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1.  A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency 
The New England journal of medicine  2014;371(15):1407-1417.
In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.
We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).
All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2 , MECOM, and other lymphoid proto-oncogenes in our patients.
This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; numbers, NCT01410019, NCT01175239, and NCT01129544.)
PMCID: PMC4274995  PMID: 25295500
2.  Interactions between lens epithelial and fiber cells reveal an intrinsic self-assembly mechanism 
Developmental biology  2013;385(2):291-303.
How tissues and organs develop and maintain their characteristic three-dimensional cellular architecture is often a poorly understood part of their developmental program; yet, as is clearly the case for the eye lens, precise regulation of these features can be critical for function. During lens morphogenesis cells become organized into a polarized, spheroidal structure with a monolayer of epithelial cells overlying the apical tips of elongated fiber cells. Epithelial cells proliferate and progeny that shift below the lens equator differentiate into new fibers that are progressively added to the fiber mass. It is now known that FGF induces epithelial to fiber differentiation; however, it is not fully understood how these two forms of cells assemble into their characteristic polarized arrangement. Here we show that in FGF-treated epithelial explants, elongating fibers become polarized/oriented towards islands of epithelial cells and mimic their polarized arrangement in vivo. Epithelial explants secrete Wnt5 into the culture medium and we show that Wnt5 can promote directed behaviour of lens cells. We also show that these explants replicate aspects of the Notch/Jagged signaling activity that has been shown to regulate proliferation of epithelial cells in vivo. Thus, our in vitro study identifies a novel mechanism, intrinsic to the two forms of lens cells, that facilitates self-assembly into the polarized arrangement characteristic of the lens in vivo. In this way the lens, with its relatively simple cellular composition, serves as a useful model to highlight the importance of such intrinsic self-assembly mechanisms in tissue developmental and regenerative processes.
PMCID: PMC3947272  PMID: 24211762
Lens epithelial cells; lens fiber cells; FGF; Notch; Jagged; Wnt; Planar cell polarity; Development and regeneration
3.  Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO) 
British Journal of Cancer  2013;109(7):1954-1964.
The association between oral contraceptive (OC) use, hormone replacement therapy (HRT) and lung cancer risk in women is still debated.
We performed a pooled analysis of six case–control studies (1961 cases and 2609 controls) contributing to the International Lung Cancer Consortium. Potential associations were investigated with multivariable unconditional logistic regression and meta-analytic models. Multinomial logistic regressions were performed to investigate lung cancer risk across histologic types.
A reduced lung cancer risk was found for OC (odds ratio (OR)=0.81; 95% confidence interval (CI): 0.68–0.97) and HRT ever users (OR=0.77; 95% CI: 0.66–0.90). Both oestrogen only and oestrogen+progestin HRT were associated with decreased risk (OR=0.76; 95% CI: 0.61–0.94, and OR=0.66; 95% CI: 0.49–0.88, respectively). No dose-response relationship was observed with years of OC/HRT use. The greatest risk reduction was seen for squamous cell carcinoma (OR=0.53; 95% CI: 0.37–0.76) in OC users and in both adenocarcinoma (OR=0.79; 95% CI: 0.66–0.95) and small cell carcinoma (OR=0.37; 95% CI: 0.19–0.71) in HRT users. No interaction with smoking status or BMI was observed.
Our findings suggest that exogenous hormones can play a protective role in lung cancer aetiology. However, given inconsistencies with epidemiological evidence from cohort studies, further and larger investigations are needed for a more comprehensive view of lung cancer development in women.
PMCID: PMC3790162  PMID: 24002594
lung cancer; exogenous hormones; oral contraceptives; hormone replacement therapy; pooled analysis
4.  The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors 
Cell Death & Disease  2014;5(10):e1450-.
Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.
PMCID: PMC4237236  PMID: 25299775
5.  Life Dissatisfaction and Eating Behaviors Among Older African Americans: The Protective Role of Social Support 
To examine (a) the influences of life dissatisfaction and dietary social support on eating behaviors (a high-fat diet and fruit/vegetable consumption) of older African Americans and (b) the moderating role of perceived dietary social support on the association between their life dissatisfaction and unhealthy eating behaviors.
Baseline data from a larger intervention study of mid-life and older African Americans. The study incorporated a quasi-experimental design with random selection of participants, stratifying for age and gender.
Six churches in North Florida.
One hundred and seventy-eight (132 females and 46 males with a median age of 60) older African Americans.
A structured questionnaire elicited personal data as well as information on eating behaviors, life dissatisfaction, and perceived dietary social support.
Older African Americans with more cumulative life adversity, as reflected by high life dissatisfaction, had significantly poorer eating behaviors including the consumption of a high-fat diet and low intake of fruits and vegetables. Older African Americans' dietary choices were also associated with their perceived social support. More importantly, perceived social support acted as a buffer to mitigate the influence of life dissatisfaction on older African Americans' eating behaviors.
Life dissatisfaction places older African Americans at risk for unhealthy eating behaviors. However, high levels of dietary social support can protect older African Americans from the influence of life dissatisfaction on unhealthy eating behaviors. There are practical implications of this research for health interventions and programming.
PMCID: PMC4074525  PMID: 23131815
Life dissatisfaction; social support; eating behavior; African American
6.  Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells 
Cell Death & Disease  2014;5(3):e1139-.
Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1flfl), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation.
PMCID: PMC3973235  PMID: 24651442
carbon monoxide; heme oxygenase-1; macrophages; differentiation
7.  Mesenchymal Stem Cells from the Retropatellar Fat Pad and Peripheral Blood Stimulate ACL Fibroblast Migration, Proliferation, and Collagen Gene Expression 
Connective tissue research  2012;54(1):10.3109/03008207.2012.715701.
Mesenchymal stem cells (MSCs) have been of recent interest as adjuncts for ligament repair. However, the effect of these cells on the resident ligament fibroblasts has not yet been defined. In this study, we hypothesized that co-culture of MSCs and ligament fibroblasts would result in increases in the proliferative rate of the ligament fibroblasts and their expression of collagen-related genes, as well as differentiation of the MSCs down a fibroblastic pathway. In addition, we hypothesized that these effects would be dependent on the source of the MSCs. Porcine MSCs were isolated from both the retro-patellar fat pad (ADSCs) and the peripheral blood (PBMCs) and co-cultured with porcine anterior cruciate ligament (ACL) fibroblasts. Fibroblast migration, proliferation, and collagen gene expression were evaluated at time points up to 14 days. ADSCs had a greater effect on stimulating ACL-fibroblast proliferation and procollagen production, while PBMCs were more effective in stimulating ligament fibroblast migration. In addition, co-culture with the ACL fibroblasts led to significant increases in collagen gene expression for ADSCs, suggesting a differentiation of these cells down a fibroblastic pathway during the co-culture period. This was not seen for the PBMCs. Thus, the effects of MSCs on in situ ACL fibroblasts were found to be source dependent, and the choice of MSC source should take into account the different performance characteristic of each type of MSC.
PMCID: PMC3836054  PMID: 22839298
mesenchymal stem cells; retropatellar fat-pad; peripheral blood mononuclear cells; ACL fibroblasts; co-cultureand
9.  Multicentric Castleman's Disease, Associated with Idiopathic Thrombocytopenic Purpura 
Case Reports in Hematology  2013;2013:269268.
The most common cause of a neck mass in young adults is hyperplastic lymphadenopathy consequent to infection and inflammation. Castleman's disease (CD), an unusual benign lymphoproliferative disorder, infrequently causes neck masses. It occurs in unicentric (UCD) and multicentric (MCD) forms and is associated with human immunodeficiency virus (HIV), human herpes virus 8 (HHV-8), and Kaposi's sarcoma. We present the third known association between MCD and previous immune thrombocytopenia in the absence of HIV and HHV-8 infection and review its association with other autoimmune disorders and attendant implications for pathogenesis. Finally, we summarize the current approach to therapy.
PMCID: PMC3807549  PMID: 24198982
10.  Anatomic Twist to a Straightforward Ablation 
Atrioventricular (AV) junction ablation for treatment of refractory atrial fibrillation is a well defined, standardized procedure and the simplest of commonly performed radiofrequency ablations in the field of cardiac electrophysiology. We report successful AV junction ablation using an inferior approach in a case of inferior vena cava interruption. Inability during the procedure to initially pass the ablation catheter into the right ventricle, combined with low amplitude electrograms, led to suspicion of an anatomic abnormality. This was determined to be a heterotaxy syndrome with inferior vena cava interruption and azygos continuation, draining in turn into the superior vena cava. Advancing Schwartz right 0 (SRO) sheath through the venous abnormality into the right atrium allowed adequate catheter stability to successfully induce complete AV block with radiofrequency energy.
PMCID: PMC3594905  PMID: 23573065
AV junction ablation; Inferior approach; IVC interruption; Azygos vein continuation; Superior vena cava; Heterotaxy syndrome; SRO sheath
11.  Web-Based Self-Management for Patients with Multiple Sclerosis: A Practical, Randomized Trial 
No studies have addressed the use of electronic personal health records (e-PHRs) for self-management in complex neurological disorders. We assessed and tested an Internet-based self-management system that utilized the e-PHR and determined its impact on self-assessed well-being, clinician-assessed well-being, and healthcare utilization in patients with multiple sclerosis (MS).
Materials and Methods
Subjects were randomized to usual care (a secure Web-based messaging system) or active intervention, which included secure messaging, self-monitoring, self-management of MS symptoms, and communication about upcoming clinic visits. Computers and Internet access were provided. Subjects were included if they had MS, lived within the county or region surrounding our MS center, had at least two appointments at our center in the previous 12 months, and demonstrated basic typing and computer skills. Study duration was 12 months.
Of 220 subjects completing informed consent, 206 met the inclusion criteria. At the study's end, 83 subjects remained in the usual care group and 84 in the enhanced care group. Both groups used the available system components. The groups did not significantly differ on the primary endpoints or healthcare utilization.
Self-management support is an emerging aspect of chronic care management. We established the feasibility of conducting a randomized, controlled trial using e-PHRs for patient self-management. We did not find that e-PHR–enabled self-management augmented multidisciplinary MS center-based care, possibly because the differences between interventions were not great enough.
PMCID: PMC3064874  PMID: 21214498
clinical trials randomized controlled (CONSORT agreement); multiple sclerosis; outcome research
12.  Effects on condom use of an HIV prevention programme 36 months postintervention: a cluster randomized controlled trial among Bahamian youth 
Data are lacking on long-term effects of HIV behavioural intervention programmes. In this study, we report intervention effects 36 months postintervention on condom use and relevant outcome variables from the theory-based programme ‘Focus on Youth in the Caribbean’ (FOYC). Participants (1360 sixth-grade youth) were randomized by school into: (1) FOYC, plus one of two brief parent interventions or (2) the control condition ‘Wondrous Wetlands’, plus a brief parent intervention. Mixed effect analysis demonstrated significant programme effects, including enhanced HIV/AIDS knowledge (effect size D = 0.44, 95% confidence interval [CI]: 0.43, 0.46), increased self-efficacy of (D = 0.42, 95% CI: 0.30, 0.54), skills for (D = 0.62, 95% CI: 0.56, 0.64) and intention to use a condom (D = 0.20, 95% CI: 0.03, 0.37). Youth who received FOYC plus the parental monitoring intervention had higher condom use rates (odds ratio = 1.49, 95% CI: 0.97, 2.28). Feedback effects from key variables were also detected, supporting the sustained effect.
PMCID: PMC3035564  PMID: 21097734
Protection Motivation Theory; preadolescent; HIV/AIDS; behavioural intervention
13.  Müllerian duct anomalies: from diagnosis to intervention 
The British Journal of Radiology  2009;82(984):1034-1042.
The purpose of this study was to review the embryology, classification, imaging features and treatment options of Müllerian duct anomalies. The three embryological phases will be described and the appearance of the seven classes of Müllerian duct anomalies will be illustrated using hysterosalpingography, ultrasound and MRI. This exhibit will also review the treatment options, including interventional therapy. The role of imaging is to help detect, classify and guide surgical management. At this time, MRI is the modality of choice because of its high accuracy in detecting and accurately characterising Müllerian duct anomalies. In conclusion, radiologists should be familiar with the imaging features of the seven classes of Müllerian duct anomalies, as the appropriate course of treatment relies upon the correct diagnosis and categorisation of each anomaly.
PMCID: PMC3473390  PMID: 19433480
14.  COMT and Cognition: Main Effects and Interaction with Educational Attainment 
Genes, brain, and behavior  2008;8(1):36-42.
Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. COMT Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient pre-frontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the WAIS-R to 328 community-derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5 to 18). We found significant genotypic effects on WAIS-R measures of long-term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers' scores improved markedly with increasing yrs ed whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11-12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps due to emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.
PMCID: PMC2693269  PMID: 19076243
working memory; long-term memory; attention; WAIS-R; COMT Val158Met; education; resilience; anxiety
15.  ING Proteins as Potential Anticancer Drug Targets 
Current drug targets  2009;10(5):442-454.
Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies.
PMCID: PMC2802283  PMID: 19442116
ING2; oncogene; molecular targeted therapy; siRNA; small molecular compounds; cancer vaccine; cancer/testis antigen; oncoantigen
16.  Treatment of high-energy tibial plateau fractures 
Treatment of high-energy fractures of the tibial plateau requires an inordinate degree of surgical effort in order to avoid complications. Fracture reduction can be a challenge to experienced hands and the soft tissue conditions are intolerant of careless dissection. In general, it is an oversimplification to use one technique of stabilisation for such a heterogenous group (even within one classification tier). This article describes the specific attributes of Schatzker type 6 injuries (AO 41C) that enable decisionmaking algorithms to be generated and balances the merits for plate stabilisation and external fixation against injury characteristics. A detailed description is given for circular fixation in these injuries to assist those unfamiliar with the technique.
PMCID: PMC2780586
External fixation; Fracture; Tibia; Ilizarov; Plateau; Internal fixation; Minimally invasive
17.  Condom-use Skills Checklist: A Proxy for Assessing Condom-use Knowledge and Skills When Direct Observation Is Not Possible 
Because of the continued importance of correct condom-use in controlling the HIV epidemic and the limited availability of tools for assessing correct condom-use, methods for assessing condom-application skills, especially when direct observation is not feasible, are needed. Accordingly, in the context of a high-risk population (The Bahamas) for HIV, a 17-item scale—the Condom-use Skills Checklist (CUSC)—was developed for use among young adolescents and adults. The rationale and approach to developing the scale and some measures of internal consistency, construct validity, and criterion-related validity have been described. It is concluded that the scale offers a reasonable alternative to direct observation among older subjects and that further development may make it more useful among pre-adolescents.
PMCID: PMC2761789  PMID: 19507756
Condom-use; Interventions; Knowledge; Scale; Skills; Bahamas
18.  Electronic Medical Record-Assisted Design of a Cluster-Randomized Trial to Improve Diabetes Care and Outcomes 
Electronic medical records (EMRs) have the potential to facilitate the design of large cluster-randomized trials (CRTs).
To describe the design of a CRT of clinical decision support to improve diabetes care and outcomes.
In the Diabetes Improvement Group-Intervention Trial (DIG-IT), we identified and balanced preassignment characteristics of 12,675 diabetic patients cared for by 147 physicians in 24 practices of 2 systems using the same vendor’s EMR. EMR-facilitated disease management was system A’s experimental intervention; system B interventions involved patient empowerment, with or without disease management. For our sample, we: (1) identified characteristics associated with response to interventions or outcomes; (2) summarized feasible partitions of 10 system A practices (2 groups) and 14 system B practices (3 groups) using intra-cluster correlation coefficients (ICCs) and standardized differences; (3) selected (blinded) partitions to effectively balance the characteristics; and (4) randomly assigned groups of practices to interventions.
In System A, 4,306 patients, were assigned to 2 groups of practices; 8,369 patients in system B were assigned to 3 groups of practices. Nearly all baseline outcome variables and covariates were well-balanced, including several not included in the initial design. DIG-IT’s balance was superior to alternative partitions based on volume, geography or demographics alone.
EMRs facilitated rigorous CRT design by identifying large numbers of patients with diabetes and enabling fair comparisons through preassignment balancing of practice sites. Our methods can be replicated in other settings and for other conditions, enhancing the power of other translational investigations.
PMCID: PMC2359510  PMID: 18373134
cluster-randomized trial; study design; health information technology; clinical decision support; diabetes mellitus
19.  Physicians' perceptions of an electronic health record-based clinical trial alert approach to subject recruitment: A survey 
Physician participation in clinical research recruitment efforts is critical to many studies' success, but it is often limited. Use of an Electronic Health Record (EHR)-based, point-of-care Clinical Trial Alert (CTA) approach has led to significant increases in physician-generated recruitment and holds promise for wider benefit. However, little is known about physicians' decision-making regarding recruitment in EHR-equipped settings or the use of such EHR-based approaches. We sought to assess physicians' perceptions about recruitment in general and using the CTA approach in particular.
We developed and delivered a Web-based survey consisting of 15 multiple-choice and free-text questions. Participants included the 114 physician subjects (10 endocrinologists and 104 general internists) who were exposed to CTAs during our preceding 4-month intervention study. Response data were descriptively analyzed, and key findings were compared between groups using appropriate statistical tests.
Sixty-nine physicians (61%) responded during the 10-week survey period. Respondents and non-respondents did not differ significantly. Twenty-seven percent of respondents felt very comfortable recruiting patients to trials in general, and 77% appreciated being reminded about a trial via a CTA. Only 11% percent felt the CTA was difficult to use, and 27% felt it was more than somewhat intrusive. Among those who ignored all CTAs, 37% cited a lack of time, 28% knowledge of the patient's ineligibility, and 13% limited knowledge about the trial as their most common reason. Thirty-eight percent wanted more information about the trial presented in the CTA, and 73% were interested in seeing CTAs for future trials. Comments and suggestions were submitted by 33% of respondents and included suggestions for improvement of the CTA approach.
Most physicians were comfortable recruiting patients for clinical trials at the point-of-care, found the EHR-based CTA approach useful and would like to see it used in the future. These findings provide insight into the perceived utility of this EHR-based approach to subject recruitment, suggest ways it might be improved, and add to the limited body of knowledge regarding physicians' attitudes toward clinical trial recruitment in EHR-equipped settings.
PMCID: PMC2374776  PMID: 18384682
20.  Effect of a Clinical Trial Alert System on Physician Participation in Trial Recruitment 
Archives of internal medicine  2005;165(19):2272-2277.
Failure to recruit a sufficient number of eligible subjects in a timely manner represents a major impediment to the success of clinical trials. Physician participation is vital to trial recruitment but is often limited.
Following 12 months of traditional recruitment to a clinical trial, we activated our Electronic Health Record (EHR)-based Clinical Trial Alert (CTA) system in selected outpatient clinics of a large, US academic health system. When a patient’s EHR data met selected trial criteria during the subsequent 4-month intervention period, the CTA prompted physician consideration of the patient’s eligibility and facilitated secure messaging to the trial’s coordinator. Subjects were the 114 physicians practicing at the selected clinics throughout our study. We compared differences in the number of physicians participating in recruitment and their recruitment rates before and after CTA activation.
The CTA intervention was associated with significant increases in the number of physicians generating referrals (5 before, 42 after, P<0.001) and enrollments (5 before, 11 after, P=0.03), as well as with a 10-fold increase in those physicians’ referral rate (5.7/month before, 59.5/month after; rate ratio-10.44, 95% CI 7.98–13.68; P<0.001) and a doubling of their enrollment rate (2.9/month before, 6.0/month after; rate ratio-2.06, 95% CI 1.22–3.46; P=0.007).
EHR-based CTA use led to significant increases in physicians’ participation in and their recruitment rates to an ongoing clinical trial. Given the trend toward EHR implementation in health centers engaged in clinical research, this approach may represent a much-needed solution to the common problem of inadequate trial recruitment.
PMCID: PMC1343501  PMID: 16246994
21.  Sildenafil (Viagra) corrects ΔF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis 
Thorax  2005;60(1):55-59.
Background: Most patients with cystic fibrosis (CF) have a ΔF508 mutation resulting in abnormal retention of mutant gene protein (ΔF508-CFTR) within the cell. This study was undertaken to investigate ΔF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move ΔF508-CFTR to its correct location in the apical cell membrane.
Method: Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect of sildenafil treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay.
Results: In most untreated CF cells ΔF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells to sildenafil (2 hours at 37°C) resulted in recruitment of ΔF508-CFTR to the apical membrane and the appearance of chloride transport activity. Sildenafil also increased ΔF508-CFTR trafficking in cells from individuals with CF with a single copy ΔF508 (ΔF508/4016ins) or with a newly described CF trafficking mutation (R1283M).
Conclusions: The findings provide proof of principle for sildenafil as a ΔF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in patients with CF.
PMCID: PMC1747155  PMID: 15618584
22.  The effect of immunomodulatory treatment on multiple sclerosis fatigue 
Methods: Fatigue was measured at baseline and six months using the fatigue impact scale (FIS). Groups (glatiramer acetate and ß interferon) were evaluated for the proportion improved, using Fisher's exact test. Logistic regression analysis assessed the relation between treatment group and improvement and controlled for confounding variables.
Results: Six month paired FIS assessments were available for 218 patients (76% female). Ages ranged between 19 and 61 years, with 86% having relapsing-remitting disease. Glatiramer acetate was used by 61% and ß interferon by 39%. At baseline, total FIS and subscale scores were comparable in the two groups. More patients improved on glatiramer acetate than on ß interferon on total FIS (24.8% v 12.9%, p = 0.033; adjusted odds ratio = 2.36, 95% confidence interval 1.03 to 5.42), and on physical (28.6% v 14.1%, p = 0.013) and cognitive subscales (21.1% v 10.6%, p = 0.045). Logistic regression analysis confirmed the association between glatiramer acetate use and improved fatigue, after accounting for baseline group differences.
Conclusions: The odds of reduced multiple sclerosis fatigue were around twice as great with glatiramer acetate treatment as with ß interferon. Confirmation of this result is required.
PMCID: PMC1739126  PMID: 15201369
24.  Treatment of high-energy tibial plateau fractures 
Treatment of high-energy fractures of the tibial plateau requires an inordinate degree of surgical effort in order to avoid complications. Fracture reduction can be a challenge to experienced hands and the soft tissue conditions are intolerant of careless dissection. In general, it is an oversimplification to use one technique of stabilisation for such a heterogenous group (even within one classification tier). This article describes the specific attributes of Schatzker type 6 injuries (AO 41C) that enable decisionmaking algorithms to be generated and balances the merits for plate stabilisation and external fixation against injury characteristics. A detailed description is given for circular fixation in these injuries to assist those unfamiliar with the technique.
PMCID: PMC2780586
External fixation; Fracture; Tibia; Ilizarov; Plateau; Internal fixation; Minimally invasive
25.  Spatial and temporal variation in malaria transmission in a low endemicity area in northern Tanzania 
Malaria Journal  2006;5:98.
Spatial and longitudinal monitoring of transmission intensity will allow better targeting of malaria interventions. In this study, data on meteorological, demographic, entomological and parasitological data over the course of a year was collected to describe malaria epidemiology in a single village of low transmission intensity.
Entomological monitoring of malaria vectors was performed by weekly light trap catches in 10 houses. Each house in the village of Msitu wa Tembo, Lower Moshi, was mapped and censused. Malaria cases identified through passive case detection at the local health centre were mapped by residence using GIS software and the incidence of cases by season and distance to the main breeding site was calculated.
The principle vector was Anopheles arabiensis and peak mosquito numbers followed peaks in recent rainfall. The entomological inoculation rate estimated was 3.4 (95% CI 0.7–9.9) infectious bites per person per year. The majority of malaria cases (85/130) occurred during the rainy season (χ2 = 62,3, p < 0.001). Living further away from the river (OR 0.96, CI 0.92–0.998, p = 0.04 every 50 m) and use of anti-insect window screens (OR 0.65, CI 0.44–0.94, p = 0.023) were independent protective factors for the risk of malaria infection. Children aged 1–5 years and 5–15 years were at greater risk of clinical episodes (OR 2.36, CI 1.41–3.97, p = 0.001 and OR 3.68, CI 2.42–5.61, p < 0.001 respectively).
These data show that local malaria transmission is restricted to the rainy season and strongly associated with proximity to the river. Transmission reducing interventions should, therefore, be timed before the rain-associated increase in mosquito numbers and target households located near the river.
PMCID: PMC1635725  PMID: 17081311

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