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1.  Progesterone vs placebo therapy for women with epilepsy 
Neurology  2012;78(24):1959-1966.
To assess progesterone treatment of intractable seizures in women with partial epilepsy.
This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles.
There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3.
There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures.
Classification of evidence:
This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.
PMCID: PMC3369508  PMID: 22649214
2.  Physician and Patient Assessment of Triamcinolone Acetonide Spray for Steroid-responsive Dermatoses 
Objective: To assess the clinical outcomes of triamcinolone acetonide spray for steroid-responsive dermatoses using investigator and patient global assessment scores and evaluate patient satisfaction. Design: This open-label, single-center, noncomparator study enrolled 42 patients (aged 18 years or older) with dermatoses. Patients were instructed to use triamcinolone acetonide spray 1 to 4 times daily, depending on investigator instructions, for up to 28 days. Measurements: Investigators and patients scored the overall severity of dermatoses based on a global assessment scale. Investigators also rated signs and symptoms of dermatoses and evaluated clinical outcomes based on an improvement assessment scale. Patient satisfaction with treatment was assessed at the end of treatment or at Day 28 using a questionnaire. Patients were evaluated on Days 7, 14, 21, and 28. Complete clearing of dermatoses warranted early discontinuation from the study. Results: Triamcinolone acetonide spray effectively improved dermatoses scores, clinical outcomes, and signs and symptoms of dermatoses. More than 80 percent of patients entered the study with moderate or severe dermatoses. Within 14 days, none had severe dermatoses, and by 28 days, 64 percent of patients were completely clear or almost clear. From the patient perspective, 51.3 percent experienced improvement in only three days, and 84.6 percent experienced improvement in seven days. An overwhelming number of patients (95%) preferred triamcinolone acetonide spray over creams and ointments, and more than half experienced a cooling effect upon contact with the spray. Conclusion: Triamcinolone acetonide spray is an effective topical corticosteroid that should be considered for patients with steroid-responsive dermatoses of all ranges of severity.
PMCID: PMC2922713  PMID: 20725566
3.  Intravesical capsaicin for treatment of detrusor hyperreflexia. 
An intravesical instillation of 100 ml 1 or 2 mmol/l capsaicin has been used to treat detrusor hyperreflexia giving rise to intractable urinary incontinence in 12 patients with spinal cord disease and two other patients with detrusor overactivity of non-spinal origin. Nine patients, all of whom had spinal cord disease, showed some improvement in bladder function. The benefit was only shortlived and partial in four, but the remaining five achieved complete continence while performing intermittent self catheterisation. Urodynamic studies in these nine patients showed an increase in mean (SD) bladder capacity from 106 (57) to 302 (212) ml and a fall in the maximum detrusor pressure from 54 (20) to 36 (10) cm of water. There were no short term ill effects from the instillation and the improvement in bladder function lasted for between three weeks to six months, when in some patients it was repeated. The improvement in bladder behaviour shown in this study can be interpreted as showing that capsaicin sensitive afferents play an important part in the pathogenesis of detrusor hyperreflexia in spinal humans. Intravesical capsaicin seems a promising means of treating intractable detrusor hyperreflexia and studies with this substance may shed new light on other disorders of detrusor activity that cause incontinence.
PMCID: PMC1072443  PMID: 8126498
4.  Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice 
Psychopharmacology  2013;10.1007/s00213-013-3235-1.
Allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of α5* nAChRs in the effects of nicotine on brain reward systems.
Materials and methods
Effects of acute (0.03125-0.5 mg/kg SC) or chronic (24 mg/kg per day; osmotic minipump) nicotine, and mecamylamine-precipitated withdrawal, on intracranial self-stimulation (ICSS) thresholds were assessed in wildtype and α5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion (CTA) procedure.
Lower nicotine doses (0.03125-0.125 mg/kg) decreased ICSS thresholds in wildtype and α5 knockout mice. At higher doses (0.25-0.5 mg/kg), threshold-lowering effects of nicotine were diminished in wildtype mice, whereas nicotine lowered thresholds across all doses tested in α5 knockout mice. Nicotine (1.5 mg/kg) conditioned a taste aversion to saccharine equally in both genotypes. Mecamylamine (5 mg/kg) elevated ICSS thresholds by a similar magnitude in wildtype and α5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated α5 knockout mice.
α5* nAChRs are not involved in reward-enhancing effects of lower nicotine doses, the reward-inhibiting effects of nicotine withdrawal, or the general noxious effects of higher nicotine doses. Instead, α5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of α5* nAChR signaling greatly expands the range of nicotine doses that facilitate brain reward activity, which may help explain the increased tobacco addiction vulnerability associated with CHRNA5 risk alleles.
PMCID: PMC3930613  PMID: 23958943
CHRNA5; α5 nicotinic receptors; nicotine; reward; aversion; habenula; interpeduncular nucleus; conditioned taste aversion
5.  Effects of Motion Sickness Severity on the Vestibular-Evoked Myogenic Potentials 
Motion sickness is a common debilitating condition associated with both actual and perceived motion. Despite the commonality, little is known about the underlying physiological mechanisms. One theory proposes that motion sickness arises from a mismatch between reality and past experience in vertical motions. Physiological tests of the vestibular system, however, have been inconclusive regarding the underlying pathogenesis. Cervical vestibular-evoked myogenic potentials (cVEMPs) arise from the saccule, which responds to vertical motion. If vertical motion elicits motion sickness, the cVEMP should be affected.
The purpose of this investigation was to determine if cVEMP characteristics differ among individuals with a range of motion sickness susceptibility from negligible to severe. The hypothesis was that individuals with high susceptibility would have larger cVEMP amplitudes and shorter cVEMP latencies relative to those who are resistant to motion sickness.
Research Design
The study had two parts. The first was quasi-experimental in which participants comprised three groups based on susceptibility to motion sickness (low, mild-moderate, high) as identified on the short version of the Motion Sickness Susceptibility Questionnaire (MSSQ-S). The second part of the study was correlational and evaluated the specific relationships between the degree of motion sickness susceptibility and characteristics of the VEMPs.
Study Sample
A total of 24 healthy young adults (ages 20–24 yr) were recruited from the university and the community without regard to motion sickness severity.
Data Collection and Analysis
Participants took the MSSQ-S, which quantifies susceptibility to motion sickness. The participants had a range of motion sickness susceptibility with MSSQ raw scores from 0.0–36.6, which correspond to percent susceptibility from 0.0–99.3%. VEMPs were elicited by 500 Hz tone-bursts monaurally in both ears at 120 dB pSPL. MSSQ-S percent scores were used to divide the participants into low, mild-moderate, and high susceptibility groups. A fixed general linear model with repeated-measures analysis of variance tested cVEMP characteristics for the susceptibility groups (between participants) and ears (within participants). A univariate analysis of variance tested the cVEMP interaural amplitudes across groups. The second analysis was a regression of the severity of motion sickness in percent on cVEMP characteristics. Significance was defined as p < 0.05.
Participants in the high susceptibility group had significantly higher cVEMP amplitudes than those in the low susceptibility group. cVEMP amplitudes did not differ between ears, and latencies did not differ between the two groups or between ears. Regression analysis on MSSQ-S percent susceptibility by VEMP amplitudes revealed a best-fit cubic function in both ears, with r2 values of more than 42%. The interaural asymmetry ratio was negatively associated with motion sickness susceptibility (r2 = 0.389).
The current study is the first to report that greater susceptibility to motion sickness is associated with larger cVEMP amplitudes and lower interaural cVEMP asymmetries. Larger interaural asymmetries in cVEMPs did not promote motion sickness susceptibility. The cVEMP findings implicate the saccule and its neural pathways in the production of motion sickness and are consistent with the theory that vertical motions elicit motion sickness. Motion sickness susceptibility may contribute to the variability in normative cVEMP amplitudes.
PMCID: PMC4332880  PMID: 25405837
Vestibular-evoked myogenic potential; motion sickness; saccule; vestibular nerve; inner ear; perception; humans; adults
6.  Gating Topology of the Proton-Coupled Oligopeptide Symporters 
Structure(London, England:1993)  2015;23(2):290-301.
Proton-coupled oligopeptide transporters belong to the major facilitator superfamily (MFS) of membrane transporters. Recent crystal structures suggest the MFS fold facilitates transport through rearrangement of their two six-helix bundles around a central ligand binding site; how this is achieved, however, is poorly understood. Using modeling, molecular dynamics, crystallography, functional assays, and site-directed spin labeling combined with double electron-electron resonance (DEER) spectroscopy, we present a detailed study of the transport dynamics of two bacterial oligopeptide transporters, PepTSo and PepTSt. Our results identify several salt bridges that stabilize outward-facing conformations and we show that, for all the current structures of MFS transporters, the first two helices of each of the four inverted-topology repeat units form half of either the periplasmic or cytoplasmic gate and that these function cooperatively in a scissor-like motion to control access to the peptide binding site during transport.
Graphical Abstract
•New higher-resolution structure of PepTSo•Salt bridges stabilizing outward-facing conformations are identified•The conserved prolines in helix 8 are shown to be important•The first two helices in each inverted-topology repeat form part of a gate
Fowler et al. use biophysical and modeling approaches to identify salt bridges in two peptide transporters that stabilize their outward-facing conformations. Their results also suggest that the first two helices in each inverted-topology repeat unit forms part of either of the two gates.
PMCID: PMC4321885  PMID: 25651061
7.  Modeling Trajectory of Depressive Symptoms Among Psychiatric Inpatients: A Latent Growth Curve Approach 
Changes in the parameters of inpatient psychiatric care have inspired a sizable literature exploring correlates of prolonged intervention as well as symptom change over varying lengths of hospitalization. However, existing data offer limited insight regarding the nature of symptom change over time. Objectives of this longitudinal research were to (a) model the trajectory of depressive symptoms within an inpatient psychiatric sample, (b) identify characteristics associated with unique patterns of change, and (c) evaluate the magnitude of expected gains using objective clinical benchmarks.
Participants included psychiatric inpatients treated between April 2008 and December 2010. Latent growth curve modeling was used to determine the trajectory of Beck Depression Inventory II depressive symptoms in response to treatment. Age, gender, trauma history, prior hospitalization, and DSM-IV diagnoses were examined as potential moderators of recovery.
Results indicate a nonlinear model of recovery, with symptom reductions greatest following admission and slowing gradually over time. Female gender, probable trauma exposure, prior psychiatric hospitalization, and primary depressive diagnosis were associated with more severe trajectories. Diagnosis of alcohol/substance use, by contrast, was associated with more moderate trajectories. Objective benchmarks occurred relatively consistently across patient groups with clinically significant change occurring between 2–4 weeks post-admission.
The nonlinear trajectory of recovery observed in these data provides insight regarding the dynamics of inpatient recovery. Across all patient groups, symptom reduction was most dramatic in the initial week of hospitalization. However, notable improvement continued for several weeks post-admission. Results suggest timelines for adequate inpatient care are largely contingent on program-specific goals.
PMCID: PMC4313384  PMID: 23759452
inpatient treatment; psychiatric hospitalization; depression; symptom trajectory; latent growth curve modeling
8.  The Common Marmoset Genome Provides Insight into Primate Biology and Evolution 
Worley, Kim C. | Warren, Wesley C. | Rogers, Jeffrey | Locke, Devin | Muzny, Donna M. | Mardis, Elaine R. | Weinstock, George M. | Tardif, Suzette D. | Aagaard, Kjersti M. | Archidiacono, Nicoletta | Rayan, Nirmala Arul | Batzer, Mark A. | Beal, Kathryn | Brejova, Brona | Capozzi, Oronzo | Capuano, Saverio B. | Casola, Claudio | Chandrabose, Mimi M. | Cree, Andrew | Dao, Marvin Diep | de Jong, Pieter J. | del Rosario, Ricardo Cruz-Herrera | Delehaunty, Kim D. | Dinh, Huyen H. | Eichler, Evan | Fitzgerald, Stephen | Flicek, Paul | Fontenot, Catherine C. | Fowler, R. Gerald | Fronick, Catrina | Fulton, Lucinda A. | Fulton, Robert S. | Gabisi, Ramatu Ayiesha | Gerlach, Daniel | Graves, Tina A. | Gunaratne, Preethi H. | Hahn, Matthew W. | Haig, David | Han, Yi | Harris, R. Alan | Herrero, Javier M. | Hillier, LaDeana W. | Hubley, Robert | Hughes, Jennifer F. | Hume, Jennifer | Jhangiani, Shalini N. | Jorde, Lynn B. | Joshi, Vandita | Karakor, Emre | Konkel, Miriam K. | Kosiol, Carolin | Kovar, Christie L. | Kriventseva, Evgenia V. | Lee, Sandra L. | Lewis, Lora R. | Liu, Yih-shin | Lopez, John | Lopez-Otin, Carlos | Lorente-Galdos, Belen | Mansfield, Keith G. | Marques-Bonet, Tomas | Minx, Patrick | Misceo, Doriana | Moncrieff, J. Scott | Morgan, Margaret B. | Muthuswamy, Raveendran | Nazareth, Lynne V. | Newsham, Irene | Nguyen, Ngoc Bich | Okwuonu, Geoffrey O. | Prabhakar, Shyam | Perales, Lora | Pu, Ling-Ling | Puente, Xose S. | Quesada, Victor | Ranck, Megan C. | Raney, Brian J. | Deiros, David Rio | Rocchi, Mariano | Rodriguez, David | Ross, Corinna | Ruffier, Magali | Ruiz, San Juana | Sajjadian, S. | Santibanez, Jireh | Schrider, Daniel R. | Searle, Steve | Skaletsky, Helen | Soibam, Benjamin | Smit, Arian F. A. | Tennakoon, Jayantha B. | Tomaska, Lubomir | Ullmer, Brygg | Vejnar, Charles E. | Ventura, Mario | Vilella, Albert J. | Vinar, Tomas | Vogel, Jan-Hinnerk | Walker, Jerilyn A. | Wang, Qing | Warner, Crystal M. | Wildman, Derek E. | Witherspoon, David J. | Wright, Rita A. | Wu, Yuanqing | Xiao, Weimin | Xing, Jinchuan | Zdobnov, Evgeny M. | Zhu, Baoli | Gibbs, Richard A. | Wilson, Richard K.
Nature genetics  2014;46(8):850-857.
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
PMCID: PMC4138798  PMID: 25038751
9.  Emerging and Resistant Infections 
Annals of the American Thoracic Society  2014;11(Suppl 4):S193-S200.
The lungs are a major target for infection and a key battleground in the fight against the development of antimicrobial drug–resistant pathogens. Ventilator-associated pneumonia (VAP) is associated with mortality rates of 24–50%. The optimal duration of antibiotic therapy against VAP is unknown, but prolonged courses are associated with the emergence of bacterial resistance. De-escalation strategies in which treatment is discontinued based on signs of clinical resolution, fixed durations of therapy (generally 7–8 d), or serum procalcitonin responses have been shown to decrease antibiotic consumption. Outcomes are comparable to longer treatment courses, with the possible exception of VAP due to nonfermenting, gram-negative bacilli such as Pseudomonas aeruginosa. Staphylococcus aureus is a leading cause of VAP and other infections. Outcomes after S. aureus infection are shaped by the interplay between environmental, bacterial, and host genetic factors. It is increasingly clear that mechanisms of pathogenesis vary in different types of S. aureus infections. Genome-scale studies of S. aureus strains, host responses, and host genetics are redefining our understanding of the pathogenic mechanisms underlying VAP. Genome-sequencing technologies are also revolutionizing our understanding of the molecular epidemiology, evolution, and transmission of influenza. Deep sequencing using next-generation technology platforms is defining the remarkable genetic diversity of influenza strains within infected hosts. Investigators have demonstrated that antiviral drug-resistant influenza may be present prior to the initiation of treatment. Moreover, drug-resistant minor variant influenza strains can be transmitted from person to person in the absence of selection pressure. Studies of lung infections and the causative pathogens will remain at the cutting edge of clinical and basic medical research.
PMCID: PMC4200571  PMID: 25148425
pneumonia; ventilator-associated pneumonia; Staphylococcus aureus; influenza
10.  Evidence that Formulations of the Selective MAO-B Inhibitor, Selegiline, which Bypass First-Pass Metabolism, also Inhibit MAO-A in the Human Brain 
Neuropsychopharmacology  2014;40(3):650-657.
Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [11C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11–70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9–68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.
PMCID: PMC4289953  PMID: 25249059
11.  In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver 
BMC Medicine  2015;13:18.
Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.
In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.
In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).
Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0251-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4310040  PMID: 25630355
DNA methylation; Liver; Maternal smoking; Vitamin B12
12.  Organisational culture and post-merger integration in an academic health centre: a mixed-methods study 
Around the world, the last two decades have been characterised by an increase in the numbers of mergers between healthcare providers, including some of the most prestigious university hospitals and academic health centres. However, many mergers fail to bring the anticipated benefits, and successful post-merger integration in university hospitals and academic health centres is even harder to achieve. An increasing body of literature suggests that organisational culture affects the success of post-merger integration and academic-clinical collaboration.
This paper reports findings from a mixed-methods single-site study to examine 1) the perceptions of organisational culture in academic and clinical enterprises at one National Health Service (NHS) trust, and 2) the major cultural issues for its post-merger integration with another NHS trust and strategic partnership with a university. From the entire population of 72 clinician-scientists at one of the legacy NHS trusts, 38 (53%) completed a quantitative Competing Values Framework survey and 24 (33%) also provided qualitative responses. The survey was followed up by semi-structured interviews with six clinician-scientists and a group discussion including five senior managers.
The cultures of two legacy NHS trusts differed and were primarily distinct from the culture of the academic enterprise. Major cultural issues were related to the relative size, influence, and history of the legacy NHS trusts, and the implications of these for respective identities, clinical services, and finances. Strategic partnership with a university served as an important ameliorating consideration in reaching trust merger. However, some aspects of university entrepreneurial culture are difficult to reconcile with the NHS service delivery model and may create tension.
There are challenges in preserving a more desirable culture at one of the legacy NHS trusts, enhancing cultures in both legacy NHS trusts during their post-merger integration, and in aligning academic and clinical cultures following strategic partnership with a university. The seeds of success may be found in current best practice, good will, and a near identical ideal of the future preferred culture. Strong, fair leadership will be required both nationally and locally for the success of mergers and post-merger integration in university hospitals and academic health centres.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0673-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4308851  PMID: 25608775
Organisational culture; Competing Values Framework (CVF); Post-merger integration; University Hospital; Academic Health Centre (AHC); Academic-Clinical Collaboration; Strategic partnership; Research and innovation; Teaching; Patient care
13.  Urbanicity, Persecutory Delusions, and Clinical Intervention: The Development of a Brief CBT Module for Helping Patients with Persecutory Delusions Enter Social Urban Environments 
Substantial epidemiological research has shown that psychotic experiences are more common in densely populated areas. Many patients with persecutory delusions find it difficult to enter busy social urban settings. The stress and anxiety caused by being outside lead many patients to remain in-doors. We therefore developed a brief CBT intervention, based upon a formulation of the way urban environments cause stress and anxiety, to help patients with paranoid thoughts to feel less distressed when outside in busy streets.
The aim was to pilot the new intervention for feasibility and acceptability and gather preliminary outcome data.
Fifteen patients with persecutory delusions in the context of a schizophrenia diagnosis took part. All patients first went outside to test their reactions, received the intervention, and then went outside again.
The intervention was considered useful by the patients. There was evidence that going outside after the intervention led to less paranoid responses than the initial exposure, but this was only statistically significant for levels of distress.
Initial evidence was obtained that a brief CBT module specifically focused on helping patients with paranoia go outside is feasible, acceptable, and may have clinical benefits. However, it could not be determined from this small feasibility study that any observed improvements were due to the CBT intervention. Challenges in this area and future work required are outlined.
PMCID: PMC4005778  PMID: 23930939
Delusions; schizophrenia; CBT; urbanicity
14.  A Host-Based RT-PCR Gene Expression Signature to Identify Acute Respiratory Viral Infection 
Science translational medicine  2013;5(203):203ra126.
Improved ways to diagnose acute respiratory viral infections could decrease inappropriate antibacterial use and serve as a vital triage mechanism in the event of a potential viral pandemic. Measurement of the host response to infection is an alternative to pathogen-based diagnostic testing and may improve diagnostic accuracy. We have developed a host-based assay with a reverse transcription polymerase chain reaction (RT-PCR) TaqMan low-density array (TLDA) platform for classifying respiratory viral infection. We developed the assay using two cohorts experimentally infected with influenza A H3N2/Wisconsin or influenza A H1N1/Brisbane, and validated the assay in a sample of adults presenting to the emergency department with fever (n = 102) and in healthy volunteers (n = 41). Peripheral blood RNA samples were obtained from individuals who underwent experimental viral challenge or who presented to the emergency department and had microbiologically proven viral respiratory infection or systemic bacterial infection. The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively. We validated this host gene expression signature in a cohort of 102 individuals arriving at the emergency department. The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%). These results show that RT-PCR–based detection of a host gene expression signature can classify individuals with respiratory viral infection and sets the stage for prospective evaluation of this diagnostic approach in a clinical setting.
PMCID: PMC4286889  PMID: 24048524
15.  Metabolic Syndrome is linked to Chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans 
Obesity (Silver Spring, Md.)  2012;20(10):2083-2092.
The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10−5), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥ 1.2) with MS. Further, we examined 29 single nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, alpha transducing 3 (GNAT3, 11 SNPs) gene, located within the 1-LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk [RR] = 1.6 and P = 0.004, RR = 1.7 respectively) and several other related traits. These two variants explained about 18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately 3-fold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans.
PMCID: PMC4287372  PMID: 22456541
Metabolic syndrome; NCEP/ATPIII; linkage/genome scan; variance components linkage analysis; single nucleotide polymorphisms; association analysis; Mexican Americans; CD36/FAT; GNAT3
16.  Genome and Phylogenetic Analyses of Trypanosoma evansi Reveal Extensive Similarity to T. brucei and Multiple Independent Origins for Dyskinetoplasty 
Two key biological features distinguish Trypanosoma evansi from the T. brucei group: independence from the tsetse fly as obligatory vector, and independence from the need for functional mitochondrial DNA (kinetoplast or kDNA). In an effort to better understand the molecular causes and consequences of these differences, we sequenced the genome of an akinetoplastic T. evansi strain from China and compared it to the T. b. brucei reference strain. The annotated T. evansi genome shows extensive similarity to the reference, with 94.9% of the predicted T. b. brucei coding sequences (CDS) having an ortholog in T. evansi, and 94.6% of the non-repetitive orthologs having a nucleotide identity of 95% or greater. Interestingly, several procyclin-associated genes (PAGs) were disrupted or not found in this T. evansi strain, suggesting a selective loss of function in the absence of the insect life-cycle stage. Surprisingly, orthologous sequences were found in T. evansi for all 978 nuclear CDS predicted to represent the mitochondrial proteome in T. brucei, although a small number of these may have lost functionality. Consistent with previous results, the F1FO-ATP synthase γ subunit was found to have an A281 deletion, which is involved in generation of a mitochondrial membrane potential in the absence of kDNA. Candidates for CDS that are absent from the reference genome were identified in supplementary de novo assemblies of T. evansi reads. Phylogenetic analyses show that the sequenced strain belongs to a dominant group of clonal T. evansi strains with worldwide distribution that also includes isolates classified as T. equiperdum. At least three other types of T. evansi or T. equiperdum have emerged independently. Overall, the elucidation of the T. evansi genome sequence reveals extensive similarity of T. brucei and supports the contention that T. evansi should be classified as a subspecies of T. brucei.
Author Summary
The single-cell parasite Trypanosoma evansi is the disease-causing trypanosome with the widest geographical distribution. The disease, called surra, has significant economic impact primarily due to infections of cattle, horses, and camels. Morphologically the parasite is indistinguishable from bloodstream stage T. brucei, a parasite causing sleeping sickness in humans and the disease nagana in animals. T. brucei, however, is strictly bound to sub-Saharan Africa where its obligate vector, the tsetse fly, resides. The lack of a complete mitochondrial genome in T. evansi further distinguishes this parasite from T. brucei. Important questions regarding the biology of T. evansi include how it escaped from Africa, whether this has happened more than once, and how exactly it is related to T. brucei. To help answer these questions we have sequenced the T. evansi nuclear genome. Our phylogenetic analysis demonstrates that T. evansi, and the closely related horse parasite T. equiperdum, evolved more than once from T. brucei. We also demonstrate extensive similarity to T. brucei, including the maintenance of numerous genes that T. evansi no longer requires. Therefore, despite the significant functional and pathological differences between T. evansi and T. brucei, our analysis supports the notion that T. evansi is not an independent species.
PMCID: PMC4288722  PMID: 25568942
17.  Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis 
Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed.
The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection.
This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality.
Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol / L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p ≤ 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission.
A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis.
PMCID: PMC4283798  PMID: 20370777
sepsis; outcomes; septic shock; progression; biomarkers
18.  Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.09.008.
Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered.
PMCID: PMC3858456  PMID: 24055497
19.  Design and Implementation of a Randomized Controlled Social and Mobile Weight Loss Trial for Young Adults (project SMART) 
Contemporary clinical trials  2013;37(1):10-18.
To describe the theoretical rationale, intervention design, and clinical trial of a two-year weight control intervention for young adults deployed via social and mobile media.
A total of 404 overweight or obese college students from three Southern California universities (Mage = 22(±4) years; MBMI=29(±2.8); 70% female) were randomized to participate in the intervention or to receive an informational web-based weight loss program. The intervention is based on behavioral theory and integrates intervention elements across multiple touch points, including Facebook, SMS, smartphone applications, blogs, and e-mail. Participants are encouraged to seek social support among their friends, self-monitor their weight weekly, post their health behaviors on Facebook, and e-mail their weight loss questions/concerns to a health coach. The intervention is adaptive because new theory-driven and iteratively tailored intervention elements are developed and released over the course of the two-year intervention in response to patterns of use and user feedback. Measures of body mass index, waist circumference, physical activity (PA), sedentary behavior (SED), diet, weight management practices, smoking, alcohol, sleep, body image, self-esteem, and depression occur at 6, 12, 18, and 24 months. Currently, all participants have been recruited, and all are in the final year of the trial.
Theory-driven, evidence-based strategies for PA, SED, and dietary intake can be embedded in an intervention using social and mobile technologies to promote healthy weight-related behaviors in young adults.
PMCID: PMC3910290  PMID: 24215774
weight loss; social support; young adult; Internet; health promotion; obesity
20.  Surveillance of Carbapenem-Resistant Klebsiella pneumoniae: Tracking Molecular Epidemiology and Outcomes through a Regional Network 
Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem-resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either blaKPC-2 (48%) or blaKPC-3 (51%). One isolate tested positive for blaNDM-1, a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with blaKPC-3 (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants.
PMCID: PMC4068524  PMID: 24798270
21.  Talking as doing: Language forms and public language 
New ideas in psychology  2014;32:10.1016/j.newideapsych.2013.03.007.
I discuss language forms as the primary means that language communities provide to enable public language use. As such, they are adapted to public use most notably in being linguistically significant vocal tract actions, not the categories in the mind as proposed in phonological theories. Their primary function is to serve as vehicles for production of syntactically structured sequences of words. However, more than that, phonological actions themselves do work in public language use. In particular, they foster interpersonal coordination in social activities. An intriguing property of language forms that likely reflects their emergence in social communicative activities is that phonological forms that should be meaningless (in order to serve their role in the openness of language at the level of the lexicon) are not wholly meaningless. In fact, the form-meaning “rift” is bridged bidirectionally: The smallest language forms are meaningful, and the meanings of lexical language forms generally inhere, in part, in their embodiment by understanders.
PMCID: PMC3868477  PMID: 24363491
language forms; embodiment; public language; form-meaning rift
22.  Adiposity and Fat Metabolism in Lactating and Fasting Northern Elephant Seals12 
Advances in Nutrition  2014;5(1):57-64.
Several taxa of animals fast completely from food and water during energy-intensive periods such as lactation, breeding, and development. In elephant seals, these behaviors are sustained by high adiposity, high rates of fat mobilization, and reduced oxidation of carbohydrates and proteins. Adiposity and the regulation of lipolysis directly affect lactation energetics, milk composition, and mating success. Long-term fasting induces changes in regulation of lipolysis and lipid metabolism that influence fatty acid (FA) availability and the onset of insulin resistance. Hypoinsulinemia and elevated circulating FAs are also associated with several unique features of carbohydrate metabolism, including elevated plasma glucose, gluconeogenesis, and Cori cycle activity as well as high rates of pyruvate and tricarboxylic acid cycling. Glucose-lactate pools and triacylglycerol-FA cycles may be linked via glyceroneogenesis and this may be an important pathway influencing both fat and carbohydrate metabolism. Together, these features allow a sustained, high intensity, fat-based metabolism without substantial accumulation of ketoacids.
PMCID: PMC3884100  PMID: 24425723
23.  Pharmacokinetics and Safety of Tenofovir in HIV-infected Women during Labor and their Infants During the First Week of Life 
Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking.
HPTN 057 was a phase 1, open label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses day 0, 3 and 5; maternal 900 mg doses/infant 6 mg/kg doses day 0, 3 and 5; maternal 600 mg doses/infant 6 mg/kg doses daily ×7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid and breast milk tenofovir concentrations were determined by liquid chromatographic – tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing.
122 mother-infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 mg and 900 mg exceeded that in non-pregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74–97% of infants receiving daily dosing.
A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in studies of TDF efficacy for HIV PMTCT and early infant treatment.
PMCID: PMC3912736  PMID: 23979002
tenofovir; neonate; pharmacokinetics
24.  Prediction scores do not correlate with clinically adjudicated categories of pulmonary embolism in critically ill patients 
Prediction scores for pretest probability of pulmonary embolism (PE) validated in outpatient settings are occasionally used in the intensive care unit (ICU).
To evaluate the correlation of Geneva and Wells scores with adjudicated categories of PE in ICU patients.
In a randomized trial of thromboprophylaxis, patients with suspected PE were adjudicated as possible, probable or definite PE. Data were then retrospectively abstracted for the Geneva Diagnostic PE score, Wells, Modified Wells and Simplified Wells Diagnostic scores. The chance-corrected agreement between adjudicated categories and each score was calculated. ANOVA was used to compare values across the three adjudicated PE categories.
Among 70 patients with suspected PE, agreement was poor between adjudicated categories and Geneva pretest probabilities (kappa 0.01 [95% CI −0.0643 to 0.0941]) or Wells pretest probabilities (kappa −0.03 [95% CI −0.1462 to 0.0914]). Among four possible, 16 probable and 50 definite PEs, there were no significant differences in Geneva scores (possible = 4.0, probable = 4.7, definite = 4.5; P=0.90), Wells scores (possible = 2.8, probable = 4.9, definite = 4.1; P=0.37), Modified Wells (possible = 2.0, probable = 3.4, definite = 2.9; P=0.34) or Simplified Wells (possible = 1.8, probable = 2.8, definite = 2.4; P=0.30).
Pretest probability scores developed outside the ICU do not correlate with adjudicated PE categories in critically ill patients. Research is needed to develop prediction scores for this population.
PMCID: PMC3938238  PMID: 24083302
Intensive care unit; Prediction models; Pulmonary embolism
25.  Caregiver Reports of Patient-Initiated Violence in Psychosis 
Aggressive behaviour in psychosis is not uncommon. Community provision for people with psychosis has left informal caregivers to take on a greater role in their care. However, few studies have explored links between patient-initiated violence in mental health caregiving relationships and caregiver functioning. Our study investigated caregiver reports of aggressive acts committed by their relative with psychosis and their links to caregiver appraisals of the caregiving relationship and caregiver outcomes.
Caregivers of patients with a recent relapse of psychosis, recruited to a psychological therapy trial, completed the audiotaped Camberwell Family Interview at baseline. This semi-structured interview includes questions on the quality of the relationship between caregiver and patient, and patient history of violence. Seventy-two transcripts of interviews were assessed for reports of patient-initiated violence.
One-half of the caregiver sample (52.9%) reported an incident of patient-initiated violence during their interview; 62.2% of these involved violence toward themselves, and 24.3% toward property. Reports of patient violence were associated with caregiver ratings of hostility expressed toward patients, lower self-esteem, and emotion-focused coping. People caring on their own were more likely to report incidents of patient violence. Younger patients, males, and inpatients were more frequently identified as having a history of this kind of violence.
Our findings suggested that caregiver reports of patient-initiated violence in psychosis are not uncommon. Mental health staff need to be aware of the risks of such violence for caregivers of people with psychosis, and consider appropriate procedures for minimizing it.
Clinical Trial Registration Number: ISRCTN83557988
PMCID: PMC4086313  PMID: 25007421
caregivers; psychosis; violence

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