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1.  Research Tools for the Measurement of Pain and Nociception 
Simple Summary
Pain is an integral aspect of many diseases and it is important to be able to measure it in the clinic so that the progression of disease and the animal’s response to treatment can be monitored. When research into pain is undertaken, it is also important to be able to measure the pain, but this time the aim is to provide meaningful results that will further our understanding of the mechanisms of pain or how it can be better treated. This change in emphasis between clinical and research measurement of pain means that the advantages and disadvantages of the many ways in which pain can be measured influence the choice of the most suitable technique and the way in which it is used. It is important to carefully select the most appropriate methodologies so that the data generated are relevant to the hypotheses being tested.
There are many ways in which pain in animals can be measured and these are based on a variety of phenomena that are related to either the perception of pain or alterations in physical or behavioural features of the animal that are caused by that pain. The features of pain that are most useful for assessment in clinical environments are not always the best to use in a research environment. This is because the aims and objectives of the two settings are different and so whilst particular techniques will have the same advantages and disadvantages in clinical and research environments, these considerations may become more or less of a drawback when moving from one environment to the other. For example, a simple descriptive pain scale has a number of advantages and disadvantages. In a clinical setting the advantages are very useful and the disadvantages are less relevant, but in a research environment the advantages are less important and the disadvantages can become more problematic. This paper will focus on pain in the research environment and after a brief revision of the pathophysiological systems involved will attempt to outline the major advantages and disadvantages of the more commonly used measurement techniques that have been used for studies in the area of pain perception and analgesia. This paper is expanded from a conference proceedings paper presented at the International Veterinary Emergency and Critical Care Conference in San Diego, USA.
PMCID: PMC5126773  PMID: 27845724
pain measurement; research techniques
The Lancet. Oncology  2015;16(15):1537-1546.
Local excision is an organ-preserving treatment alternative for patients with stage I rectal cancer. However, local excision alone is associated with a high risk of local recurrence and inferior survival compared to transabdominal rectal resection. Here we investigate the oncologic and functional outcomes of neoadjuvant chemoradiotherapy and local excision for T2N0 rectal cancer.
This was a prospective, multi-institutional, single arm phase 2 trial for patients with clinically-staged T2N0 distal rectal cancer, treated with neoadjuvant chemoradiotherapy consisting of capecitabine (original dose 825mg/m2, twice daily, on days 1-14 and 22-35) , oxaliplatin (50mg/m2 weeks 1, 2, 4, 5), and radiation (5 days/week at 1.8 Gy/day for 5 weeks to a dose of 45 Gy, then a boost, for a total dose of 54 Gy) followed by local excision. Due to adverse events during chemoradiotherapy, the dose of capecitabine was reduced to 725 mg /m2, twice daily, 5 days/week, for 5 weeks, and the total dose of radiation to 50.4 Gy. Patients were followed at scheduled intervals and evaluated for recurrence and survival. Anorectal function (ARF) and quality of life (QOL) were assessed at baseline and one year after surgery, using validated instruments. The primary endpoint was 3-year disease-free survival for all eligible patients and for patients who completed chemotherapy and radiation, and had ypT0, ypT1, or ypT2 tumors, and negative resection margins. This trial is registered with, number NCT00114231.
Seventy-nine eligible patients were accrued to the trial, and started nCRT. Three patients did not complete nCRT or LE per-protocol. Four additional patients completed protocol treatment, but one had a positive margin and three had ypT3 tumours. Median follow-up was 56 months. Of the 79 patients, five (6%) developed distant recurrence, and three (4%) recurred locally. All but two underwent salvage surgery. Three-year disease-free survival and overall survival for the entire group were 88% (0.88 (95% CI: 0.81, 0.96) and 95% (95% CI: 0.90, 1.00), respectively. Overall 14 (29%) of 79 patients had grade 3-4 gastrointestinal adverse events, 12 (16%) of 79 patients had grade 3-4 pain as an adverse event, 12 (16%) of 79 patients had grade 3-4 hematological adverse events, and 9 (11%) of 79 patients had grade 3 dermatologic adverse events during chemoradiation. Six (8%) of the 77 patients who had surgery had grade 3 pain, 3(4%) of 77 patients had grade 3-4 hemorrhage, 3 (4%) of 77 patients had gastrointestinal adverse events, 2 (3%) of 77 patients had infectious/febrile neutropenia, 2 (3%) of 77 patients had hematological adverse events, and one (1%) had neurological adverse events. The rectum was preserved in 72 of the 79 (91%) patients. ARF and QOL were unchanged one year after surgery compared to baseline.
Most patients with T2N0 rectal cancer treated with nCRT and LE achieved organ preservation without deterioration of their quality of life. The estimated 3-year DFS rate was within the defined margin of efficacy. Our data suggest that nCRT followed by LE may be considered as an organ-preserving alternative in carefully selected patients with clinically-staged T2N0 tumours who refuse, or are not candidates for, transabdominal resection.
PMCID: PMC4984260  PMID: 26474521
3.  A Good Death? Report of the Second Newcastle Meeting on Laboratory Animal Euthanasia 
Simple Summary
Millions of laboratory animals are killed each year worldwide. However, there is a lack of consensus regarding what methods of killing are humane for many species and stages of development. This report summarises research findings and discussions from an international meeting of experts and stakeholders, with recommendations to inform good practice for humane killing of mice, rats and zebrafish. It provides additional guidance and perspectives for researchers designing projects that involve euthanasing animals, researchers studying aspects of humane killing, euthanasia device manufacturers, regulators, and institutional ethics or animal care and use committees that wish to review local practice.
Millions of laboratory animals are killed each year worldwide. There is an ethical, and in many countries also a legal, imperative to ensure those deaths cause minimal suffering. However, there is a lack of consensus regarding what methods of killing are humane for many species and stages of development. In 2013, an international group of researchers and stakeholders met at Newcastle University, United Kingdom to discuss the latest research and which methods could currently be considered most humane for the most commonly used laboratory species (mice, rats and zebrafish). They also discussed factors to consider when making decisions about appropriate techniques for particular species and projects, and priorities for further research. This report summarises the research findings and discussions, with recommendations to help inform good practice for humane killing.
PMCID: PMC5035945  PMID: 27563926
animal welfare; carbon dioxide; euthanasia; humane killing; mouse; rat; refinement; 3Rs; zebrafish
4.  Racial and Ethnic Differences in Self-Reported Periodontal Disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Racial and ethnic disparities in periodontal disease exist in the United States. This study examined the prevalence of self-reported periodontal disease, and the extent to which racial/ethnic disparities in the reported disease were reduced or eliminated after controlling for various risk factors in a multi-ethnic study population of older adults.
Materials and Methods
Information from the baseline examination (July 2000–August 2002) of the Multi-Ethnic Study of Atherosclerosis (MESA) was used. Study participants (N=6,256) were age 45–84 years, and identified themselves as either: White, Black, Hispanic, or Chinese. Periodontal disease was assessed by self-report, and demographic, socioeconomic status (SES) indicators, biomedical risk factors, and psychosocial stress factors were used as predictors of self-reported periodontal disease.
Chinese displayed the highest prevalence of self-reported periodontal disease (39.8%), followed by blacks (32.0%) and whites (26.0%), with Hispanics displaying the lowest prevalence (17.4%). Chinese and black participants had a significantly higher prevalence of disease compared to whites that persisted after adjusting for demographic, SES indicators, biomedical risk factors, and psychosocial stress factors. Hispanics did not differ significantly from whites in their reporting of disease, after such adjustment.
Racial/ethnic disparities in self-reported periodontal disease persisted after adjusting for all study covariates. This study highlights the need for continued research into the determinants of racial/ethnic disparities in periodontal disease in order to better target interventions aimed at reducing the burden of disease in all segments of our population.
PMCID: PMC4970861  PMID: 26870845
Race; Ethnicity; Periodontal diseases; Healthcare Disparities; Minority Health
5.  Genome Sequence of Streptomyces aureofaciens ATCC Strain 10762 
Genome Announcements  2016;4(3):e00615-16.
Streptomyces aureofaciens is a Gram-positive actinomycete that produces the antibiotics tetracycline and chlortetracycline. Here, we report the assembly and initial annotation of the draft genome sequence of S. aureofaciens ATCC strain 10762.
PMCID: PMC4919415  PMID: 27340076
6.  Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks 
Microarrays  2016;5(2):13.
Metastasis is the major cause of cancer deaths and control of gene transcription has emerged as a critical contributing factor. RhoA- and RhoC-induced gene transcription via the actin-regulated transcriptional co-activator megakaryocytic leukemia (MKL) and serum response factor (SRF) drive metastasis in breast cancer and melanoma. We recently identified a compound, CCG-1423, which blocks Rho/MKL/SRF-mediated transcription and inhibits PC-3 prostate cancer cell invasion. Here, we undertook a genome-wide expression study in PC-3 cells to explore the mechanism and function of this compound. There was significant overlap in the genes modulated by CCG-1423 and Latrunculin B (Lat B), which blocks the Rho/MKL/SRF pathway by preventing actin polymerization. In contrast, the general transcription inhibitor 5,6-dichloro-1-β-d-ribofuranosyl-1H-benzimidazole (DRB) showed a markedly different pattern. Effects of CCG-1423 and Lat B on gene expression correlated with literature studies of MKL knock-down. Gene sets involved in DNA synthesis and repair, G1/S transition, and apoptosis were modulated by CCG-1423. It also upregulated genes involved in endoplasmic reticulum stress. Targets of the known Rho target transcription factor family E2F and genes related to melanoma progression and metastasis were strongly suppressed by CCG-1423. These results confirm the ability of our compound to inhibit expression of numerous Rho/MKL-dependent genes and show effects on stress pathways as well. This suggests a novel approach to targeting aggressive cancers and metastasis.
PMCID: PMC5003489  PMID: 27600078
metastasis; transcription; cell cycle; Rho
7.  Ocean acidification reverses the positive effects of seawater pH fluctuations on growth and photosynthesis of the habitat-forming kelp, Ecklonia radiata 
Scientific Reports  2016;6:26036.
Ocean acidification (OA) is the reduction in seawater pH due to the absorption of human-released CO2 by the world’s oceans. The average surface oceanic pH is predicted to decline by 0.4 units by 2100. However, kelp metabolically modifies seawater pH via photosynthesis and respiration in some temperate coastal systems, resulting in daily pH fluctuations of up to ±0.45 units. It is unknown how these fluctuations in pH influence the growth and physiology of the kelp, or how this might change with OA. In laboratory experiments that mimicked the most extreme pH fluctuations measured within beds of the canopy-forming kelp Ecklonia radiata in Tasmania, the growth and photosynthetic rates of juvenile E. radiata were greater under fluctuating pH (8.4 in the day, 7.8 at night) than in static pH treatments (8.4, 8.1, 7.8). However, pH fluctuations had no effect on growth rates and a negative effect on photosynthesis when the mean pH of each treatment was reduced by 0.3 units. Currently, pH fluctuations have a positive effect on E. radiata but this effect could be reversed in the future under OA, which is likely to impact the future ecological dynamics and productivity of habitats dominated by E. radiata.
PMCID: PMC4882519  PMID: 27229624
8.  Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function 
The European respiratory journal  2015;47(2):553-563.
Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown.
We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively. In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2×10−6) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF.
Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure.
PMCID: PMC4831135  PMID: 26647441
9.  Habitual Starvation and Provocative Behaviors: Two Potential Routes to Extreme Suicidal Behavior in Anorexia Nervosa 
Behaviour research and therapy  2010;48(7):634-645.
Anorexia nervosa (AN) is perhaps the most lethal mental disorder, in part due to starvation-related health problems, but especially because of high suicide rates. One potential reason for high suicide rates in AN may be that those affected face pain and provocation on many fronts, which may in turn reduce their fear of pain and thereby increase risk for death by suicide. The purpose of the following studies was to explore whether repetitive exposure to painful and destructive behaviors such as vomiting, laxative use, and non-suicidal self-injury (NSSI) was a mechanism that linked AN-binge-purging (ANBP) subtype, as opposed to AN-restricting subtype (ANR), to extreme suicidal behavior. Study 1 utilized a sample of 787 individuals diagnosed with one or the other subtype of AN, and structural equation modeling results supported provocative behaviors as a mechanism linking ANBP to suicidal behavior. A second, unexpected mechanism emerged linking ANR to suicidal behavior via restricting. Study 2, which used a sample of 249 AN patients, replicated these findings, including the second mechanism linking ANR to suicide attempts. Two potential routes to suicidal behavior in AN appear to have been identified: one route through repetitive experience with provocative behaviors for ANBP, and a second for exposure to pain through the starvation of restricting in ANR.
PMCID: PMC4731222  PMID: 20398895
anorexia; suicide; restricting; purging; self-injury
10.  Refining Behavioral Dysregulation in Borderline Personality Disorder Using a Sample of Women with Anorexia Nervosa 
Personality disorders  2010;1(4):250-257.
One of the primary facets of borderline personality disorder (BPD) is behavioral dysregulation, a wide array of behaviors that are difficult to control and harmful to the individual. The purpose of this study was to explore the association between BPD and a variety of dysregulated behaviors, some of which have received little empirical attention. Using a large sample of individuals diagnosed with anorexia nervosa, 41 individuals diagnosed with BPD were compared to the rest of the sample on the presence of dysregulated behaviors using logistic regression analyses. Anorexia nervosa subtypes, age, and other Cluster B personality disorders were used as covariates. Results support an association between BPD and alcohol misuse, hitting someone/breaking things, provoking fights/ arguments, self-injury, overdosing, street drug use, binge-eating, impulsive spending, shoplifting/stealing and risky sexual behaviors. Differences between dichotomous and continuous measures of BPD yielded somewhat different results.
PMCID: PMC4688899  PMID: 22448667
borderline personality disorder; behavioral dysregulation; substance abuse; anorexia nervosa
11.  Is season of birth related to disordered eating and personality in women with eating disorders? 
Eating and weight disorders : EWD  2010;15(3):e186-e189.
We assessed the relation between season of birth and eating disorder symptoms and personality characteristics in a sample of 880 women with eating disorders and 580 controls from two Price Foundation Studies. Eating disorder symptoms were assessed using Structured Interview of Anorexic and Bulimic Disorders and the Structured Clinical Interview for DSM-IV. Personality traits were assessed using the Temperament and Character Inventory and the Frost Multidimensional Perfectionism Scale. Date of birth was obtained from a sociodemographic questionnaire.
No significant differences were observed 1) in season of birth across eating disorder subtypes and controls; nor 2) for any clinical or personality variables and season of birth. We found no evidence of season of birth variation in eating disorders symptoms or personality traits. Contributing to previous conflicting findings, the present results do not support a season of birth hypothesis for eating disorders.
PMCID: PMC4683582  PMID: 21150253
anorexia nervosa; bulimia nervosa; eating disorders; season of birth
12.  The Role of Leptin, Melanocortin, and Neurotrophin System Genes on Body Weight in Anorexia Nervosa and Bulimia Nervosa 
Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN.
Our sample consisted of 745 individuals with AN without a history of BN, 245 with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems.
There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p=0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p=0.0018).
To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetics and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.
PMCID: PMC4191922  PMID: 24831852
anorexia nervosa; bulimia nervosa; candidate gene association; body weight; melanocortins; neurotrophins
14.  Determining the Impact of Prenatal Tobacco Exposure on Self-regulation at Six Months 
Developmental psychology  2014;50(6):1746-1756.
The goal of the present study was to examine the effects of maternal smoking during pregnancy on infant self-regulation, exploring birth weight as a mediator and sex as a moderator of risk. A prospective sample of 218 infants was assessed at 6 months of age. Infants completed a battery of tasks assessing working memory/inhibition, attention, and emotional reactivity and regulation. Propensity scores were used to statistically control for confounding risk factors associated with maternal smoking during pregnancy. After prenatal and postnatal confounds were controlled, prenatal tobacco exposure was related to reactivity to frustration and control of attention during stimulus encoding. Birth weight did not mediate the effect of prenatal exposure, but was independently related to reactivity and working memory/inhibition. The effect of tobacco exposure was not moderated by sex.
PMCID: PMC4050340  PMID: 24512173
Prenatal tobacco exposure; infancy; self-regulation; attention; emotion regulation
15.  Age-related variations in the methylome associated with gene expression in human monocytes and T cells 
Nature communications  2014;5:5366.
Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age- and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55–94 years). None of the age-eMS detected in 227 T cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers, and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may play in the aging process.
PMCID: PMC4280798  PMID: 25404168
16.  Transcriptomic profiles of aging in purified human immune cells 
BMC Genomics  2015;16(1):333.
Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.
Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.
Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.
An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1522-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4417516  PMID: 25898983
Aging; Monocyte; T cell; Transcriptome; Mitochondrial ribosome; Translation; Protein synthesis; Ribonucleoprotein complex; Oxidative phosphorylation; Autophagy; Methylation
17.  Large-Scale Geographic Variation in Distribution and Abundance of Australian Deep-Water Kelp Forests 
PLoS ONE  2015;10(2):e0118390.
Despite the significance of marine habitat-forming organisms, little is known about their large-scale distribution and abundance in deeper waters, where they are difficult to access. Such information is necessary to develop sound conservation and management strategies. Kelps are main habitat-formers in temperate reefs worldwide; however, these habitats are highly sensitive to environmental change. The kelp Ecklonia radiate is the major habitat-forming organism on subtidal reefs in temperate Australia. Here, we provide large-scale ecological data encompassing the latitudinal distribution along the continent of these kelp forests, which is a necessary first step towards quantitative inferences about the effects of climatic change and other stressors on these valuable habitats. We used the Autonomous Underwater Vehicle (AUV) facility of Australia’s Integrated Marine Observing System (IMOS) to survey 157,000 m2 of seabed, of which ca 13,000 m2 were used to quantify kelp covers at multiple spatial scales (10–100 m to 100–1,000 km) and depths (15–60 m) across several regions ca 2–6° latitude apart along the East and West coast of Australia. We investigated the large-scale geographic variation in distribution and abundance of deep-water kelp (>15 m depth) and their relationships with physical variables. Kelp cover generally increased with latitude despite great variability at smaller spatial scales. Maximum depth of kelp occurrence was 40–50 m. Kelp latitudinal distribution along the continent was most strongly related to water temperature and substratum availability. This extensive survey data, coupled with ongoing AUV missions, will allow for the detection of long-term shifts in the distribution and abundance of habitat-forming kelp and the organisms they support on a continental scale, and provide information necessary for successful implementation and management of conservation reserves.
PMCID: PMC4334971  PMID: 25693066
18.  A benchmark comparison of deterministic and probabilistic methods for defining manual review datasets in duplicate records reconciliation 
Clinical databases require accurate entity resolution (ER). One approach is to use algorithms that assign questionable cases to manual review. Few studies have compared the performance of common algorithms for such a task. Furthermore, previous work has been limited by a lack of objective methods for setting algorithm parameters. We compared the performance of common ER algorithms: using algorithmic optimization, rather than manual parameter tuning, and on two-threshold classification (match/manual review/non-match) as well as single-threshold (match/non-match).
We manually reviewed 20 000 randomly selected, potential duplicate record-pairs to identify matches (10 000 training set, 10 000 test set). We evaluated the probabilistic expectation maximization, simple deterministic and fuzzy inference engine (FIE) algorithms. We used particle swarm to optimize algorithm parameters for a single and for two thresholds. We ran 10 iterations of optimization using the training set and report averaged performance against the test set.
The overall estimated duplicate rate was 6%. FIE and simple deterministic algorithms allowed a lower manual review set compared to the probabilistic method (FIE 1.9%, simple deterministic 2.5%, probabilistic 3.6%; p<0.001). For a single threshold, the simple deterministic algorithm performed better than the probabilistic method (positive predictive value 0.956 vs 0.887, sensitivity 0.985 vs 0.887, p<0.001). ER with FIE classifies 98.1% of record-pairs correctly (1/10 000 error rate), assigning the remainder to manual review.
Optimized deterministic algorithms outperform the probabilistic method. There is a strong case for considering optimized deterministic methods for ER.
PMCID: PMC3912727  PMID: 23703827
Medical Records Systems, Computerized [L01.700.508.300.695]; Medical Record Linkage [N04.452.859.564.550]
19.  Primary Amenorrhea in Anorexia Nervosa: Impact on Characteristic Masculine and Feminine Traits 
Animal studies indicate gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using General Linear Models based on the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.
PMCID: PMC4266542  PMID: 24123541
Organizational effects; sex differences; amenorrhea; pubertal timing; anorexia nervosa
20.  Purifying selection in Porcine reproductive and respiratory syndrome virus ORF5a protein influences variation in envelope glycoprotein 5 glycosylation 
Porcine Reproductive and Respiratory Syndrome Virus ORF5a protein is encoded in an alternate open reading frame upstream of the major envelope glycoprotein (GP5) in subgenomic mRNA5. Bioinformatic analysis of 3,466 Type 2 PRRSV sequences showed that the two proteins have co-evolved through a fine balance of purifying codon usage to maintain a conserved RQ-rich motif in ORF5a protein, while eliciting a variable N-linked glycosylation motif in the alternative GP5 reading frame. Conservation of the ORF5a protein RQ-motif also explains an anomalous uracil desert in GP5 hypervariable glycosylation region. The N-terminus of the mature GP5 protein was confirmed to start with amino acid 32, the hypervariable region of the ectodomain. Since GP5 glycosylation variability is assumed to result from immunological selection against neutralizing antibodies, these findings show that an alternative possibility unrelated to immunological selection not only exists, but provides a foundation for investigating previously unsuspected aspects of PRRSV biology. Understanding functional consequences of subtle nucleotide sequence modifications in the region responsible for critical function in ORF5a protein and GP5 glycosylation is essential for rational design of new vaccines against PRRS.
PMCID: PMC3875317  PMID: 24084290
natural selection; evolution; PRRSV
21.  Factors Associated With Recovery from Anorexia Nervosa 
Journal of psychiatric research  2013;47(7):972-979.
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
PMCID: PMC3682792  PMID: 23535032
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
22.  Age and sex affect protein metabolism at protein intakes that span the range of adequacy: comparison of leucine kinetics and nitrogen balance data☆ 
The Journal of nutritional biochemistry  2012;24(4):10.1016/j.jnutbio.2012.03.021.
Research suggests that changes in leucine oxidation (leuox) with feeding may reflect adult protein requirements. We evaluated this possibility by assessing the effects of age, sex, and different protein intakes on whole-body leucine kinetics and nitrogen balance. Thirty-four young (n = 18, 22–46 years) and old (n= 16, 63–81 years) men and women completed three 18-day trials with protein intakes of 0.50, 0.75 and 1.00 g protein·kg body weight−1·d−1. Fasting and fed-state leucine kinetics were quantified on day 12 of each trial using a primed, constant infusion of L-[1-13C]leucine. Protein requirement was estimated using classical nitrogen balance measurements and calculations. Leucine kinetics parameters were influenced by age and sex across all protein intakes. With feeding, leuox increased more in old vs. young adults. Independent of age, fasting and fed-state leuox were lower, and net leucine balance (fasting+fed-state) was higher in women vs. men. Among all subjects and protein intakes, nitrogen balance was correlated with fed-state leuox (r=0.39), fed-state leucine balance (r=0.60), net leucine balance (r=0.49) and the change in leuox from the fasting to fed state (r=0.49) (P<.05 for all results). At the highest protein intake, the change in leuox with feeding was inversely correlated with protein requirement (r=−0.39). These findings indicate that leucine kinetics, especially leuox, reflect nitrogen balance-based estimates of the need for dietary protein and generally support the view that protein requirement is comparable between young and old adults.
PMCID: PMC3885868  PMID: 22841544
Dietary protein; Protein adequacy; Protein metabolism
23.  Temporal Sequence of Comorbid Alcohol Use Disorder and Anorexia Nervosa 
Addictive behaviors  2012;38(3):1704-1709.
Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n = 161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.
PMCID: PMC3558554  PMID: 23254222
anorexia nervosa; alcohol use disorder; comorbidity; age of onset
24.  Nutrient Ingestion, Protein Intake, and Sex, but Not Age, Affect the Albumin Synthesis Rate in Humans123 
The Journal of nutrition  2007;137(7):1734-1740.
The aim of this study was to assess the effects of nutrient ingestion, dietary protein intake, age, and sex on the fractional synthesis rate (FSR) of albumin. Thirty-six healthy free-living individuals (8 females and 10 males aged 21–43 y and 9 females and 9 males aged 63–79 y) completed three 18-d periods of controlled feeding with protein intakes of 125% (P125, 1.00 g protein · kg−1 · d−1), 94% (P94, 0.75 g protein · kg−1 · d−1), and 63% (P63, 0.50 g protein · kg−1 · d−1) of the recommended dietary allowance. On d 12 of each trial, postabsorptive (PA) serum albumin concentration was determined and PA and postprandial (PP) albumin FSR were estimated from the rate of L-[1-13C] leucine incorporation into plasma albumin during an 8-h infusion. There were no age-related differences in PA and PP albumin FSR. Albumin FSR was higher PP than PA (P < 0.0001), and the increase in albumin FSR from PA to PP was smaller as dietary protein intake decreased from P125 to P94 and P63 (P < 0.05). Independent of protein intake, males had a higher albumin FSR (P < 0.05) and a greater increase in albumin FSR with feeding (P < 0.05). There was no age or dietary protein effect on serum albumin concentrations, but males had higher albumin concentrations than females (P < 0.0001). These results show that older persons are responsive to nutrient ingestion and dietary protein-related changes in albumin FSR. The greater albumin synthesis rate in males might contribute to a higher albumin concentration set point.
PMCID: PMC3885871  PMID: 17585023
25.  Predictors of Accessing Substance Abuse Services Among Individuals With Mental Disorders Released From Correctional Custody 
Journal of dual diagnosis  2012;9(1):11-22.
In the context of an increasing correctional population and corresponding rates of mental illness and substance abuse among this population, this study focuses on describing the predictors of substance abuse service utilization for ex-inmates with dual disorders. Our aim is to assess the likelihood and characteristics of ex-inmates with mental disorders who access substance abuse treatment services within two years of correctional release.
Using merged administrative data on all ex-inmates with open mental health cases released from Massachusetts Department of Corrections and two County Houses of Corrections from 2007 to 2009 (N=2,280) and substance abuse treatment outcome data through 2011, we analyze the influence of demographics, behavioral and mental disorders, and criminal justice variables on entry into substance abuse treatment within 24 months post release. We also describe primary drug use and services utilized for all the ex-inmates who accessed substance abuse services (N=1,383). Regression techniques were used to analyze the probability of utilizing substance abuse treatment services by various demographic, behavioral, and criminal involvement characteristics.
The prevalence of a history of substance use disorders is high in this population (69%; n = 1,285). Subsequently, at 24 months post release 61% (n = 1,383) of ex-inmates with open mental health cases utilized substance abuse treatment services. This group was disproportionately female, with a preincarceration history of substance abuse, an increased number of previous incarcerations, and more likely released under correctional supervision.
Substance abuse is a chronic relapsing disorder and dual diagnosis is common among individuals with mental disorders involved with the criminal justice system. Their service needs and contacts across substance abuse, mental health, and criminal justice systems highlight individuals caught up in the institutional circuit. Study results point to the need for expanded and targeted dual diagnosis treatment approaches and relapse prevention for ex-inmates with mental disorders post correctional release.
PMCID: PMC3608478  PMID: 23543790
mental illness; mental disorder; substance abuse; criminal justice; dual diagnosis; history of substance abuse services; substance abuse treatment services; ex-inmates

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