolhoda , Rahimi Nastaran , Javadi-Paydar Mehrak , Gharedaghi Mohammad Hadi , Norouzi-Javidan Abbas , Dehpour Ahmad R.
Published: August 2016

Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.
Comparative effects of piperine and simvastatin in fat accumulation and antioxidative status in high fat-induced hyperlipidemic rats
Authors: Tunsophon Sakara , Chootip Krongkarn
Published: August 2016

The present study investigated the comparative effects of piperine (PIP) — the active ingredient of black and long peppers — and simvastatin (SIM) on hepatic steatosis in hyperlipidemic rats. Male Wistar rats were fed a cholesterol mixture daily by intragastric gavage for 8 weeks. Piperine was given by oral gavage 8 h after cholesterol feeding. The animals were divided into 4 groups: control, high fat (HF), high fat plus 40 mg PIP/kg, and high fat plus 2 mg SIM/kg. At the end of the treatment, liver cholesterol, triglyceride, thiobaribituric reacting substances, superoxide dismutase (SOD), serum aminotransferase (AST), and alanine transferase (ALT) were measured. The result demonstrated that PIP and SIM significantly reduced the accumulation of cholesterol, triglyceride, and lipid peroxidation in the liver, while elevation of SOD was observed. The activities of AST and ALT significantly decreased in PIP when compared with the HF group. Our in vitro study of pancreatic lipase also showed the inhibitory effect of PIP higher than 30% at 5 mmol/L. These results demonstrate that PIP has beneficial effects in the treatment and (or) prevention of fat accumulation in the liver and that this mechanism is due to the inhibition of pancreatic lipase and the improvement of oxidative status.
The physiology of juvenile shortnose sturgeon (Acipenserbrevirostrum) during an acute saltwater challenge
Authors: Downie Adam T. , Kieffer James D.
Published: August 2016

One-year-old shortnose sturgeons (Acipenser brevirostrum LeSueur, 1818) were exposed to seawater (32 ppt) and brackish water (16 and 24 ppt) for 12, 24, 48, and 72 h and % body mass loss, plasma ions, energy metabolites, and oxygen-carrying variables were measured to evaluate survival and the physiological response to the acute salinity challenges. Survival in seawater was poor and plasma ion concentration was elevated in seawater. In sturgeons exposed to 24 ppt brackish water, ion concentrations remained elevated for 48 h, but began to decrease by 72 h. Fish exposed to 16 ppt brackish water did not show significant changes in ion concentrations over the 72 h period. Exposure to 32 ppt seawater resulted in significant and large decreases in body mass (about 20%–25%), whereas body mass loss was significantly less in fish exposed to 16 and 24 ppt brackish water. Overall, these findings suggest that juvenile sturgeons are able to tolerate lower salinities well but are less capable to endure higher salinities even on the short term (>48 h). These results suggest that juvenile A. brevirostrum could inhabit brackish environments earlier than previously expected, and that there appears to be a threshold at which salinity becomes a significant stress to these animals.
Gene flow, recombination, and positive selection inStenotrophomonas maltophilia: mechanisms underlying the diversity of the widespread opportunistic pathogen
Authors: Yu Dong , Yin Zhiqiu , Li Beiping , Jin Yuan , Ren Hongguang , Zhou Jing , Zhou Wei , Liang Long , Yue Junjie
Published: August 2016

Stenotrophomonas maltophilia is a global multidrug-resistant human opportunistic pathogen in clinical environments. Stenotrophomonas maltophilia is also ubiquitous in aqueous environments, soil, and plants. Various molecular typing methods have revealed that S. maltophilia exhibits high levels of phenotypic and genotypic diversity. However, information regarding the genomic diversity within S. maltophilia and the corresponding genetic mechanisms resulting in said diversity remain scarce. The genome sequences of 17 S. maltophilia strains were selected to investigate the mechanisms contributing to genetic diversity at the genome level. The core and large pan-genomes of the species were first estimated, resulting in a large, open pan-genome. A species phylogeny was also reconstructed based on 344 orthologous genes with one copy per genome, and the contribution of four evolutionary mechanisms to the species genome diversity was quantified: 15%–35% of the genes showed evidence for recombination, 0%–25% of the genes in one genome were likely gained, 0%–44% of the genes in some genomes were likely lost, and less than 0.3% of the genes in a genome were under positive selection pressures. We observed that, among the four main mechanisms, homologous recombination plays a key role in maintaining diversity in S. maltophilia. In this study, we provide an overview of evolution in S. maltophilia to provide a better understanding of its evolutionary dynamics and its relationship with genome diversity.
Blood capillary rarefaction and lymphatic capillary neoangiogenesis are key contributors to renal allograft fibrosis in an ACE inhibition rat model
Authors: Hamar Péter , Kerjaschki Dontscho
Published: August 2016

Chronic allograft fibrosis is the major cause of graft loss in kidney transplantation. Progression can only be reduced by inhibition of the renin-angiotensin system (RAS). We tested the hypothesis that the protection provided by angiotensin-converting enzyme (ACE) inhibition also decreases capillary rarefaction, lymphangiogenesis, and podocyte injury in allograft fibrosis. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats treated with enalapril (60 mg/kg per day) (ACE inhibitor, ACEi) or vehicle. Proteinuria, blood urea nitrogen, and plasma creatinine were regularly assessed, and grafts were harvested for morphological and immunohistological analysis at various times up to 32 wk. In the vehicle group, many new lymphatic capillaries and severe and diffuse mononuclear infiltration of allografts were observed already 1 wk after transplantation. Lymphangiogenesis increased until week 4, by which time inflammatory infiltration became focal. Lymphatic capillaries were often located at sites of inflammation. Progressive interstitial fibrosis, glomerulosclerosis, capillary rarefaction, and proteinuria appeared later, at weeks 4–12. The number of lymphatic capillary cross sections strongly correlated with the interstitial fibrosis score. Podoplanin immunostaining, a marker of healthy podocytes, disappeared from inflamed or sclerotic glomerular areas. ACEi protected from lymphangiogenesis and associated inflammation, preserved glomerular podoplanin protein expression, and reduced glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, and blood capillary rarefaction at 32 wk. In conclusion, ACEi considerably decreased and/or delayed both glomerulosclerosis and tubulointerstitial injury. Prevention of glomerular podoplanin loss and proteinuria could be attributed to the known intraglomerular pressure-lowering effects of ACEi. Reduction of lymphangiogenesis could contribute to amelioration of tubulointerstitial fibrosis and inflammatory infiltration after ACEi.
Comprehensive metabolic modeling of multiple13C-isotopomer data sets to study metabolism in perfused working hearts
Authors: Crown Scott B. , Kelleher Joanne K. , Rouf Rosanne , Muoio Deborah M. , Antoniewicz Maciek R.
Published: August 2016

In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using13C-metabolic flux analysis (13C-MFA) aided by multiple tracer experiments and integrated data analysis. Using13C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different13C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of13C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems.