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author:("brenner, S")
1.  Two- to eight-month-old infants’ perception of dynamic auditory-visual spatial co-location 
Child development  2011;82(4):1210-1223.
From birth, infants detect associations between the locations of static visual objects and sounds they emit, but there is limited evidence regarding their sensitivity to the dynamic equivalent when a sound-emitting object moves. In four experiments involving 36 2-month-olds, 48 5-month-olds and 48 8-month-olds, we investigated infants’ ability to process this form of spatial co-location. Whereas there was no evidence of spontaneous sensitivity, all age groups detected a dynamic co-location during habituation, and looked longer at test trials in which sound and sight were dislocated. Only 2-month-olds showed clear sensitivity to the dislocation relation, although 8-month-olds did so following additional habituation. These results are discussed relative to the intersensory redundancy hypothesis and work suggesting increasing specificity in processing with age.
doi:10.1111/j.1467-8624.2011.01593.x
PMCID: PMC3134617  PMID: 21545580
2.  Diarylacylhydrazones: Clostridium-Selective Antibacterials with Activity Against Stationary-Phase Cells 
Current antibiotics for treating Clostridium difficile infections (CDI), i.e. metronidazole, vancomycin and more recently fidaxomicin, are mostly effective but treatment failure and disease relapse remain as significant clinical problems. The shortcomings of these agents are attributed to their low selectivity for C. difficile over normal gut microflora and their ineffectiveness against C. difficile spores. This paper reports that certain diarylacylhydrazones identified during a high-throughput screening/counter-screening campaign show selective activity against two Clostridium species (C. difficile and C. perfringens) over common gut commensals. Representative examples are shown to possess activity similar to vancomycin against clinical C. difficile strains and to kill stationary-phase C. difficile cells, which are responsible for spore production. Structure-activity relationships with additional synthesised analogues suggested a protonophoric mechanism may play a role in the observed activity/selectivity and this was supported by the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) showing selective anti-Clostridium effects and activity similar to diarylacylhydrazones against stationary-phase C. difficile cells. Two diarylacylhydrazones were shown to be non-toxic towards human FaDu and Hep G2 cells indicating that further studies with the class are warranted towards new drugs for CDI.
doi:10.1016/j.bmcl.2013.12.015
PMCID: PMC3912389  PMID: 24360560
Clostridium difficile; antibacterial; protonophore; diarylacylhydrazone; CCCP; stationary phase cells
3.  The Clinical Education Partnership Initiative: an innovative approach to global health education 
BMC Medical Education  2014;14:1043.
Background
Despite evidence that international clinical electives can be educationally and professionally beneficial to both visiting and in-country trainees, these opportunities remain challenging for American residents to participate in abroad. Additionally, even when logistically possible, they are often poorly structured. The Universities of Washington (UW) and Nairobi (UoN) have enjoyed a long-standing research collaboration, which recently expanded into the UoN Medical Education Partnership Initiative (MEPI). Based on MEPI in Kenya, the Clinical Education Partnership Initiative (CEPI) is a new educational exchange program between UoN and UW. CEPI allows UW residents to partner with Kenyan trainees in clinical care and teaching activities at Naivasha District Hospital (NDH), one of UoN’s MEPI training sites in Kenya.
Methods
UW and UoN faculty collaborated to create a curriculum and structure for the program. A Chief Resident from the UW Department of Medicine coordinated the program at NDH. From August 2012 through April 2014, 32 UW participants from 5 medical specialties spent between 4 and 12 weeks working in NDH. In addition to clinical duties, all took part in formal and informal educational activities. Before and after their rotations, UW residents completed surveys evaluating clinical competencies and cross-cultural educational and research skills. Kenyan trainees also completed surveys after working with UW residents for three months.
Results
UW trainees reported a significant increase in exposure to various tropical and other diseases, an increased sense of self-reliance, particularly in a resource-limited setting, and an improved understanding of how social and cultural factors can affect health. Kenyan trainees reported both an increase in clinical skills and confidence, and an appreciation for learning a different approach to patient care and professionalism.
Conclusions
After participating in CEPI, both Kenyan and US trainees noted improvement in their clinical knowledge and skills and a broader understanding of what it means to be clinicians. Through structured partnerships between institutions, educational exchange that benefits both parties is possible.
Electronic supplementary material
The online version of this article (doi:10.1186/s12909-014-0246-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12909-014-0246-5
PMCID: PMC4335420  PMID: 25547408
International; Clinical rotation; Medical education; Residents; Kenya
4.  Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial☆, ☆☆, ★ 
Contraception  2014;90(4):407-412.
Objective
Fifty percent of pregnancies in the United States are unintended despite numerous contraceptive methods available to women. The only male contraceptive methods, vasectomy and condoms, are used by 10% and 16% of couples, respectively. Prior studies have shown efficacy of male hormonal contraceptives in development, but few have evaluated patient acceptability and potential use if commercially available. The objective of this study is to determine if a transdermal gel-based male hormonal contraceptive regimen, containing testosterone and Nestorone® gels, would be acceptable to study participants as a primary contraceptive method.
Study Design
As part of a three-arm, 6-month, double-blind, randomized controlled trial of testosterone and nestorone gels at two academic medical centers, subjects completed a questionnaire to assess the acceptability of the regimen. Of the 99 men randomized, 79 provided data for analysis.
Results
Overall, 56% (44/79) of men were satisfied or extremely satisfied with this gel-based method of contraception, and 51% (40/79) reported that they would recommend this method to others. One third of subjects (26/79) reported that they would use this as their primary method of contraception if it were commercially available today. However, men with concerns about sexually transmitted disease were significantly less satisfied than men without such concerns (p=0.03).
Conclusions
A majority of the men who volunteered to participate in this trial of an experimental male hormonal contraceptive were satisfied with this transdermal male hormonal contraceptive. If commercially available, a combination of topical nesterone and testosterone gels could provide a reversible, effective method of contraception that is appealing to men.
Implications
A substantial portion of men report they would use this transdermal male contraceptive regimen if commercially available. This method would provide a novel, reversible method of contraception for men, whose current choices are limited to condoms and vasectomy.
doi:10.1016/j.contraception.2014.05.013
PMCID: PMC4269220  PMID: 24981149
Contraception; Acceptability; Testosterone; Nestorone; Spermatogenesis
5.  Temporal Analysis of Reference Frames in Parietal Cortex Area 5d during Reach Planning 
The Journal of Neuroscience  2014;34(15):5273-5284.
The neural encoding of spatial and postural reference frames in posterior parietal cortex has traditionally been studied during fixed epochs, but the temporal evolution of these representations (or lack thereof) can provide insight into the underlying computations and functions of this region. Here we present single-unit data recorded from two rhesus macaques during a reach planning task. We found that area 5d coded the position of the hand relative to gaze before presentation of the reach target, but switched to coding the target location relative to hand position soon after target presentation. In the pretarget period the most relevant information for success in the task is the position of the hand relative to gaze; however, after target onset, the most task-relevant spatial relationship is the location of the target relative to the hand. The switch in coding suggests that population activity in area 5d may represent postural and spatial information in the reference frame that is most pertinent at each stage of the task. Moreover, although target−hand coding was dominant from soon after the reach target onset, this representation was not static but built in strength as movement onset approached, which we speculate could reflect a role for this region in building an accurate state estimate for the limb. We conclude that representations in area 5d are more flexible and dynamic than previously reported.
doi:10.1523/JNEUROSCI.2068-13.2014
PMCID: PMC3983803  PMID: 24719105
monkey; neurophysiology; parietal; reaching; reference frames
6.  Posttraumatic Stress Disorder and Incidence of Coronary Heart Disease: A Twin Study 
Journal of the American College of Cardiology  2013;62(11):10.1016/j.jacc.2013.04.085.
Objectives
To determine whether posttraumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD.
Background
It has long been hypothesized that PTSD increases the risk of CHD but empirical evidence using objective measures is limited.
Methods
We conducted a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Among twin pairs without self-reported CHD at baseline, we selected pairs discordant for a lifetime history of PTSD, pairs discordant for a lifetime history of major depression, and pairs without either condition. All underwent a clinic visit after a median follow-up of 13 years. Outcomes included clinical events (myocardial infarction, other hospitalizations for CHD and coronary revascularization) and quantitative measures of myocardial perfusion by [N13] positron emission tomography, including a stress total severity score (STSS) and coronary flow reserve (CFR).
Results
A total of 562 twins (281 pairs) were included with mean age of 42.6 yrs at baseline. The incidence of CHD was more than double in twins with PTSD (22.6%) than those without PTSD (8.9%; p<0.001). The association remained robust after adjusting for lifestyle factors, other CHD risk factors and major depression (OR=2.2, 95% confidence interval, 1.2-4.1). STSS was significantly higher (+ 95%, p=0.001) and CFR lower (−0.21, p=0.02) in twins with PTSD than those without, denoting worse myocardial perfusion. Associations were only mildly attenuated within 117 twin pairs discordant for PTSD.
Conclusions
Among Vietnam era veterans, PTSD is a risk factor for CHD.
doi:10.1016/j.jacc.2013.04.085
PMCID: PMC3823367  PMID: 23810885
cardiovascular diseases; risk factors; epidemiology; stress
7.  Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone® gels 
Andrology  2013;1(6):899-905.
SUMMARY
Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5–10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4 weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to <1 million/mL after 24 weeks. Indeed, luteinizing hormone or follicle-stimulating hormone concentrations greater than 1 IU/L after 4 weeks of transdermal testosterone/nestorone treatment were 97% sensitive for predicting failure to suppress spermatogenesis after 24 weeks of treatment. Serum nestorone concentrations were significantly associated with suppression, but serum testosterone concentrations were not. Early suppression of gonadotropins is associated with, but does not ensure, adequate suppression of spermatogenesis. This information may allow for rapid identification of non-responders in male hormonal contraceptive trials.
doi:10.1111/j.2047-2927.2013.00135.x
PMCID: PMC4151496  PMID: 24123845
contraception; gonadotropins; nestorone; spermatogenesis; testosterone
8.  Adherence to clinical practice guidelines among three primary contact professions: a best evidence synthesis of the literature for the management of acute and subacute low back pain 
Aim:
To determine adherence to clinical practice guidelines in the medical, physiotherapy and chiropractic professions for acute and subacute mechanical low back pain through best-evidence synthesis of the healthcare literature.
Methods:
A structured best-evidence synthesis of the relevant literature through a literature search of relevant databases for peer-reviewed papers on adherence to clinical practice guidelines from 1995 to 2013. Inclusion of papers was based on selection criteria and appraisal by two reviewers who independently applied a modified Downs & Black appraisal tool. The appraised papers were summarized in tabular form and analysed by the authors.
Results:
The literature search retrieved 23 potentially relevant papers that were evaluated for methodological quality, of which 11 studies met the inclusion criteria. The main finding was that no profession in the study consistently attained an overall high concordance rating. Of the three professions examined, 73% of chiropractors adhered to current clinical practice guidelines, followed by physiotherapists (62%) and then medical practitioners (52%).
Conclusions:
This review showed that quality papers in this area of research are very limited. Notwithstanding, chiropractors appear to adhere to clinical practice guidelines more so than physiotherapists and medical practitioners, although there is scope for improvement across all three professions.
PMCID: PMC4139767  PMID: 25202150
evidence based guidelines; chiropractic; low back pain; medicine; physiotherapy; directives basées sur des données probantes; chiropratique; lombalgie; médecine; physiothérapie
9.  Real world costs and cost-effectiveness of Rituximab for diffuse large B-cell lymphoma patients: a population-based analysis 
BMC Cancer  2014;14(1):586.
Background
Current treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice.
Methods
We performed a population-based retrospective cohort study from 1997 to 2007, using linked administrative databases in Ontario, Canada, to evaluate the costs and cost-effectiveness of RCHOP compared to CHOP alone. A historical control cohort (n = 1,099) with DLBCL who received CHOP before rituximab approval was hard-matched on age and treatment intensity and then propensity-score matched on sex, comorbidity, and histology to 1,099 RCHOP patients. All costs and outcomes were adjusted for censoring using the inverse probability weighting method. The main outcome measure was incremental cost per life-year gained (LYG).
Results
Rituximab was associated with a life expectancy increase of 3.2 months over 5 years at an additional cost of $16,298, corresponding to an incremental cost-effectiveness ratio of $61,984 (95% CI $34,087‒$135,890) per LYG. The probability of being cost-effective was 90% if the willingness-to-pay threshold was $100,000/LYG. The cost-effectiveness ratio was most favourable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60–79 years old and $110,100/LYG for patients ≥80 years old. We found that post-market survival benefits of rituximab are similar to or lower than those reported in clinical trials, while the costs, incremental costs and cost-effectiveness ratios are higher than in published economic models and differ by age.
Conclusions
Our results showed that the addition of rituximab to standard CHOP chemotherapy was associated with improvement in survival but at a higher cost, and was potentially cost-effective by standard thresholds for patients <60 years old. However, cost-effectiveness decreased significantly with age, suggesting that rituximab may be not as economically attractive in the very elderly on average. This has important clinical implications regarding age-related use and funding decisions on this drug.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-586) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-586
PMCID: PMC4148552  PMID: 25117912
10.  Depressive Symptoms Are Associated with Mental Stress-Induced Myocardial Ischemia after Acute Myocardial Infarction 
PLoS ONE  2014;9(7):e102986.
Objectives
Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI.
Methods
We studied 98 patients (49 women and 49 men) age 38–60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores.
Results
There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress.
Conclusion
Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress.
doi:10.1371/journal.pone.0102986
PMCID: PMC4111307  PMID: 25061993
11.  Trajectory Perception and Object Continuity: Effects of Shape and Color Change on 4-Month-Olds’ Perception of Object Identity 
Developmental psychology  2012;49(6):1021-1026.
Previous work has demonstrated that infants use object trajectory continuity as a cue to the constant identity of an object, but results are equivocal regarding the role of object features, with some work suggesting that a change in the appearance of an object does not cue a change in identity. In an experiment involving 72 participants, we investigated the effects of changing object shape and color, singly and in combination, on 4-month-olds’ perception of object continuity. A change in the shape of an object while it passed behind an occluder had no effect on perception of continuity, whereas a change in shape and color led to perception of discontinuity, and a change in color led to no clear percept regarding continuity or discontinuity. These results are discussed in terms of a perceptual learning model of development of object identity.
doi:10.1037/a0029398
PMCID: PMC4085165  PMID: 22799585
trajectory; object identity; shape; color; occlusion
12.  E2f2 induces cone photoreceptor apoptosis independent of E2f1 and E2f3 
Cell Death and Differentiation  2013;20(7):931-940.
The ‘activating' E2fs (E2f1-3) are transcription factors that potently induce quiescent cells to divide. Work on cultured fibroblasts suggested they were essential for division, but in vivo analysis in the developing retina and other tissues disproved this notion. The retina, therefore, is an ideal location to assess other in vivo adenovirus E2 promoter binding factor (E2f) functions. It is thought that E2f1 directly induces apoptosis, whereas other activating E2fs only induce death indirectly by upregulating E2f1 expression. Indeed, mouse retinoblastoma (Rb)-null retinal neuron death requires E2f1, but not E2f2 or E2f3. However, we report an entirely distinct mechanism in dying cone photoreceptors. These neurons survive Rb loss, but undergo apoptosis in the cancer-prone retina lacking both Rb and its relative p107. We show that while E2f1 killed Rb/p107 null rod, bipolar and ganglion neurons, E2f2 was required and sufficient for cone death, independent of E2f1 and E2f3. Moreover, whereas E2f1-dependent apoptosis was p53 and p73-independent, E2f2 caused p53-dependent cone death. Our in vivo analysis of cone photoreceptors provides unequivocal proof that E2f-induces apoptosis independent of E2f1, and reveals distinct E2f1- and E2f2-activated death pathways in response to a single tumorigenic insult.
doi:10.1038/cdd.2013.24
PMCID: PMC3679457  PMID: 23558950
retinoblastoma; E2f; p53; cone photoreceptor; retina
13.  Comparison of the Immediate Effects of Surgical Incision upon Dorsal Horn Neuronal Receptive Field Size and Responses during Postnatal Development 
Anesthesiology  2008;109(4):698-706.
Background
Pain behavior in response to skin incision is developmentally regulated but little is known about the underlying neuronal mechanisms. We hypothesize that the spatial activation and intensity of dorsal horn neuron responses to skin incision differs in immature and adult spinal cord.
Methods
Single wide dynamic range dorsal horn cell spike activity was recorded for a minimum of 2 hours from anesthetized rat pups 7 and 28 days of age. Cutaneous pinch and brush receptive fields were mapped and von Frey hair thresholds determined on the plantar hindpaw before and 1-hour after a skin incision was made.
Results
Baseline receptive field areas for brush and pinch were larger and von Frey thresholds lower in the younger animals. One hour after the incision, brush and pinch receptive field area, spontaneous firing and evoked spike activity had significantly increased in the 7 day old animals, but not in the 28 day old animals. Von Frey hair thresholds decreased at both ages.
Conclusions
Continuous recording from single dorsal horn cells both pre- and post-injury shows that sensitization of receptive fields and of background and afferent evoked spike activity at 1 hour is greater in younger animals. This difference is not reflected in von Frey mechanical thresholds. These results highlight the importance of studying the effects of injury upon sensory neuron physiology. Injury in young animals induces a marked and rapid increase in afferent evoked activity in second order sensory neurons which may be important when considering long term effects and analgesic interventions.
doi:10.1097/ALN.0b013e3181870a32
PMCID: PMC4041528  PMID: 18813050
14.  Posttraumatic Stress Disorder and Impaired Autonomic Modulation in Male Twins 
Biological psychiatry  2013;73(11):1103-1110.
Background
Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system may be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death.
Methods
We measured HRV by power spectral analysis on 24-hour ambulatory ECG in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs.
Results
Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low frequency (VLF) and low frequency (LF) HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower LF HRV than their brothers without PTSD (p<0.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD.
Conclusion
In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and may reverse with remission of PTSD.
doi:10.1016/j.biopsych.2013.01.019
PMCID: PMC3648627  PMID: 23434412
Autonomic nervous system; heart rate variability; posttraumatic stress disorder; military combat trauma; mental stress; heart disease
15.  MAOA Genotype, Childhood Trauma and Subclinical Atherosclerosis: A Twin Study 
Psychosomatic medicine  2013;75(5):471-477.
Objective
A functional promoter polymorphism in the MAOA gene has been implicated in neuropsychiatric disorders and also moderates the association between early life stress and mental disorders, which often co-occur with cardiovascular disease. No study has examined the relationship between MAOA genotype, childhood trauma and subclinical atherosclerosis. The objective of this investigation was to examine whether childhood trauma moderates the association between MAOA genotype and subclinical atherosclerosis.
Methods
A sample including 289 middle-aged male twin pairs was studied. Subclinical atherosclerosis was assessed by brachial flow-mediated dilation (FMD) using ultrasound. Childhood trauma, before age 18, was measured with the Early Trauma Inventory and included physical, emotional, and sexual abuse as well as general trauma. Generalized estimating equation models were used to test the main and interactive effects of the MAOA genotype and each domain of childhood trauma on FMD, adjusting for known risk factors.
Results
General trauma was the most prevalent childhood trauma (28.4%), followed by physical abuse (25.0%), emotional abuse (19.4%) and sexual abuse (11.6%). MAOA genotype was not associated with any domain of childhood trauma (β ≥ 0.36). There was no significant evidence for a main effect for the MAOA genotype (β = 0.02, p = 0.82) or childhood trauma (0.005 < β < 0.10, p > 0.54) on early atherosclerosis. However, a significant interaction was observed between MAOA genotype and physical (βinteraction = 0.37, p = 0.026) or emotional abuse (βinteraction = 0.43, p = 0.025) on subclinical atherosclerosis.
Conclusion
This study provides initial evidence that childhood trauma modulates the impact of MAOA variant on subclinical atherosclerosis, independent of traditional cardiovascular risk factors.
doi:10.1097/PSY.0b013e318292922a
PMCID: PMC3739689  PMID: 23723362
MAOA genotype; childhood trauma; gene × environment interaction; subclinical atherosclerosis; twin study
16.  Health care costs for prostate cancer patients receiving androgen deprivation therapy: treatment and adverse events 
Current Oncology  2014;21(3):e457-e465.
Background
Serious adverse events have been associated with androgen deprivation therapy (adt) for prostate cancer (pca), but few studies address the costs of those events.
Methods
All pca patients (ICD-9-CM 185) in Ontario who started 90 days or more of adt or had orchiectomy at the age of 66 or older during 1995–2005 (n = 26,809) were identified using the Ontario Cancer Registry and drug and hospital data. Diagnosis dates of adverse events—myocardial infarction, acute coronary syndrome, congestive heart failure, stroke, deep vein thrombosis or pulmonary embolism, any diabetes, and fracture or osteoporosis—before and after adt initiation were determined from administrative data. We excluded patients with the same diagnosis before and after adt, and we allocated each patient’s time from adt initiation to death or December 31, 2007, into health states: adt (no adverse event), adt-ae (specified single adverse event), Multiple (>1 event), and Final (≤180 days before death). We used methods for Canadian health administrative data to estimate annual total health care costs during each state, and we examined monthly trends.
Results
Approximately 50% of 21,811 patients with no pre-adt adverse event developed 1 or more events after adt. The costliest adverse event state was stroke ($26,432/year). Multiple was the most frequent (n = 2,336) and the second most costly health state ($24,374/year). Costs were highest in the first month after diagnosis (from $1,714 for diabetes to $14,068 for myocardial infarction). Costs declined within 18 months, ranging from $784 per 30 days (diabetes) to $1,852 per 30 days (stroke). Adverse events increased the costs of adt by 100% to 265%.
Conclusions
The economic burden of adverse events is relevant to programs and policies from clinic to government, and that burden merits consideration in the risks and benefits of adt.
doi:10.3747/co.21.1865
PMCID: PMC4059810  PMID: 24940106
Prostatic neoplasms; androgen deprivation therapy; costs; adverse events; cost analysis
17.  Suppression of dislocations by Sb spray in the vicinity of InAs/GaAs quantum dots 
Nanoscale Research Letters  2014;9(1):278.
The effect of Sb spray prior to the capping of a GaAs layer on the structure and properties of InAs/GaAs quantum dots (QDs) grown by molecular beam epitaxy (MBE) is studied by cross-sectional high-resolution transmission electron microscopy (HRTEM). Compared to the typical GaAs-capped InAs/GaAs QDs, Sb-sprayed QDs display a more uniform lens shape with a thickness of about 3 ~ 4 nm rather than the pyramidal shape of the non-Sb-sprayed QDs. Particularly, the dislocations were observed to be passivated in the InAs/GaAs interface region and even be suppressed to a large extent. There are almost no extended dislocations in the immediate vicinity of the QDs. This result is most likely related to the formation of graded GaAsSb immediately adjacent to the InAs QDs that provides strain relief for the dot/capping layer lattice mismatch.
PACS
81.05.Ea; 81.07.-b; 81.07.Ta
doi:10.1186/1556-276X-9-278
PMCID: PMC4051383  PMID: 24948897
Quantum dots; InAs; HRTEM; Dislocations
18.  Pharmacokinetics of Modified Slow-Release Oral Testosterone Over 9 Days in Normal Men With Experimental Hypogonadism 
Journal of andrology  2011;33(3):420-426.
Oral administration of testosterone has potential use for the treatment of hypogonadism. We have recently demonstrated that a novel formulation of oral testosterone transiently normalized serum testosterone in a single-dose pharmacokinetic study. In this report, we present the steady-state pharmacokinetics of this formulation. Twelve healthy young men were rendered hypogonadal with the gonadotropin-releasing hormone antagonist acyline (300 µg/kg subcutaneously) and administered 300 mg of oral testosterone 3 times daily for 9 days. Serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone–binding globulin (SHBG) were measured before and 1, 2, 4, 5, 6, 8, 10, 11, 12, 14, 16, and 24 hours on the first and ninth day of dosing. Before testosterone administration, all men had serum testosterone under 75 ng/dL. Over day 1, the 24-hour average (geometric mean [%CV]) serum total testosterone was 378 (45) ng/dL. This decreased to 315 (41) ng/dL after 9 days of continuous treatment (P = .1 compared with day 1). The 24-hour average serum SHBG was 27 (46) nmol/L on day 1 and was significantly reduced to 19 (47) nmol/L by day 9 (P > .01). As a result, the calculated free testosterone values were similar between day 1 and day 9: 8.7 (43) and 8.3 (37) ng/dL, respectively. DHT was in the reference range and estradiol was slightly below on day 9. Oral testosterone (300 mg) dosed 3 times daily normalized serum testosterone in men with experimentally induced hypogonadism after 9 days of dosing and significantly suppressed SHBG. This formulation of oral testosterone may have efficacy for the treatment of testosterone deficiency.
doi:10.2164/jandrol.111.014514
PMCID: PMC4034539  PMID: 21868746
Androgen; drug delivery; dihydrotestosterone; DHT; estradiol; acyline
19.  Association between Posttraumatic Stress Disorder and Inflammation: A Twin Study 
Brain, behavior, and immunity  2013;30:125-132.
The association of posttraumatic stress disorder (PTSD) with cardiovascular disease risk may be mediated by inflammation. Our objective was to examine the association between PTSD and measures of inflammation and to determine whether these associations are due to shared familial or genetic factors. We measured lifetime history of PTSD using the Structured Clinical Interview for DSM-IV in 238 male middle-aged military veteran twin pairs (476 individuals), selected from the Vietnam Era Twins Registry, who were free of cardiovascular disease at baseline. We assessed inflammation using levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), fibrinogen, white blood cells, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (ICAM-1). Geometric mean levels and percent differences by PTSD were obtained from mixed-model linear regression analyses with adjustment for potential confounders. Within-pair analysis was conducted to adjust for shared family environment and genetics (monozygotic pairs). Overall, 12.4% of participants had a lifetime history of PTSD. Adjusted mean levels of hsCRP and ICAM-1 were significantly higher among those with vs. without PTSD [hsCRP: 1.75 vs. 1.31 mg/l (33% difference); ICAM-1: 319 vs. 293 ng/ml (9% difference)]. Adjustment for depression rendered the association of PTSD with hsCRP non-statistically significant. For IL-6, no consistent association was seen. Within-pair analysis produced associations that were similar in direction for all three markers but lesser in magnitude for hsCRP and IL-6. There was no evidence of interaction by zygosity. Elevated hsCRP and ICAM-1 are associated with PTSD, and these associations may be confounded by shared non-genetic, antecedent familial and environmental factors.
doi:10.1016/j.bbi.2013.01.081
PMCID: PMC3641167  PMID: 23379997
posttraumatic stress disorder; inflammation; cardiovascular disease; twins; Vietnam veterans
20.  Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease 
Medici, Marco | Porcu, Eleonora | Pistis, Giorgio | Teumer, Alexander | Brown, Suzanne J. | Jensen, Richard A. | Rawal, Rajesh | Roef, Greet L. | Plantinga, Theo S. | Vermeulen, Sita H. | Lahti, Jari | Simmonds, Matthew J. | Husemoen, Lise Lotte N. | Freathy, Rachel M. | Shields, Beverley M. | Pietzner, Diana | Nagy, Rebecca | Broer, Linda | Chaker, Layal | Korevaar, Tim I. M. | Plia, Maria Grazia | Sala, Cinzia | Völker, Uwe | Richards, J. Brent | Sweep, Fred C. | Gieger, Christian | Corre, Tanguy | Kajantie, Eero | Thuesen, Betina | Taes, Youri E. | Visser, W. Edward | Hattersley, Andrew T. | Kratzsch, Jürgen | Hamilton, Alexander | Li, Wei | Homuth, Georg | Lobina, Monia | Mariotti, Stefano | Soranzo, Nicole | Cocca, Massimiliano | Nauck, Matthias | Spielhagen, Christin | Ross, Alec | Arnold, Alice | van de Bunt, Martijn | Liyanarachchi, Sandya | Heier, Margit | Grabe, Hans Jörgen | Masciullo, Corrado | Galesloot, Tessel E. | Lim, Ee M. | Reischl, Eva | Leedman, Peter J. | Lai, Sandra | Delitala, Alessandro | Bremner, Alexandra P. | Philips, David I. W. | Beilby, John P. | Mulas, Antonella | Vocale, Matteo | Abecasis, Goncalo | Forsen, Tom | James, Alan | Widen, Elisabeth | Hui, Jennie | Prokisch, Holger | Rietzschel, Ernst E. | Palotie, Aarno | Feddema, Peter | Fletcher, Stephen J. | Schramm, Katharina | Rotter, Jerome I. | Kluttig, Alexander | Radke, Dörte | Traglia, Michela | Surdulescu, Gabriela L. | He, Huiling | Franklyn, Jayne A. | Tiller, Daniel | Vaidya, Bijay | de Meyer, Tim | Jørgensen, Torben | Eriksson, Johan G. | O'Leary, Peter C. | Wichmann, Eric | Hermus, Ad R. | Psaty, Bruce M. | Ittermann, Till | Hofman, Albert | Bosi, Emanuele | Schlessinger, David | Wallaschofski, Henri | Pirastu, Nicola | Aulchenko, Yurii S. | de la Chapelle, Albert | Netea-Maier, Romana T. | Gough, Stephen C. L. | Meyer zu Schwabedissen, Henriette | Frayling, Timothy M. | Kaufman, Jean-Marc | Linneberg, Allan | Räikkönen, Katri | Smit, Johannes W. A. | Kiemeney, Lambertus A. | Rivadeneira, Fernando | Uitterlinden, André G. | Walsh, John P. | Meisinger, Christa | den Heijer, Martin | Visser, Theo J. | Spector, Timothy D. | Wilson, Scott G. | Völzke, Henry | Cappola, Anne | Toniolo, Daniela | Sanna, Serena | Naitza, Silvia | Peeters, Robin P.
PLoS Genetics  2014;10(2):e1004123.
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10−8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10−8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10−6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10−4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10−7 and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10−5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10−3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
Author Summary
Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction.
doi:10.1371/journal.pgen.1004123
PMCID: PMC3937134  PMID: 24586183
21.  Coping with Persistent Pain, Effectiveness Research into Self-management (COPERS): statistical analysis plan for a randomised controlled trial 
Trials  2014;15:59.
Background
The Coping with Persistent Pain, Effectiveness Research into Self-management (COPERS) trial assessed whether a group-based self-management course is effective in reducing pain-related disability in participants with chronic musculoskeletal pain. This article describes the statistical analysis plan for the COPERS trial.
Methods and design
COPERS was a pragmatic, multicentre, unmasked, parallel group, randomised controlled trial. This article describes (a) the overall analysis principles (including which participants will be included in each analysis, how results will be presented, which covariates will be adjusted for, and how we will account for clustering in the intervention group); (b) the primary and secondary outcomes, and how each outcome will be analysed; (c) sensitivity analyses; (d) subgroup analyses; and (e) adherence-adjusted analyses.
Trial registration
ISRCTN24426731
doi:10.1186/1745-6215-15-59
PMCID: PMC3930300  PMID: 24528484
Statistical analysis plan; Randomised controlled trial; Self-management; Chronic musculoskeletal pain; Complex intervention
22.  Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality 
Context
Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.
Objective
To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.
Data Sources and Study Selection
The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.
Data Extraction
Individual data on 55 287 participants with 542 494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25 977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.
Results
Among 55 287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51 837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86–1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96–1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28–2.80) for a TSH level of 10 to 19.9 mIU/L (n=70 events/235; 38.4/1000 person-years; P<.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91–1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03–1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10–2.27, n=28 deaths/333; 7.7/1000 person-years; P=.005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.
Conclusions
Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.
doi:10.1001/jama.2010.1361
PMCID: PMC3923470  PMID: 20858880
23.  Association Between Ideal Cardiovascular Health and Carotid Intima‐Media Thickness: A Twin Study 
Background
The American Heart Association (AHA) recently developed the Cardiovascular Health Index (CVHI), a health metric consisting of 7 modifiable risk factors. The relationship of the CVHI with preclinical markers, such as carotid intima‐media thickness (CIMT) has not been assessed.
Methods
We examined 490 male monozygotic and dizygotic twins without overt cardiovascular disease. CIMT was measured using B‐mode ultrasonography. Each of the 7 CVHI components (blood pressure, fasting glucose, total cholesterol, body mass index, physical activity, healthy diet, and smoking) was given a point score of 0, 1, or 2 to represent poor, intermediate, or ideal health, respectively. A CVHI summation score was computed (range 0 to 14) and categorized as inadequate (0 to 4), average (5 to 9), or optimum (10 to 14) cardiovascular health. Mixed‐model regression was used to examine the association of the CVHI with CIMT.
Results
The mean age of the twins was 55.4 years, and 61% were monozygotic. The mean CIMT was 0.75 (±0.11) mm and the mean CVHI score was 7.7 (±2.1). There was an inverse correlation between CVHI and CIMT (Spearman r=−0.22, P<0.01). For every 5‐unit increase in overall CVHI score (indicating better cardiovascular health category), CIMT decreased by 0.045 mm (P<0.001) after adjusting for demographic variables and other confounders. Within monozygotic twin pairs, a 5‐unit increment in CVHI score was associated with a 0.05 mm lower CIMT (P<0.001).
Conclusions
The CVHI is independently associated with CIMT and the association is not confounded by shared genetic and other familial factors.
doi:10.1161/JAHA.113.000282
PMCID: PMC3959690  PMID: 24385450
epidemiology; prevention; risk factors
24.  Serum INSL3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose hCG: a randomized-controlled trial 
Fertility and sterility  2012;99(1):132-139.
Objective
To study the potential role for using serum biomarkers including insulin-like factor 3 (INSL3), 17-hydroxyprogesterone (17-OHP), anti-Müllerian hormone (AMH) and inhibin B (INHB) as correlates of intratesticular testosterone (IT-T) concentrations in men.
Design
Prospective, randomized-controlled trial
Setting
University-based medical center
Patients
37 healthy men ages 18–50
Interventions
All men received the gonadotropin-releasing hormone antagonist, acyline, plus very low doses of human chorionic gonadotropin (hCG) (0 IU, 15 IU, 60 IU or 125 IU) subcutaneously every other day or 7.5 grams testosterone gel daily (7.5 mg delivered). IT-T concentrations obtained by percutaneous testicular aspiration with simultaneous serum protein and steroid concentrations were measured at baseline and after 10 days of treatment.
Main Outcome Measures
Intratesticular and serum hormone and gonadotropin concentrations
Results
Following 10 days of gonadotropin suppression, serum INSL3 decreased by over 90% and correlated highly with IT-T concentrations. In contrast, serum INHB, AMH and 17-OHP did not correlate with IT-T. Serum INSL3 increased with the dose of hCG administered and returned to baseline after treatment.
Conclusions
Serum INSL3 correlates highly with IT-T and serum testosterone concentrations during acute gonadotropin suppression in men. HCG stimulates dose-dependent increases in INSL3 and IT-T in healthy men and might be a useful biomarker of IT-T concentration in some clinical settings.
Clinicaltrials.gov NCT# 00839319
doi:10.1016/j.fertnstert.2012.09.009
PMCID: PMC3534941  PMID: 23040523
Androgens; INSL3; Male Infertility; Gonadotropins; Intratesticular Testosterone
25.  LETTER TO THE EDITOR Screening for Fingolimod Associated Macular Oedema: Experience Versus Guidelines 
We report adherence to United Kingdom national guidelines on surveillance for Fingolimod associated macular oedema (FAME) and the impact on clinical services at our unit. We conducted a 9-month study, measuring referral interval, visual function and performing OCT scans for all patients referred for FAME surveillance. 38 patients in total were seen, representing 9% of all new ophthalmic referrals during the study period. 26% were seen between 2 and 4 months after starting Fingolimod treatment, 74% between 3 and 4 months after starting Fingolimod treatment. The impact on clinical services is discussed.
doi:10.2174/1874364101408010073
PMCID: PMC4192831  PMID: 25317219
Fingolimod; guidelines; macular oedema; screening.

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