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1.  Influence of Patient Age on Procedural Selection in Mitral Valve Surgery 
The Annals of thoracic surgery  2010;90(5):1479-1486.
Previous studies suggest that mitral valve replacement is comparable to repair in the elderly, and a national trend exists toward tissue valves. However, few direct comparison data are available, and this study evaluated the effects of patient age on risk-adjusted survival after mitral procedures.
From 1986 to 2006, 2,064 patients underwent isolated primary mitral operations (±CABG). Maximal follow-up was 20 years with a median of 5 years. Valve disease etiology was the following: degenerative, 864; ischemic, 450; rheumatic, 416; endocarditis, 98; and “other,” 236. Overall, 58% had repair and 39% had concomitant coronary artery bypass grafting. Survival differences were evaluated with a Cox proportional hazards model that included baseline characteristics, valve disease etiology, and choice of repair versus replacement with tissue or mechanical valves.
Baseline risk profiles generally were better for mechanical valves, and age was the most significant multivariable predictor of late mortality [hazard ratio = 1.4 per 10-year increment, Wald χ2 = 32.7, p < 0.0001]. As compared with repair, risk-adjusted survival was inferior with either tissue valves [1.8, 27.6, <0.0001] or mechanical valves [1.3, 8.1, 0.0044], and no treatment interaction was observed with age (p = 0.18). At no patient age did tissue valves achieve equivalent survival to either repair or mechanical valves.
Mitral repair is associated with better survival than valve replacement across the spectrum of patient age. If replacement is required, mechanical valves achieve better outcomes, even in the elderly. These data suggest that tissue valves should be reserved only for patients with absolute contraindications to anticoagulation who are not amenable to repair.
PMCID: PMC4322678  PMID: 20971244
2.  Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting 
Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.
PMCID: PMC4322756  PMID: 23543398
Clopidogrel; CABG; Dual antiplatelet therapy; Coronary artery bypass surgery; Outcomes
3.  Central Venous Pressure After Coronary Artery Bypass Surgery: Does it Predict Postoperative Mortality or Renal Failure? 
Journal of critical care  2014;29(6):1006-1010.
While hemodynamic monitoring is often performed following coronary artery bypass grafting (CABG), the relationship between postoperative central venous pressure (CVP) measurement and clinical outcomes is unknown.
Detailed clinical data were analyzed from 2,390 randomly selected patients undergoing high risk CABG or CABG/valve at 55 hospitals participating in the Society of Thoracic Surgeons' National Cardiac Surgery Database from 2004 to 2005. Eligible patients underwent elective/urgent isolated CABG with an ejection fraction < 40%, or elective/urgent CABG at age ≥65 years with diabetes or a glomerular filtration rate 60 mL/min per 1.73 m2. Correlation between post-operative CVP and in-hospital / 30-day mortality and renal failure was assessed as a continuous variable, both unadjusted and after adjusting for important clinical factors using logistic regression modeling.
Mean age was 72 years, 54% of patients had diabetes mellitus, 49% were urgent procedures, and mean cardiopulmonary bypass time was 105 minutes. Patients’ CVP 6 hours post-operation was strongly associated with in-hospital and 30 day mortality: odds ratio (OR) 1.5 (95% confidence interval [CI] 1.23, 1.87) for every 5 mmHg increase in CVP, p<0.0001. This association remained significant after risk-adjustment for cardiac index: adjusted OR 1.44 (95% CI 1.10, 1.89), p<0.01. A model adjusting for cardiac index also revealed increased incidence of mortality or renal failure: adjusted OR 1.5 (95% CI 1.28, 1.86) for every 5 mmHg increase in CVP, p<0.0001.
Patients’ central venous pressure at 6 hours following CABG surgery was highly predictive of operative mortality or renal failure, independent of cardiac index and other important clinical variables. Future studies will need to assess whether post-operative CVP can be used to guide intervention and improve outcomes.
PMCID: PMC4315310  PMID: 25035048
5.  The impact of childhood vaccines on bacterial carriage in the nasopharynx: a longitudinal study 
There is increasing evidence that childhood vaccines have effects that extend beyond their target disease. The objective of this study was to assess the effects of routine childhood vaccines on bacterial carriage in the nasopharynx.
A cohort of children from rural Gambia was recruited at birth and followed up for one year. Nasopharyngeal swabs were taken immediately after birth, every two weeks for the first six months and then every other month. The presence of bacteria in the nasopharynx (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus) was compared before and after the administration of DTP-Hib-HepB and measles-yellow fever vaccines.
A total of 1,779 nasopharyngeal swabs were collected from 136 children for whom vaccination data were available. The prevalence of bacterial carriage was high: 82.2% S. pneumoniae, 30.6%, S.aureus, 27.8% H. influenzae. Carriage of H. influenzae (OR = 0.36; 95% CI: 0.13, 0.99) and S. pneumoniae (OR = 0.25; 95% CI: 0.07, 0.90) were significantly reduced after measles-yellow fever vaccination; while DTP-Hib-HepB had no effect on bacterial carriage.
Nasopharyngeal bacterial carriage is unaffected by DTP-Hib-HepB vaccination and reduced after measles-yellow fever vaccination.
PMCID: PMC4312604  PMID: 25642277
Non-specific vaccine effects; Measles; DTP; Nasopharyngeal bacterial carriage
6.  Trophic factor and hormonal regulation of neurite outgrowth in sensory neuron-like 50B11 cells 
Neuroscience letters  2013;558:120-125.
Sensory axon integrity and regenerative capacity are important considerations in understanding neuropathological conditions characterized by hyper- or insensitivity. However, our knowledge of mechanisms regulating axon outgrowth are limited by an absence of suitable high-throughput assay systems. The 50B11 cell line generated from rat embryonic dorsal root ganglion neurons offers a promising model for screening assays. Prior characterization shows that these cells express cytoskeletal proteins and genes encoding ion channels and neurotrophin receptors in common with sensory nociceptor neurons. In the present study we further characterized 50B11 cells in regard to their phenotypes and responsiveness to neurotrophic and hormonal factors.
50B11 cells express neuronal cytoplasmic proteins including beta-3 tubulin, peripherin (a marker of unmyelinated neurons), and the pan-neuronal ubiquitin hydrolase, PGP9.5. Only PGP9.5 immunoreactivity was uniformly distributed throughout soma and axons, and therefore presents the best means for visualizing the entire axon arbor. All cells co-express both NGF and GDNF receptors and addition of ligands increased neurite length. 50B11 cells also showed immunoreactivity for the estrogen receptor-α and the angiotensin receptor type II, and both 17-β estradiol and angiotensin II increased outgrowth by differentiated cells.
50B11 cells therefore show features reported previously for primary unmyelinated nociceptor neurons, including responsiveness to classical neurotrophins and hormonal modulators. Coupled with their ease of culture and predictable differentiation, 50B11 cells represent a promising cell line on which to base assays that more clearly reveal mechanisms regulating axon outgrowth and integrity.
PMCID: PMC3903183  PMID: 24269872
Dorsal root ganglion; Neuron; Axon; Neurotrophic factors; Hormones; Outgrowth; High throughput screening
7.  Broader health coverage is good for the nation's health: evidence from country level panel data 
Progress towards universal health coverage involves providing people with access to needed health services without entailing financial hardship and is often advocated on the grounds that it improves population health. The paper offers econometric evidence on the effects of health coverage on mortality outcomes at the national level. We use a large panel data set of countries, examined by using instrumental variable specifications that explicitly allow for potential reverse causality and unobserved country-specific characteristics. We employ various proxies for the coverage level in a health system. Our results indicate that expanded health coverage, particularly through higher levels of publicly funded health spending, results in lower child and adult mortality, with the beneficial effect on child mortality being larger in poorer countries.
PMCID: PMC4280714  PMID: 25598588
Health coverage; Health financing; Mortality; Panel data econometrics; Reverse causality
8.  The Inaccuracy of National Character Stereotypes 
Journal of research in personality  2013;47(6):10.1016/j.jrp.2013.08.006.
Consensual stereotypes of some groups are relatively accurate, whereas others are not. Previous work suggesting that national character stereotypes are inaccurate has been criticized on several grounds. In this article we (a) provide arguments for the validity of assessed national mean trait levels as criteria for evaluating stereotype accuracy; and (b) report new data on national character in 26 cultures from descriptions (N=3,323) of the typical male or female adolescent, adult, or old person in each. The average ratings were internally consistent and converged with independent stereotypes of the typical culture member, but were weakly related to objective assessments of personality. We argue that this conclusion is consistent with the broader literature on the inaccuracy of national character stereotypes.
PMCID: PMC3811946  PMID: 24187394
National character; stereotypes; Five-Factor Model; personality traits; cross-cultural
9.  Serum Drug Concentrations Predictive of Pulmonary Tuberculosis Outcomes 
The Journal of Infectious Diseases  2013;208(9):1464-1473.
Background. Based on a hollow-fiber system model of tuberculosis, we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic variability.
Methods. Clinical and pharmacokinetic data were prospectively collected from 142 tuberculosis patients in Western Cape, South Africa. Compartmental pharmacokinetic parameters of isoniazid, rifampin, and pyrazinamide were identified for each patient. Patients were then followed for up to 2 years. Classification and regression tree analysis was used to identify and rank clinical predictors of poor long-term outcome such as microbiologic failure or death, or relapse.
Results. Drug concentrations and pharmacokinetics varied widely between patients. Poor long-term outcomes were encountered in 35 (25%) patients. The 3 top predictors of poor long-term outcome, by rank of importance, were a pyrazinamide 24-hour area under the concentration–time curve (AUC) ≤ 363 mg·h/L, rifampin AUC ≤ 13 mg·h/L, and isoniazid AUC ≤ 52 mg·h/L. Poor outcomes were encountered in 32/78 patients with the AUC of at least 1 drug below the identified threshold vs 3/64 without (odds ratio = 14.14; 95% confidence interval, 4.08–49.08). Low rifampin and isoniazid peak and AUC concentrations preceded all cases of acquired drug resistance.
Conclusions. Low drug AUCs are predictive of clinical outcomes in tuberculosis patients.
PMCID: PMC3789573  PMID: 23901086
tuberculosis; nonlinear systems; classification and regression tree analysis; pharmacokinetic variability; drug concentrations; hollow-fiber system; outcomes
10.  Understanding Usage of a Hybrid Website and Smartphone App for Weight Management: A Mixed-Methods Study 
Advancements in mobile phone technology offer huge potential for enhancing the timely delivery of health behavior change interventions. The development of smartphone-based health interventions (apps) is a rapidly growing field of research, yet there have been few longitudinal examinations of how people experience and use these apps within their day-to-day routines, particularly within the context of a hybrid Web- and app-based intervention.
This study used an in-depth mixed-methods design to examine individual variation in (1) impact on self-reported goal engagement (ie, motivation, self-efficacy, awareness, effort, achievement) of access to a weight management app (POWeR Tracker) when provided alongside a Web-based weight management intervention (POWeR) and (2) usage and views of POWeR Tracker.
Thirteen adults were provided access to POWeR and were monitored over a 4-week period. Access to POWeR Tracker was provided in 2 alternate weeks (ie, weeks 1 and 3 or weeks 2 and 4). Participants’ goal engagement was measured daily via self-report. Mixed effects models were used to examine change in goal engagement between the weeks when POWeR Tracker was and was not available and whether the extent of change in goal engagement varied between individual participants. Usage of POWeR and POWeR Tracker was automatically recorded for each participant. Telephone interviews were conducted and analyzed using inductive thematic analysis to further explore participants’ experiences using POWeR and POWeR Tracker.
Access to POWeR Tracker was associated with a significant increase in participants’ awareness of their eating (β1=0.31, P=.04) and physical activity goals (β1=0.28, P=.03). The level of increase varied between individual participants. Usage data showed that participants used the POWeR website for similar amounts of time during the weeks when POWeR Tracker was (mean 29 minutes, SD 31 minutes) and was not available (mean 27 minutes, SD 33 minutes). POWeR Tracker was mostly accessed in short bursts (mean 3 minutes, SD 2 minutes) during convenient moments or moments when participants deemed the intervention content most relevant. The qualitative data indicated that nearly all participants agreed that it was more convenient to access information on-the-go via their mobiles compared to a computer. However, participants varied in their views and usage of the Web- versus app-based components and the informational versus tracking tools provided by POWeR Tracker.
This study provides evidence that smartphones have the potential to improve individuals’ engagement with their health-related goals when used as a supplement to an existing online intervention. The perceived convenience of mobile access to information does not appear to deter use of Web-based interventions or strengthen the impact of app access on goal engagement. A mixed-methods design enabled exploration of individual variation in daily usage of the app-based tools.
PMCID: PMC4259922  PMID: 25355131
qualitative research; weight loss; behavioral research; mobile apps; Internet; health; program acceptability; behavior; mixed-methods
11.  Efforts toward broadening the spectrum of arylomycin antibiotic activity 
New antibiotics are needed, and one source may be ‘latent’ antibiotics, natural products whose once broad-spectrum activity is currently limited by the evolution of resistance in nature. We have identified a potential class of latent antibiotics, the arylomycins, which are lipopeptides with a C-terminal macrocycle that target signal peptidase and whose spectrum is limited by a resistance-conferring mutation in many bacteria. Herein, we report the synthesis and evaluation of several arylomycin derivatives, and demonstrate that both C-terminal homologation with a glycylal dehyde and addition of a positive charge to the macrocycle increase the activity and spectrum of the arylomycin scaffold.
PMCID: PMC3981466  PMID: 24012184
Signal peptidase; Protein secretion; Latent antibiotic; C-terminal electrophile
12.  Synthetic Hemozoin (β-Hematin) Crystals Nucleate at the Surface of Neutral Lipid Droplets that Control Their Sizes 
Crystal growth & design  2013;13(10):10.1021/cg4009416.
Emulsions of monopalmitoylglycerol (MPG) and of a neutral lipid blend (NLB), consisting of MPG, monostearoylglycerol, dipalmitoylglycerol, dioleoylglycerol and dilineoylglycerol (4:2:1:1:1), the composition associated with hemozoin from the malaria parasite Plasmodium falciparum, have been used to mediate the formation of β-hematin microcrystals. Transmission electron microscopy (TEM), electron diffraction and electron spectroscopic imaging/electron energy loss spectroscopy (ESI/EELS) have been used to characterize both the lipid emulsion and β-hematin crystals. The latter have been compared with β-hematin formed at a pentanol/aqueous interface and with hemozoin both within P. falciparum parasites and extracted from the parasites. When lipid and ferriprotoporphyrin IX solutions in 1:9 v/v acetone/methanol were thoroughly pre-mixed either using an extruder or ultrasound, β-hematin crystals were found formed in intimate association with the lipid droplets. These crystals resembled hemozoin crystals, with prominent {100} faces. Lattice fringes in TEM indicated that these faces made contact with the lipid surface. The average length of these crystals was 0.62 times the average diameter of NLB droplets and their size distributions were statistically equivalent after 10 min incubation, suggesting that the lipid droplets also controlled the sizes of the crystals. This most closely resembles hemozoin formation in the helminth worm Schistosoma mansoni, while in P. falciparum, crystal formation appears to be associated with the much more gently curved digestive vacuole membrane which apparently leads to formation of much larger hemozoin crystals, similar to those formed at the flat pentanol-water interface.
PMCID: PMC3826461  PMID: 24244110
13.  Job strain, health behaviours and heart disease 
PMCID: PMC3787174  PMID: 24082043
14.  Angiotensin II receptor type 2 activation is required for cutaneous sensory hyperinnervation and hypersensitivity in a rat hind paw model of inflammatory pain 
Many pain syndromes are associated with abnormal proliferation of peripheral sensory fibers. We showed previously that angiotensin II, acting through its type 2 receptor (AT2), stimulates axon outgrowth by cultured dorsal root ganglion neurons. In this study, we assessed whether AT2 mediates nociceptor hyperinnervation in the rodent hind paw model of inflammatory pain. Plantar injection of complete Freund’s adjuvant (CFA), but not saline, produced marked thermal and mechanical hypersensitivity through 7 days. This was accompanied by proliferation of dermal and epidermal PGP9.5- and calcitonin gene-related peptide-immunoreactive (CGRP-ir) axons, and dermal axons immunoreactive for GFRα2 but not tyrosine hydroxylase or neurofilament H. Continuous infusion of the AT2 antagonist PD123319 beginning with CFA injection completely prevented hyperinnervation as well as hypersensitivity over a 7 day period. A single PD123319 injection 7 days after CFA also reversed thermal hypersensitivity and partially reversed mechanical hypersensitivity 3 hours later, without affecting cutaneous innervation. Angiotensin II synthesizing proteins renin and angiotensinogen were largely absent after saline but abundant in T-cells and macrophages in CFA-injected paws with or without PD123319. Thus, emigrant cells at the site of inflammation apparently establish a renin-angiotensin system, and AT2 activation elicits nociceptor sprouting and heightened thermal and mechanical sensitivity.
Short-term AT2 activation is a potent contributor to thermal hypersensitivity, while long-term effects (such as hyperinnervation) also contribute to mechanical hypersensitivity. Pharmacological blockade of AT2 signaling represents a potential therapeutic strategy aimed at biological mechanisms underlying chronic inflammatory pain.
PMCID: PMC3971648  PMID: 23726047
Mechanical allodynia; Thermal sensitivity; Dorsal root ganglion; Sprouting; Nociceptors
15.  Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924 
Molecular cancer therapeutics  2013;12(10):1958-1967.
The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for ovarian cancer patients. In this investigation we evaluated the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, in ovarian cancer cells. Efficacy of MLN4924 both alone and in combination with platinum was assessed. Overall, single agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. However, the combination of MLN4924 with cisplatin or carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as, in primary ovarian cancer cell lines established from high grade serous, clear cell, and serous borderline ovarian tumors. The efficacy of cisplatin plus MLN4924 was also evident in several in vitro models of platinum resistant ovarian cancer. Mechanistically, the combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An siRNA screen was used to investigate the contribution of each member of the Cullin RING-Ligase (CRL) family of E3 ubiquitin ligases, the best characterized downstream mediators of MLN4924’s biological effects . Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3 ovarian cancer cells. This investigation identifies inhibition of Neddylation as a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer.
PMCID: PMC3795967  PMID: 23939375
MLN4924; cisplatin; ovarian cancer; neddylation; cullin ring ligase; platinum resistance
16.  The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals 
Isoniazid preventive therapy is recommended in patients on antiretroviral therapy. Isoniazid inhibits CYP3A4, which metabolizes nevirapine. Administration of isoniazid may cause higher nevirapine concentrations and toxicity. We studied the effect of isoniazid on nevirapine concentrations in 21 patients randomized to either placebo (n=13) or isoniazid (n=8) in an ongoing trial of IPT in patients on ART. Isoniazid was associated with a 24% increase in median nevirapine AUC0-12, which was not statistically significant (p=0.66).
PMCID: PMC4176729  PMID: 23407222
Isoniazid; nevirapine; drug interactions; HIV
17.  Design, Rationale, and Initiation of the Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial: A Report from the Cardiothoracic Surgical Trials Network 
Patients with moderate ischemic mitral regurgitation have demonstrably poorer outcome compared to coronary artery disease patients without mitral regurgitation. The optimal treatment of this condition has become increasingly controversial and a randomized trial evaluating current practices is warranted.
Methods and Results
We describe the design and initial execution of the Cardiothoracic Surgical Trials Network moderate ischemic mitral regurgitation trial. This is an ongoing prospective, multi-center, randomized, controlled clinical trial designed to test the safety and efficacy of mitral repair in addition to coronary artery bypass grafting in the treatment of moderate ischemic mitral regurgitation.
The results of the Cardiothoracic Surgical Trials Network ischemic mitral regurgitation trials will provide long-awaited information on controversial therapies for a morbid disease process.
PMCID: PMC4166424  PMID: 21788032
18.  Transfusion outcomes in patients undergoing coronary artery bypass grafting treated with prasugrel or clopidogrel: TRITON-TIMI 38 retrospective data analysis 
Coronary artery bypass grafting-related bleeding and associated transfusion is a concern with dual antiplatelet therapy in patients with acute coronary syndromes. The objective of the present study was to characterize a potential risk-adjusted difference in transfusion requirements between prasugrel and clopidogrel cohorts.
The data from 422 patients undergoing isolated coronary artery bypass grafting from the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 were analyzed retrospectively.
We found no difference in baseline transfusion risk scores between cohorts. As predicted, the number of units of red blood cells transfused perioperatively correlated with the transfusion risk score (P <.0001). Overall, the 12-hour chest tube drainage volumes and platelet transfusion rates in the prasugrel cohort were significantly greater. However, no statistically significant differences were found in the number of red blood cell transfusions, total hemostatic components transfused, or total blood donor exposure. A significantly greater number of platelet units were transfused postoperatively in the prasugrel patients who underwent surgery within 5 days or less after withdrawal of drug. In an analysis adjusted for the predicted risk of mortality, total donor exposure was not associated with increased mortality.
The use of prasugrel compared with clopidogrel was associated with greater 12-hour chest tube drainage volumes and platelet transfusion rates but without any significant differences in red blood cell transfusions, total hemostatic components transfused, or total blood donor exposure.
PMCID: PMC4151878  PMID: 22995726
19.  Placebo use in vaccine trials: Recommendations of a WHO expert panel 
Vaccine  2014;32(37):4708-4712.
•Placebo controls may be acceptable even when an efficacious vaccine exists, in the following four possible situations:•When developing a locally affordable vaccine.•When evaluating the local safety and efficacy of an existing vaccine.•When testing a new vaccine when an existing vaccine is not considered appropriate locally.•When determining the local burden of disease.
Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.
PMCID: PMC4157320  PMID: 24768580
Vaccine trials; Trial design; Ethics; Placebo controls; Risk; International research
20.  Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation 
Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited.
We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank.
At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P = 0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P = 0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months.
We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes. (Funded by the National Institutes of Health and the Canadian Institutes of Health; number, NCT00807040.)
PMCID: PMC4128011  PMID: 24245543
21.  Interpositional substitution of free vas deferens segment autografts in rat: feasibility and potential implications 
BMC Urology  2014;14:61.
Insufficient vas length for performing a tension-free vasovasostomy is a problem occasionally encountered by microsurgeons. Herein we evaluated utilization of a non-vascularized vas deferens autograft in a rat model.
Segments of isolated vas deferens, 2.5 cm in length, were used as bilateral autografts in 15 rats. Each autograft was implanted between the two transected ends of vas deferens using end-to-end anastomosis. Fertility, sperm motility, and graft survival was evaluated and compared with the control group.
At the end of the 3 months, 9/15 (60%) rats were able to breed successfully and 24 (80%) vas grafts were patent and viable. Large granulomata developed at the proximal anastomosis sites in 6 (20%) autografts that failed. Unilateral minimal fluid leakage was observed in 6 (20%) of the proximal (testicular end) anastomosis sites in those rats that were able to breed. Histological evaluations demonstrated that graft survival was associated with mild to severe changes in the structure of the vas autograft. On semen analysis 76% of the sperms in the experimental group had forward motility compared to 78% in the control group (p > 0.05).
Vas autograft can successfully be performed in a rat model with ultimate breeding capability.
PMCID: PMC4148407  PMID: 25103862
Vas deferens; Autograft; Microsurgery; Fertility; Histology; Spermatozoa
22.  Regeneration in the Era of Functional Genomics and Gene Network Analysis 
The Biological bulletin  2011;221(1):18-34.
What gives an organism the ability to regrow tissues and to recover function where another organism fails is the central problem of regenerative biology. The challenge is to describe the mechanisms of regeneration at the molecular level, delivering detailed insights into the many components that are cross-regulated. In other words, a broad, yet deep dissection of the system-wide network of molecular interactions is needed. Functional genomics has been used to elucidate gene regulatory networks (GRNs) in developing tissues, which, like regeneration, are complex systems. Therefore, we reason that the GRN approach, aided by next generation technologies, can also be applied to study the molecular mechanisms underlying the complex functions of regeneration. We ask what characteristics a model system must have to support a GRN analysis. Our discussion focuses on regeneration in the central nervous system, where loss of function has particularly devastating consequences for an organism. We examine a cohort of cells conserved across all vertebrates, the reticulospinal (RS) neurons, which lend themselves well to experimental manipulations. In the lamprey, a jawless vertebrate, there are giant RS neurons whose large size and ability to regenerate make them particularly suited for a GRN analysis. Adding to their value, a distinct subset of lamprey RS neurons reproducibly fail to regenerate, presenting an opportunity for side-by-side comparison of gene networks that promote or inhibit regeneration. Thus, determining the GRN for regeneration in RS neurons will provide a mechanistic understanding of the fundamental cues that lead to success or failure to regenerate.
PMCID: PMC4109899  PMID: 21876108
23.  Biomechanical Model for Evaluation of Pediatric Upper Extremity Joint Dynamics during Wheelchair Mobility 
Journal of biomechanics  2013;47(1):269-276.
Pediatric manual wheelchair users (MWU) require high joint demands on their upper extremity (UE) during wheelchair mobility, leading them to be at risk of developing pain and pathology. Studies have examined UE biomechanics during wheelchair mobility in the adult population; however, current methods for evaluating UE joint dynamics of pediatric MWU are limited. An inverse dynamics model is proposed to characterize three-dimensional UE joint kinematics and kinetics during pediatric wheelchair mobility using a SmartWheel instrumented handrim system. The bilateral model comprises thorax, clavicle, scapula, upper arm, forearm, and hand segments and includes the sternoclavicular, acromioclavicular, glenohumeral, elbow and wrist joints. A single 17 year-old male with a C7 spinal cord injury (SCI) was evaluated while propelling his wheelchair across a 15-meter walkway. The subject exhibited wrist extension angles up to 60°, large elbow ranges of motion and peak glenohumeral joint forces up to 10% body weight. Statistically significant asymmetry of the wrist, elbow, glenohumeral and acromioclavicular joints was detected by the model. As demonstrated, the custom bilateral UE pediatric model may provide considerable quantitative insight into UE joint dynamics to improve wheelchair prescription, training, rehabilitation and long-term care of children with orthopaedic disabilities. Further research is warranted to evaluate pediatric wheelchair mobility in a larger population of children with SCI to investigate correlations to pain, function and transitional changes to adulthood.
PMCID: PMC4106158  PMID: 24309622
Biomechanics; manual wheelchair; pediatric; upper extremity; inverse dynamics
24.  Artificial Neural Network Based Analysis of High Throughput Screening Data for Improved Prediction of Active Compounds 
Journal of biomolecular screening  2009;14(10):1236-1244.
Artificial Neural Networks (ANNs) are trained using High Throughput Screening (HTS) data to recover active compounds from a large data set. Improved classification performance was obtained on combining predictions made by multiple ANNs. The HTS data, acquired from a Methionine Aminopeptidases Inhibition study, consisted of a library of 43,347 compounds, and the ratio of active to non-active compounds, RA/N, was 0.0321. Back-propagation ANNs were trained and validated using Principal Components derived from the physico-chemical features of the compounds. On selecting the training parameters carefully, an ANN recovers one-third of all active compounds from the validation set with a three-fold gain in RA/N value. Further gains in RA/N values were obtained upon combining the predictions made by a number of ANNs. The generalization property of the back-propagation ANNs was utilized to train those ANNs with the same training samples, after being initialized with different sets of random weights. As a result, only 10% of all available compounds were needed for training and validation, and the rest of the data set was screened with more than a ten-fold gain of the original RA/N value. Thus, ANNs trained with limited HTS data might become useful in recovering active compounds from large data sets.
PMCID: PMC4080791  PMID: 19940083
pattern classification; neural networks; generalization property
25.  Developments in HIV-1 immunotherapy and therapeutic vaccination 
F1000Prime Reports  2014;6:43.
Since the human immunodeficiency virus (HIV-1) pandemic began, few prophylactic vaccines have reached phase III trials. Only one has shown partial efficacy in preventing HIV-1 infection. The introduction of antiretroviral therapy (ART) has had considerable success in controlling infection and reducing transmission but in so doing has changed the nature of HIV-1 infection for those with access to ART. Access, compliance, and toxicity alongside the emergence of serious non-AIDS morbidity and the sometimes poor immune reconstitution in ART-treated patients have emphasized the need for additional therapies. Such therapy is intended to contribute to control of HIV-1 infection, permit structured treatment interruptions, or even establish a functional cure of permanently suppressed and controlled infection. Both immunotherapy and therapeutic vaccination have the potential to reach these goals. In this review, the latest developments in immunotherapy and therapeutic vaccination are discussed.
PMCID: PMC4047951  PMID: 24991420

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