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1.  A Mouse Model of Endocardial Fibroelastosis 
Endocardial Fibroelastosis (EFE) is a pathologic condition of abnormal deposition of collagen and elastin within the endocardium of the heart. It is seen in conjunction with a variety of diseases including hypoplastic left heart syndrome and viral endocarditis. While an experimental model using heterotopic heart transplant in rats has been described, we sought to fully describe a mouse model that can be used to further elucidate the potential mechanisms of and treatments for EFE.
Materials and Methods
The hearts of 2-day-old C57BL/6 mice were transplanted into the abdomen of 7-week-old C57BL/6 mice. At 2 weeks, the hearts were harvested and histologic analysis performed using hematoxylin and eosin, Masson’s Trichrome, Russell-Movat’s Pentachrome, Picrosirius Red, Hart’s, Verhoeff-Van Gieson, and Weigert’s Resorcin-Fuschin stains. Additionally, one heart was analysed using transmission electron microscopy (TEM).
Specimens demonstrated abnormal accumulation of both collagen and elastin within the endocardium with occasional expansion in to the myocardium. Heterogeneity in extracellular matrix deposition was noted in the histologic specimens. In addition, TEM demonstrated the presence of excess collagen within the endocardium.
The heterotopic transplantation of an immature heart into a mouse results in changes consistent with EFE. This model is appropriate to investigate the etiology and treatment of endocardial fibroelastosis.
PMCID: PMC4747030  PMID: 26363814
Endocardial fibroelastosis; EFE; Unloaded heterotopic heart transplant; Mouse model; Congenital heart disease
2.  Genetics of Autoimmune Thyroiditis in Type 1 Diabetes Reveals a Novel Association With DPB1*0201: Data From the Type 1 Diabetes Genetics Consortium 
Diabetes Care  2015;38(Suppl 2):S21-S28.
Autoimmune thyroiditis occurs in 10–25% of patients with type 1 diabetes (T1D). Most of these patients are also positive for thyroid peroxidase (TPO) antibodies. Thyroid dysfunction complicates T1D metabolic control and is a component of the autoimmune polyglandular syndrome (APS, type 2 or 3). Previous studies of isolated T1D and of T1D combined with other autoimmune disorders showed genetic susceptibility for alleles in HLA-DQB1 and -DRB1 and also CTLA4 and PTPN22.
We analyzed the Type 1 Diabetes Genetics Consortium Autoantibody Workshop data by differentiating those T1D probands with and without TPO antibodies or thyroid disease with respect to polymorphisms in HLA, CTLA4, INS, PTPN22, and VDR, taking into account the ethnic origin. Genotype and clinical/immunogenic phenotype data were analyzed by gene counting methods and logistic regression analysis.
The presence of TPO antibodies (25.2%) and thyroid disease (8.4%) was associated with older age, female sex, and presence of other autoantibodies (GAD65, ATPase, 21-OH) (all P < 0.001). The highest prevalence was in patients of Hispanic ancestry (31%) and the lowest in those of African ancestry (8%). In T1D non-Hispanic whites, HLA-DRB1*0101 is significantly (P < 0.0001) less frequent in TPO-positive than in TPO-negative individuals, whereas HLA-DRB1*0404, -DQB1*0301, and -DPB1*0201 are significantly (P < 0.0001) more frequent. Subjects with a high titer of TPO autoantibodies and with thyroid disease were associated with female sex and older age and negatively associated with DRB1*0401-DQB1*0302 (P < 0.0001). No significant differences were observed for an association of TPO positivity or thyroid disease with single nucleotide polymorphisms in the INS, CTLA4, or VDR loci, with nominal significance (P = 0.01) for PTPN22 R620W variant.
Thyroid autoimmunity is highly prevalent in T1D patients of non-Hispanic white, Asian, or Hispanic origin. The strongest disease risk is conferred by female sex and older age. This risk is modulated by HLA-DRB1 and HLA-DPB1 loci. The immunogenetic profile for T1D with thyroid autoimmunity may identify distinct pathways regulating polyglandular autoimmunity and disease.
PMCID: PMC4582911  PMID: 26405068
3.  Malaria risk factor assessment using active and passive surveillance data from Aceh Besar, Indonesia, a low endemic, malaria elimination setting with Plasmodium knowlesi, Plasmodium vivax, and Plasmodium falciparum 
Malaria Journal  2016;15(1):468.
As malaria transmission declines, it becomes more geographically focused and more likely due to asymptomatic and non-falciparum infections. To inform malaria elimination planning in the context of this changing epidemiology, local assessments on the risk factors for malaria infection are necessary, yet challenging due to the low number of malaria cases.
A population-based, cross-sectional study was performed using passive and active surveillance data collected in Aceh Besar District, Indonesia from 2014 to 2015. Malaria infection was defined as symptomatic polymerase chain reaction (PCR)-confirmed infection in index cases reported from health facilities, and asymptomatic or symptomatic PCR-confirmed infection identified in reactive case detection (RACD). Potential risk factors for any infection, species-specific infection, or secondary-case detection in RACD were assessed through questionnaires and evaluated for associations.
Nineteen Plasmodium knowlesi, 12 Plasmodium vivax and six Plasmodium falciparum cases were identified passively, and 1495 community members screened in RACD, of which six secondary cases were detected (one P. knowlesi, three P. vivax, and two P. falciparum, with four being asymptomatic). Compared to non-infected subjects screened in RACD, cases identified through passive or active surveillance were more likely to be male (AOR 12.5, 95 % CI 3.0–52.1), adult (AOR 14.0, 95 % CI 2.2–89.6 for age 16–45 years compared to <15 years), have visited the forest in the previous month for any reason (AOR 5.6, 95 % CI 1.3–24.2), and have a workplace near or in the forest and requiring overnight stays (AOR 7.9, 95 % CI 1.6–39.7 compared to workplace not near or in the forest). Comparing subjects with infections of different species, differences were observed in sub-district of residence and other demographic and behavioural factors. Among subjects screened in RACD, cases compared to non-cases were more likely to be febrile and reside within 100 m of the index case.
In this setting, risk of malaria infection in index and RACD identified cases was associated with forest exposure, particularly overnights in the forest for work. In low-transmission settings, utilization of data available through routine passive and active surveillance can support efforts to target individuals at high risk.
PMCID: PMC5020529  PMID: 27619000
Risk factor; Passive surveillance; Active surveillance; Reactive case detection; Aceh Besar; Indonesia; Low-endemic setting; Malaria elimination; Plasmodium knowlesi; Plasmodium vivax; Mixed species
4.  Community-Acquired Clostridium difficile Infection, Queensland, Australia 
Emerging Infectious Diseases  2016;22(9):1659-1661.
PMCID: PMC4994354  PMID: 27533328
Clostridium difficile; community-acquired infections; medication; exposure; Australia; bacteria; enteric infections
5.  Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes 
Diabetes  2015;64(8):3017-3027.
Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes–affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity.
PMCID: PMC4512221  PMID: 25829454
6.  Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies 
Clinical endocrinology  2012;76(5):617-624.
Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD). Progression to AD can take months to years, and early detection of metabolic decompensation may prevent morbidity and mortality.
To define optimal methods of predicting progression to overt AD (defined by subnormal peak cortisol response to Cosyntropin) in 21OH-AA+ individuals.
Design, Setting and Participants
Individuals were screened for 21OH-AA at the Barbara Davis Center from 1993 to 2011. Subjects positive for 21OH-AA (n = 87) were tested, and the majority prospectively followed for the development of Addison's disease, including seven diagnosed with AD upon 21OH-AA discovery (discovered), seven who progressed to AD (progressors) and 73 nonprogressors.
Main Outcome Measured
Plasma renin activity (PRA), ACTH, baseline cortisol, peak cortisol and 21OH-AA were measured at various time points relative to diagnosis of AD or last AD-free follow-up.
Compared with nonprogressors, in the time period 2 months–2 years prior to the onset of AD, progressors were significantly more likely to have elevated ACTH (11–22 pm, P < 1E-4), with no significant differences in mean PRA (P = 0·07) or baseline cortisol (P = 0·08), and significant but less distinct differences seen with 21OH-AA levels (P < 1E-4) and poststimulation cortisol levels (P = 6E-3).
Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol, in the 2 months–2 years preceding the onset of AD.
PMCID: PMC4963152  PMID: 22066755
7.  Metabolomic analysis reveals decreased skeletal muscle amino acid content and altered fatty acid handling in obese humans 
Obesity (Silver Spring, Md.)  2015;23(5):981-988.
Investigate the effects of obesity and high fat diet (HFD) exposure on fatty acid oxidation and TCA cycle intermediates and amino acids in skeletal muscle to better characterize energy metabolism.
Design and Methods
Plasma and skeletal muscle metabolomic profiles were measured from lean and obese males before and after a 5 day HFD in the 4h post-prandial condition.
At both time points, plasma short-chain acylcarnitine species (SCAC) were higher in the obese subjects, while the amino acids glycine, histidine, methionine, and citrulline were lower in skeletal muscle of obese subjects. Skeletal muscle medium-chain acylcarnitines (MCAC) C6, C8, C10:2, C10:1, C10, and C12:1 increased in obese subjects, but decreased in lean subjects, from Pre- to Post-HFD. Plasma content of C10:1 was also decreased in lean, but increased in the obese subjects from Pre- to Post-HFD. CD36 increased from Pre- to Post-HFD in obese but not lean subjects.
Lower skeletal muscle amino acid content and accumulation of plasma SCAC in obese subjects could reflect increased anaplerosis for TCA cycle intermediates, while accumulation of MCAC suggests limitations in β-oxidation. These measures may be important markers of or contributors to dysregulated metabolism observed in skeletal muscle of obese humans.
PMCID: PMC4414721  PMID: 25864501
Amino acid; Anaplerosis; Acylcarnitine; Fat Metabolism; Obesity
8.  Glyco-centric lectin magnetic bead array (LeMBA) − proteomics dataset of human serum samples from healthy, Barrett׳s esophagus and esophageal adenocarcinoma individuals 
Data in Brief  2016;7:1058-1062.
This data article describes serum glycoprotein biomarker discovery and qualification datasets generated using lectin magnetic bead array (LeMBA) – mass spectrometry techniques, “Serum glycoprotein biomarker discovery and qualification pipeline reveals novel diagnostic biomarker candidates for esophageal adenocarcinoma” [1]. Serum samples collected from healthy, metaplastic Barrett׳s esophagus (BE) and esophageal adenocarcinoma (EAC) individuals were profiled for glycoprotein subsets via differential lectin binding. The biomarker discovery proteomics dataset consisting of 20 individual lectin pull-downs for 29 serum samples with a spiked-in internal standard chicken ovalbumin protein has been deposited in the PRIDE partner repository of the ProteomeXchange Consortium with the data set identifier PRIDE: PXD002442. Annotated MS/MS spectra for the peptide identifications can be viewed using MS-Viewer (〈〉) using search key “jn7qafftux”. The qualification dataset contained 6-lectin pulldown-coupled multiple reaction monitoring-mass spectrometry (MRM-MS) data for 41 protein candidates, from 60 serum samples. This dataset is available as a supplemental files with the original publication [1].
PMCID: PMC4927955  PMID: 27408916
Proteomics; Glycoprotein; Biomarker; Esophageal adenocarcinoma; Barrett׳s esophagus
9.  Studies of a Large Odd‐Numbered Odd‐Electron Metal Ring: Inelastic Neutron Scattering and Muon Spin Relaxation Spectroscopy of Cr8Mn 
The spin dynamics of Cr8Mn, a nine‐membered antiferromagnetic (AF) molecular nanomagnet, are investigated. Cr8Mn is a rare example of a large odd‐membered AF ring, and has an odd‐number of 3d‐electrons present. Odd‐membered AF rings are unusual and of interest due to the presence of competing exchange interactions that result in frustrated‐spin ground states. The chemical synthesis and structures of two Cr8Mn variants that differ only in their crystal packing are reported. Evidence of spin frustration is investigated by inelastic neutron scattering (INS) and muon spin relaxation spectroscopy (μSR). From INS studies we accurately determine an appropriate microscopic spin Hamiltonian and we show that μSR is sensitive to the ground‐spin‐state crossing from S=1/2 to S=3/2 in Cr8Mn. The estimated width of the muon asymmetry resonance is consistent with the presence of an avoided crossing. The investigation of the internal spin structure of the ground state, through the analysis of spin‐pair correlations and scalar‐spin chirality, shows a non‐collinear spin structure that fluctuates between non‐planar states of opposite chiralities.
PMCID: PMC4744977  PMID: 26748964
inelastic neutron scattering; molecular magnetism; muon spin relaxation; spin chirality; spin frustration
10.  Do Participants With Different Patterns of Loss to Follow-Up Have Different Characteristics? A Multi-Wave Longitudinal Study 
Journal of Epidemiology  2016;26(1):45-49.
To identify patterns of loss to follow-up and baseline predictors of each pattern.
The Mater-University Study of Pregnancy collected baseline information for 7718 pregnant women who attended Mater Hospital in Brisbane, Australia, from 1981 through 1983. Follow-up data for 6753 eligible participants were collected at 6 months, 5 years, 14 years, 21 years, and 27 years after giving birth. Participants were partitioned into groups of ‘Always Responders’, ‘Returners’, ‘Leavers’, ‘Intermittents’, and ‘Never Responders’. Multinomial logistic regression was used to simultaneously compare baseline characteristics of the last four groups with ‘Always Responders’.
Being younger, less educated, having no partner, and living in rented housing were associated with being a ‘Returner’. Not owning housing, receiving welfare benefits, and being younger, less educated, not married, a smoker, an Aboriginal/Islander, and born in a non-English-speaking country were associated with being a ‘Leaver’, an ‘Intermittent’, or a ‘Never-responder’. Having higher mental health score and drinking before pregnancy were associated with being a ‘Leaver’ or an ‘Intermittent’. Being unemployed and not physically active were associated with being a ‘Leaver’ or ‘Never Responder’. The groups ‘Leavers’ and ‘Never Responders’ were the most different from the ‘Always Responders’. The group that was most similar to ‘Always Responders’ was the ‘Returners’.
Patterns of loss to follow-up should be considered in the application of missing data techniques, where researchers make assumptions about the characteristics of those subjects who do not respond to assess the type of missing data. This information can be used to prevent individuals who are at high risk of dropping out of a study from doing so.
PMCID: PMC4690740  PMID: 26321060
patterns of loss to follow-up; longitudinal study; missing data; attrition; characteristics
11.  The Appendix and Aganglionosis. A Note of Caution—How the Histology Can Mislead the Surgeon in Total Colonic Hirschsprung Disease 
We present the case of a child with presumed total colonic Hirschsprung disease (HD) to highlight the problems the surgeon is likely to encounter if he/she relies on the appendix alone for histopathologic diagnosis. A newborn male infant, who was presumed to have total colonic aganglionosis when the appendix was found to be aganglionic at the time of initial exploratory laparoscopy, was managed with an ileostomy in the newborn period; however, at the time of his planned pull-through procedure, the rectal biopsy revealed normal ganglion cells. The child was subsequently managed with ileostomy closure and observed for normal feeding and stooling prior to discharge home. We discuss the histopathologic findings of the appendix in separate cases of confirmed total colonic HD seen in our center, and review the normal histopathologic findings of the appendix.
PMCID: PMC4487127  PMID: 26171305
appendix; histopathology; Hirschsprung
12.  Transcriptome sequencing and analysis of the entomopathogenic fungus Hirsutella sinensis isolated from Ophiocordyceps sinensis 
BMC Genomics  2015;16(1):106.
Ophiocordyceps sinensis, a worm and fungus combined mixture which Hirsutella sinensis is parasitic on the caterpillar body, has been used as a traditional medicine or healthy food in China for thousands of years. H. sinensis is reported as the only correct anamorph of O. sinensis and its main active ingredients are similar to the natural O. sinensis.
H. sinensis L0106, asexual strain of O. sinensis, was isolated and identified in this study. Three transcriptomes of H. sinensis at different cultivation periods (growth period 3d, pre-stable period 6d and stable period 9d) were sequenced for the first time by RNA-Seq method, and 25,511 unigenes (3d), 25,214 unigenes (6d) and 16,245 unigenes (9d) were assembled and obtained, respectively. These unigenes of the three samples were further assembled into 20,822 unigenes (All), and 62.3 percent of unigenes (All) could be annotated based on protein databases. Subsequently, the genes and enzymes involved in the biosynthesis of the active ingredients according to the sequencing and annotation results were predicted. Based on the predictions, we further investigated the interaction of different pathway networks and the corresponding enzymes. Furthermore, the differentially expressed genes (DEGs) of H. sinensis grown during different developmental stages (3d-VS-6d, 3d-VS-9d and 6d-VS-9d) were globally detected and analyzed based on the data from RNA-Seq, and 764 DEGs between 3d and 6d, 1,869 DEGs between 3d and 9d, and 770 DEGs between 6d and 9d were found, respectively.
This work presented here would aid in understanding and carrying out future studies on the genetic basis of H. sinensis and contribute to the further artificial production and application of this organism. This study provided a substantial contribution and basis to further characterize the gene expression profiles of H. sinensis in the metabolic pathways of active ingredients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1269-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4342880  PMID: 25765329
Ophiocordyceps sinensis; Hirsutella sinensis; Transcriptome sequencing; Metabolic pathways; Gene differential expression
13.  Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial 
Trials  2015;16:24.
Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.
The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.
Trial registration
The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health register, reference number: NCT02176122 (registered 24 June 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0541-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4311465  PMID: 25623485
Extended-spectrum beta-lactamase; ESBL; Plasmid-AmpC; Therapy; Resistance; Beta-lactam/beta-lactamase inhibitor; Carbapenem; Clinical trial
14.  Gastroenteritis due to typhoidal Salmonella: a decade of observation at an urban and a rural diarrheal disease hospital in Bangladesh 
BMC Infectious Diseases  2014;14:435.
The study aimed to compare the socio-demographic, host and clinical characteristics, seasonality and antimicrobial susceptibility of Typhoidal Salmonella (Salmonella enterica serovar Typhi and Paratyphi) (TS) with diarrhea between urban and rural Bangladesh.
Relevant information of 77/25,767 (0.30%) and 290/17,622 (1.65%) patients positive with TS (in stool) were extracted from the data archive of Diarrheal Disease Surveillance System of icddr,b (urban Dhaka and rural Matlab Hospitals respectively) during 2000–2012. Comparison group (diarrhea patients negative for TS) was randomly selected from the database (1:3 ratio). Two poisson regression models were investigated for modelling seasonal effects on the number of cases.
Salmonella Typhi was more frequently isolated in Dhaka than Matlab (57% vs. 5%, p < 0.001); while Salmonella Paratyphi was more frequent in Matlab than Dhaka (96% vs. 43%; p < 0.001). Fever [adj. OR-5.86 (95% CI: 2.16, 15.94)], antimicrobial use at home [5.08 (2.60, 9.90)], and fecal red blood cells [2.53 (1.38, 4.64)] were significantly associated with detection of TS in stool of patient from Dhaka. For Matlab, the correlates were, vomiting [1.88 (1.35, 2.64)], fecal macrophage [1.89 (1.29, 2.74)] in addition to fever and duration of diarrhea and antimicrobial use. At Dhaka, all Salmonella Typhi isolates were susceptible to ceftriaxone; while in Dhaka and Matlab however, for ciprofloxacin it was 45% and 91%, respectively. Susceptibility to chloramphenicol, ampicillin, trimethoprim-sulphamethoxazole and nalidixic acid ranged from 12%-58%. Salmonella Paratyphi were susceptible to ceftriaxone (99%). A significant seasonal trend and year difference (before and after 2007) for Matlab was observed (p < 0.001 for all effects). Dhaka does not show significant year or seasonal effects (p = 0.07 for years and p = 0.81 and p = 0.18 for the cos and sin components, respectively). While not significant, two seasonal peaks were observed in Dhaka (January-February and September-November); while a single peak (August-November) was observed in Matlab.
Proportion of serovar distribution of TS and their clinical characteristics, antimicrobial susceptibility and seasonal pattern were different among diarrhea patients in urban Dhaka and rural Matlab of Bangladesh.
PMCID: PMC4132926  PMID: 25098316
Bangladesh; Diarrhea; Rural; Typhoidal Salmonella; Urban
16.  Cost-effectiveness analysis of vaccinating children in Malawi with RTS,S vaccines in comparison with long-lasting insecticide-treated nets 
Malaria Journal  2014;13:66.
New RTS,S malaria vaccines may soon be licensed, yet its cost-effectiveness is unknown. Before the widespread introduction of RTS,S vaccines, cost-effectiveness studies are needed to help inform governments in resource-poor settings about how best to prioritize between the new vaccine and existing malaria interventions.
A Markov model simulated malaria progression in a hypothetical Malawian birth cohort. Parameters were based on published data. Three strategies were compared: no intervention, vaccination at one year, and long-lasting, insecticide-treated nets (LLINs) at birth. Both health service and societal perspectives were explored. Health outcomes were measured in disability-adjusted life years (DALYs) averted and costed in 2012 US$. Incremental cost-effectiveness ratios (ICERs) were calculated and extensive sensitivity analyses were conducted. Three times GDP per capita ($1,095) per DALY averted was used for a cost-effectiveness threshold, whilst one times GDP ($365) was considered ‘very cost-effective’.
From a societal perspective the vaccine strategy was dominant. It averted 0.11 more DALYs than LLINs and 0.372 more DALYs than the no intervention strategy per person, while costing $10.04 less than LLINs and $59.74 less than no intervention. From a health service perspective the vaccine’s ICER was $145.03 per DALY averted, and thus can be considered very cost-effective. The results were robust to changes in all variables except the vaccine and LLINs’ duration of efficacy. Vaccines remained cost-effective even at the lowest assumed efficacy levels of 49.6% (mild malaria) and 14.2% (severe malaria), and the highest price of $15. However, from a societal perspective, if the vaccine duration efficacy was set below 2.69 years or the LLIN duration of efficacy was greater than 4.24 years then LLINs became the more cost-effective strategy.
The results showed that vaccinating Malawian children with RTS,S vaccines was very cost-effective from both a societal and a health service perspective. This result was robust to changes in most variables, including vaccine price and vaccine efficacy, but was sensitive to the duration of efficacy of the vaccine and LLINs. Given the best evidence currently available, vaccines can be considered as a very cost-effective component of Malawi’s future malaria control programmes. However, long-term follow-up studies on both interventions are needed.
PMCID: PMC4016032  PMID: 24564883
RTS,S vaccine; Malaria vaccine; Cost-effectiveness analysis; Long-lasting insecticide-treated net; Bed net; Malawi; Malaria
17.  Concurrent and Simultaneous Polydrug Use: Latent Class Analysis of an Australian Nationally Representative Sample of Young Adults 
Background: Alcohol use and illicit drug use peak during young adulthood (around 18–29 years of age), but comparatively little is known about polydrug use in nationally representative samples of young adults. Drawing on a nationally representative cross-sectional survey (Australian National Drug Strategy Household Survey), this study examines polydrug use patterns and associated psychosocial risk factors among young adults (n = 3,333; age 19–29).
Method: The use of a broad range of licit and illicit drugs were examined, including alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, ketamine, GHB, inhalants, steroids, barbiturates, meth/amphetamines, heroin, methadone/buprenorphine, other opiates, painkillers, and tranquilizers/sleeping pills. Latent class analysis was employed to identify patterns of polydrug use.
Results: Polydrug use in this sample was best described using a 5-class solution. The majority of young adults predominantly used alcohol only (52.3%), alcohol and tobacco (34.18%). The other classes were cannabis, ecstasy, and licit drug use (9.4%), cannabis, amphetamine derivative, and licit drug use (2.8%), and sedative and alcohol use (1.3%). Young adult males with low education and/or high income were most at risk of polydrug use.
Conclusion: Almost half of young adults reported polydrug use, highlighting the importance of post-high school screening for key risk factors and polydrug use profiles, and the delivery of early intervention strategies targeting illicit drugs.
PMCID: PMC3860005  PMID: 24350230
young adults; polydrug use; latent class analysis; cluster; risk and protective factors; simultaneous
18.  Histopathologic Evaluation of Patent Ductus Arteriosus Stents After Hybrid Stage I Palliation 
Pediatric cardiology  2011;32(4):10.1007/s00246-010-9870-y.
The aim of this study was to determine the histopathology of patent ductus arteriosus (PDA) in-stent stenosis after hybrid stage I palliation. The hybrid approach to palliation of hypoplastic left heart syndrome can be complicated by the development of in-stent stenosis of the PDA. This may obstruct retrograde aortic arch flow, decrease systemic circulation, and lead to interstage interventional procedures. Stented PDA samples removed from eight patients undergoing comprehensive stage II repair were examined by way of radiography and histochemistry (hematoxylin and eosin, Movat pentachrome, α-smooth muscle actin, and proliferating cell nuclear antigen). A retrospective chart review of the patients was also performed. PDA stents were in place in the PDA for a mean period of 169 ± 28 days in patients who had a mean age of 176 ± 30 days at the time of stent removal. Stent deployment caused chronic inflammation, caused fibrin deposition, and induced vascular smooth muscle–cell (VSMC) proliferation in the area immediately surrounding the stent struts. The neointimal region was composed largely of smooth muscle cells that appeared to be fully differentiated by the lack of PCNA staining. Neointimal thickening occurs in the PDA after stent placement for hybrid palliation of HLHS and is the result of inflammation, extracellular matrix deposition, and smooth muscle–cell proliferation in the peristrut region. This finding suggests that proliferating VSMCs in the peristrut region may provide the impetus for inward neointimal formation and therefore the manifestation of in-stent stenosis.
PMCID: PMC3822434  PMID: 21298382
Ductus arteriosus; Stent; Neointima; In-stent stenosis
19.  Mental health issues decrease diabetes-specific quality of life independent of glycaemic control and complications: findings from Australia’s living with diabetes cohort study 
While factors associated with health-related quality of life for people with chronic diseases including diabetes are well researched, far fewer studies have investigated measures of disease-specific quality of life. The purpose of this study is to assess the impact of complications and comorbidities on diabetes-specific quality of life in a large population-based cohort of type 2 diabetic patients.
The Living with Diabetes Study recruited participants from the National Diabetes Services Scheme in Australia. Data were collected via a mailed self-report questionnaire. Diabetes-specific quality of life was measured using the Audit of Diabetes-Dependent Quality of Life (ADDQoL) questionnaire. The analyses are for 3609 patients with type 2 diabetes. Regression models with adjustment for control variables investigated the association of complications and comorbidities with diabetes-specific quality of life. Next, the most parsimonious model for diabetes-specific quality of life after controlling for important covariates was examined.
The expected associations with better diabetes-specific quality of life were evident, such as increased income, not on insulin, better glycaemic control and older age. However, being single and having been diagnosed with cancer were also associated with better ADDQoL. Additionally, poorer diabetes-specific quality of life was strongly sensitive to the presence of diabetes complications and mental health conditions such as depression, anxiety and schizophrenia. These relationships persisted after adjustment for gender, age, duration of diabetes, treatment regimen, sampling region and other treatment and socio-demographic variables.
A greater appreciation of the complexities of diabetes-specific quality of life can help tailor disease management and self-care messages given to patients. Attention to mental health issues may be as important as focusing on glycaemic control and complications. Therefore clinicians’ ability to identify and mange mental health issues and/or refer patients is critical to improving patients’ diabetes-specific quality of life.
PMCID: PMC3853250  PMID: 24131673
Diabetes-specific quality of life; Audit of Diabetes-Dependent Quality of Life (ADDQoL); Type 2 diabetes; Adults
20.  At-risk but viable myocardium in a large animal model of non ST-segment elevation acute coronary syndrome: cardiovascular magnetic resonance with ex vivo validation 
Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees of salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces acute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant necrosis by late gadolinium enhancement (LGE).
In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium. Myocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing.
Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 ± 0.72 ng/mL in model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote myocardium (53.2 ± 4.9 vs. 43.6 ± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant irreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly lower in model vs. sham animals (0.72 ± 0.07 vs. 1.04 ± 0.07, p < 0.001). Lower RRR corresponded to higher final TnI levels (R2 = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression.
A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage. Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.
PMCID: PMC3852225  PMID: 24107555
Myocardial ischemia; Oxygen consumption; Cardiovascular magnetic resonance; Canine model; Mitochondria
21.  Ribonuclease 7, an antimicrobial peptide up-regulated during infection, contributes to microbial defense of the human urinary tract 
Kidney international  2013;83(4):615-625.
The mechanisms that maintain sterility in the urinary tract are incompletely understood; however, recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Ribonuclease 7 (RNase 7), a potent antimicrobial peptide contributing to urinary tract sterility, is expressed by intercalated cells in the renal collecting tubules and is present in the urine at levels sufficient to kill bacteria at baseline. Here, we characterize the expression and function of RNase 7 in the human urinary tract during infection. Both quantitative real-time PCR and ELISA assays demonstrated increases in RNASE7 expression in the kidney along with kidney and urinary RNase 7 peptide concentrations with infection. While immunostaining localized RNase 7 production to the intercalated cells of the collecting tubule during sterility, its expression during pyelonephritis was found to increase throughout the nephron but not in glomeruli or the interstitium. Recombinant RNase 7 exhibited antimicrobial activity against uropathogens at low micromolar concentrations by disrupting the microbial membrane as determined by atomic force microscopy. Thus, RNase 7 expression is increased in the urinary tract with infection, and has antibacterial activity against uropathogens at micromolar concentrations.
PMCID: PMC3612368  PMID: 23302724
Ribonuclease 7; Antimicrobial Peptide; Pyelonephritis; Urinary Tract Infection; Intercalated Cells; Innate Immunity; Immunology
22.  Unusual case of a vanishing bronchus of the left allograft in a lung transplant recipient 
Annals of Thoracic Medicine  2013;8(4):229-230.
We present an interesting case of a complete vanishing of the left main bronchus in a lung transplant recipient who had a successful outcome due to acute respiratory support with venovenous extracorporeal membrane oxygenation in order to perform airway dilation.
PMCID: PMC3821284  PMID: 24250738
Acute; extracorporeal membrane oxygenation; left main bronchus; lung transplantation; vanishing; venovenous
23.  Screening and Improving the Recombinant Nitrilases and Application in Biotransformation of Iminodiacetonitrile to Iminodiacetic Acid 
PLoS ONE  2013;8(6):e67197.
In this study, several nitrilase genes from phylogenetically distinct organisms were expressed and purified in E. coli in order to study their ability to mediate the biotransformation of nitriles. We identified three nitrilases: Acidovorax facilis nitrilase (AcN); Alcaligenes fecalis nitrilase (AkN); and Rhodococcus rhodochrous nitrilase (RkN), which catalyzed iminodiacetonitrile (IDAN) to iminodiacetic acid (IDA). AcN demonstrated 8.8-fold higher activity for IDAN degradation as compared to AkN and RkN. Based on homology modeling and previously described ‘hot spot’ mutations, several AcN mutants were screened for improved activity. One mutant M3 (F168V/L201N/S192F) was identified, which demonstrates a 41% enhancement in the conversion as well as a 2.4-fold higher catalytic efficiency towards IDAN as compared to wild-type AcN.
PMCID: PMC3695085  PMID: 23826231
24.  Type 2 diabetes: a cohort study of treatment, ethnic and social group influences on glycated haemoglobin 
BMJ Open  2012;2(5):e001477.
To assess whether in people with poorly controlled type 2 diabetes (HbA1c>7.5%) improvement in HbA1c varies by ethnic and social group.
Prospective 2-year cohort of type 2 diabetes treated in general practice.
Setting and participants
All patients with type 2 diabetes in 100 of the 101 general practices in two London boroughs. The sample consisted of an ethnically diverse group with uncontrolled type 2 diabetes aged 37–71 years in 2007 and with HbA1c recording in 2008–2009.
Outcome measure
Change from baseline HbA1c in 2007 and achievement of HbA1c control in 2008 and 2009 were estimated for each ethnic, social and treatment group using multilevel modelling.
The sample consisted of 6104 people; 18% were white, 63% south Asian, 16% black African/Caribbean and 3% other ethnic groups. HbA1c was lower after 1 and 2 years in all ethnic groups but south Asian people received significantly less benefit from each diabetes treatment. After adjustment, south Asian people were found to have 0.14% less reduction in HbA1c compared to white people (95% CI 0.04% to 0.24%) and white people were 1.6 (95% CI 1.2 to 2.0) times more likely to achieve HbA1c controlled to 7.5% or less relative to south Asian people. HbA1c reduction and control in black African/Caribbean and white people did not differ significantly. There was no evidence that social deprivation influenced HbA1c reduction or control in this cohort.
In all treatment groups, south Asian people with poorly controlled diabetes are less likely to achieve controlled HbA1c, with less reduction in mean HbA1c than white or black African/Caribbean people.
PMCID: PMC3488709  PMID: 23087015
diabetes & endocrinology; primary care; therapeutics; public health
25.  Current challenges in software solutions for mass spectrometry-based quantitative proteomics 
Amino Acids  2012;43(3):1087-1108.
Mass spectrometry-based proteomics has evolved as a high-throughput research field over the past decade. Significant advances in instrumentation, and the ability to produce huge volumes of data, have emphasized the need for adequate data analysis tools, which are nowadays often considered the main bottleneck for proteomics development. This review highlights important issues that directly impact the effectiveness of proteomic quantitation and educates software developers and end-users on available computational solutions to correct for the occurrence of these factors. Potential sources of errors specific for stable isotope-based methods or label-free approaches are explicitly outlined. The overall aim focuses on a generic proteomic workflow.
PMCID: PMC3418498  PMID: 22821268
LC–MS; Quantitative proteomics; Quantification software; Stable isotope labeling; Label-free

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