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1.  Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS 
Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS.
In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer–specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients).
Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM.
Although I-IBTR increased the risk for breast cancer–related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.
PMCID: PMC3107729  PMID: 21398619
2.  The feasibility and safety of high-intensity focused ultrasound combined with low-dose external beam radiotherapy as supplemental therapy for advanced prostate cancer following hormonal therapy 
Asian Journal of Andrology  2011;13(3):499-504.
The aim of this study was to investigate the feasibility and safety of high-intensity focused ultrasound (HIFU) combined with (+) low-dose external beam radiotherapy (LRT) as supplemental therapy for advanced prostate cancer (PCa) following hormonal therapy (HT). Our definition of HIFU+LRT refers to treating primary tumour lesions with HIFU in place of reduced field boost irradiation to the prostate, while retaining four-field box irradiation to the pelvis in conventional-dose external beam radiotherapy (CRT). We performed a prospective, controlled and non-randomized study on 120 patients with advanced PCa after HT who received HIFU, CRT, HIFU+LRT and HT alone, respectively. CT/MR imaging showed the primary tumours and pelvic lymph node metastases visibly shrank or even disappeared after HIFU+LRT treatment. There were significant differences among four groups with regard to overall survival (OS) and disease-specific survival (DSS) curves (P=0.018 and 0.015). Further comparison between each pair of groups suggested that the long-term DSS of the HIFU+LRT group was higher than those of the other three groups, but there was no significant difference between the HIFU+LRT group and the CRT group. Multivariable Cox's proportional hazard model showed that both HIFU+LRT and CRT were independently associated with DSS (P=0.001 and 0.035) and had protective effects with regard to the risk of death. Compared with CRT, HIFU+LRT significantly decreased incidences of radiation-related late gastrointestinal (GI) and genitourinary (GU) toxicity grade ≥II. In conclusion, long-term survival of patients with advanced PCa benefited from strengthening local control of primary tumour and regional lymph node metastases after HT. As an alternative to CRT, HIFU+LRT showed good efficacy and better safety.
PMCID: PMC3739332  PMID: 21399650
complication; high-intensity focused ultrasound; hormonal therapy; low-dose external beam radiotherapy; prostate cancer; survival rate
3.  Protocol of a Randomized Controlled Trial of Culturally Sensitive Interventions to Improve African Americans' and Non-African Americans' Early, Shared, and Informed Consideration of Live Kidney Transplantation: The talking about Live Kidney Donation (TALK) study 
BMC Nephrology  2011;12:34.
Live kidney transplantation (LKT) is underutilized, particularly among ethnic/racial minorities. The effectiveness of culturally sensitive educational and behavioral interventions to encourage patients' early, shared (with family and health care providers) and informed consideration of LKT and ameliorate disparities in consideration of LKT is unknown.
We report the protocol of the Talking About Live Kidney Donation (TALK) Study, a two-phase study utilizing qualitative and quantitative research methods to design and test culturally sensitive interventions to improve patients' shared and informed consideration of LKT. Study Phase 1 involved the evidence-based development of culturally sensitive written and audiovisual educational materials as well as a social worker intervention to encourage patients' engagement in shared and informed consideration of LKT. In Study Phase 2, we are currently conducting a randomized controlled trial in which participants with progressing chronic kidney disease receive: 1) usual care by their nephrologists, 2) usual care plus the educational materials, or 3) usual care plus the educational materials and the social worker intervention. The primary outcome of the randomized controlled trial will include patients' self-reported rates of consideration of LKT (including family discussions of LKT, patient-physician discussions of LKT, and identification of an LKT donor). We will also assess differences in rates of consideration of LKT among African Americans and non-African Americans.
The TALK Study rigorously developed and is currently testing the effectiveness of culturally sensitive interventions to improve patients' and families' consideration of LKT. Results from TALK will provide needed evidence on ways to enhance consideration of this optimal treatment for patients with end stage renal disease.
Trial Registration number, NCT00932334
PMCID: PMC3150247  PMID: 21736762
4.  A cluster randomized trial of standard quality improvement versus patient-centered interventions to enhance depression care for African Americans in the primary care setting: study protocol NCT00243425 
Several studies document disparities in access to care and quality of care for depression for African Americans. Research suggests that patient attitudes and clinician communication behaviors may contribute to these disparities. Evidence links patient-centered care to improvements in mental health outcomes; therefore, quality improvement interventions that enhance this dimension of care are promising strategies to improve treatment and outcomes of depression among African Americans. This paper describes the design of the BRIDGE (Blacks Receiving Interventions for Depression and Gaining Empowerment) Study. The goal of the study is to compare the effectiveness of two interventions for African-American patients with depression--a standard quality improvement program and a patient-centered quality improvement program. The main hypothesis is that patients in the patient-centered group will have a greater reduction in their depression symptoms, higher rates of depression remission, and greater improvements in mental health functioning at six, twelve, and eighteen months than patients in the standard group. The study also examines patient ratings of care and receipt of guideline-concordant treatment for depression.
A total of 36 primary care clinicians and 132 of their African-American patients with major depressive disorder were recruited into a cluster randomized trial. The study uses intent-to-treat analyses to compare the effectiveness of standard quality improvement interventions (academic detailing about depression guidelines for clinicians and disease-oriented care management for their patients) and patient-centered quality improvement interventions (communication skills training to enhance participatory decision-making for clinicians and care management focused on explanatory models, socio-cultural barriers, and treatment preferences for their patients) for improving outcomes over 12 months of follow-up.
The BRIDGE Study includes clinicians and African-American patients in under-resourced community-based practices who have not been well-represented in clinical trials to improve depression care. The patient-centered and culturally targeted approach to depression care is a relatively new one that has not been tested in most previous studies. The study will provide evidence about whether patient-centered accommodations improve quality of care and outcomes to a greater extent than standard quality improvement strategies for African Americans with depression.
Trial Registration NCT00243425
PMCID: PMC2838803  PMID: 20178624
5.  Your Path to Transplant: a randomized controlled trial of a tailored computer education intervention to increase living donor kidney transplant 
BMC Nephrology  2014;15(1):166.
Because of the deceased donor organ shortage, more kidney patients are considering whether to receive kidneys from family and friends, a process called living donor kidney transplantation (LDKT). Although Blacks and Hispanics are 3.4 and 1.5 times more likely, respectively, to develop end stage renal disease (ESRD) than Whites, they are less likely to receive LDKTs. To address this disparity, a new randomized controlled trial (RCT) will assess whether Black, Hispanic, and White transplant patients’ knowledge, readiness to pursue LDKT, and receipt of LDKTs can be increased when they participate in the Your Path to Transplant (YPT) computer-tailored intervention.
Nine hundred Black, Hispanic, and White ESRD patients presenting for transplant evaluation at University of California, Los Angeles Kidney and Pancreas Transplant Program (UCLA-KPTP) will be randomly assigned to one of two education conditions, YPT or Usual Care Control Education (UC). As they undergo transplant evaluation, patients in the YPT condition will receive individually-tailored telephonic coaching sessions, feedback reports, video and print transplant education resources, and assistance with reducing any known socioeconomic barriers to LDKT. Patients receiving UC will only receive transplant education provided by UCLA-KPTP. Changes in transplant knowledge, readiness, pros and cons, and self-efficacy to pursue LDKT will be assessed prior to presenting at the transplant center (baseline), during transplant evaluation, and 4- and 8-months post-baseline, while completion of transplant evaluation and receipt of LDKTs will be assessed at 18-months post-baseline. The RCT will determine, compared to UC, whether Black, Hispanic, and White patients receiving YPT increase in their readiness to pursue LDKT and transplant knowledge, and become more likely to complete transplant medical evaluation and pursue LDKT. It will also examine how known patient, family, and healthcare system barriers to LDKT act alone and in combination with YPT to affect patients’ transplant decision-making and behavior. Statistical analyses will be performed under an intent-to-treat approach.
At the conclusion of the study, we will have assessed the effectiveness of an innovative and cost-effective YPT intervention that could be utilized to tailor LDKT discussion and education based on the needs of individual patients of different races in many healthcare settings.
Trial registration, number NCT02181114.
PMCID: PMC4213461  PMID: 25315644
Kidney transplantation; Living donor; Racial disparities; African-Americans; Hispanics; Patient education; Health knowledge/attitudes; Transtheoretical model
6.  Time to Renal Disease and End-Stage Renal Disease in PROFILE: A Multiethnic Lupus Cohort 
PLoS Medicine  2006;3(10):e396.
Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE).
Methods and Findings
PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic–demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.
In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcγRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD but does not explain the ethnic disparities in renal disease progression.
Editors' Summary
Systemic lupus erythematosis (SLE, commonly known as “lupus”) is an illness of many manifestations that appear to result from the immune system attacking components of the body's own cells. One of the unfortunate effects of SLE is kidney damage, which can, in a minority of patients, progress to kidney failure (formally called “end-stage renal disease,” or ESRD). Compared to White Americans, other ethnic groups tend to develop renal complications of lupus more often and with worse outcomes.
Why Was This Study Done?
It is unclear why some people with lupus develop kidney problems. The purpose of this US-based study was to confirm the factors that increase the risk of kidney damage and kidney failure, particularly in racial and ethnic minority patients, and to determine which of these factors accelerate the pace of kidney disease. Knowing these risk factors could allow the development and targeting of interventions, such as screening tests and preventive treatments, to prevent long-term loss of kidney function in patients with lupus.
What Did the Researchers Do and Find?
The researchers measured a number of factors in a multi-ethnic group of 1,008 patients with lupus, almost half of whom had some degree of kidney involvement. They found that those who developed kidney damage after being diagnosed with lupus tended to be younger, to have had lupus for a longer time, and to have experienced more effects of lupus in general than those who did not have kidney involvement. Those who developed kidney problems were also more likely to have been unemployed, to have had fewer years of formal education, and to have had high blood pressure before developing kidney involvement. African-American and Texan Hispanic individuals with lupus were more likely to develop kidney involvement, and tended to develop it more rapidly, than White Americans or Puerto Rican Hispanic ethnicity. Actual kidney failure (ESRD requiring dialysis or kidney transplantation) was more likely to occur among Texan Hispanics with kidney involvement than in the other ethnic groups. Diabetes and high blood pressure were not found to predict ESRD, but people with a particular variant of a protein that helps antibodies bind to cells (know as Fc-gamma receptor IIIa, or FcγRIIIa) were found to be more likely to develop ESRD, and to develop it more quickly.
What Do These Findings Mean?
These results suggest that the emergence and progression of kidney disease in patients with lupus depends on medical, genetic, and socioeconomic factors. Because no single test or intervention can be expected to address all of these factors, those treating patients with lupus must remain aware of the complexity of their patients lives at a variety of levels. In particular, ethnic disparities in the risk of serious kidney disease remain to be addressed.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus page on lupus
Lupus Foundation of America
American College of Rheumatology pages on lupus
Wikipedia entry on lupus (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
PMCID: PMC1626549  PMID: 17076550
7.  Project Eban: An HIV/STD Intervention for African American Couples 
To describe the Eban HIV/STD Risk Reduction Intervention being evaluated in the NIMH Multisite HIV/STD Prevention trial for heterosexual African American couples, including the integrated theoretical framework, the structure, core elements and procedures of the intervention and how the content was shaped by culturally congruent concepts to address the needs of the study target population.
The Eban HIV/STD Risk Reduction Intervention is designed to address multilevel individual, interpersonal and community level factors that contribute to HIV/STD transmission risk behaviors among heterosexual African American couples who are HIV serodiscordant.
The Eban HIV/STD Risk Reduction Intervention employs a mixed modality, couples-based approach that is based on an integrated ecological framework incorporating social cognitive theory and uses an Afro-centric paradigm that is informed by previous evidence-based couples HIV prevention interventions. For this randomized controlled trial, African American serodiscordant couples were recruited from four urban sites (Atlanta, Los Angeles, New York and Philadelphia) and were randomized to either the Eban HIV/STD Risk Reduction Intervention (treatment condition) or a Health Promotion Intervention that served as an attentional control condition. Both interventions had 4 individual couple sessions and 4 group sessions, but only the treatment condition was focused on reducing HIV/STD risk behaviors. Behavioral and biological data were collected at baseline, immediately after the intervention, and at 6 and 12 months. The theoretical framework, core elements and content of each session are described and lessons learned from this intervention trial are discussed.
An HIV prevention intervention combining couple and group sessions can be feasibly implemented with African American HIV serodiscordant couples who remain at high risk of HIV/STD transmission. The lessons learned from the trial suggest that the participants responded very well to both the couple and group sessions. Participant feedback suggests that the cultural congruence of the intervention and use of African American co-facilitators made them feel comfortable disclosing risky behaviors. Participant feedback also suggests that the intervention’s couples-based focus on enhancing dyadic communication and decision-making skills were key to helping the couples work together to overcome barriers to using condoms.
Participant and facilitator evaluations of the Eban Risk Reduction Intervention suggest that couples responded well to the Afro-centric content and mixed modalities of the intervention sessions. Couple sessions were optimal for enhancing interpersonal and microlevel factors, including communication, problem solving, and decision making.
PMCID: PMC3274174  PMID: 18724186
HIV; behavioral intervention; African American; couple-level; sexual behavior; culturally congruent
8.  Rationale and design: telephone-delivered behavioral skills interventions for Blacks with type 2 diabetes 
Trials  2010;11:35.
African Americans with Type 2 diabetes (T2DM) have higher prevalence of diabetes, poorer metabolic control, and greater risk for complications and death compared to American Whites. Poor outcomes in African Americans with T2DM can be attributed to patient, provider, and health systems level factors. Provider and health system factors account for <10% of variance in major diabetes outcomes including hemoglobin A1c (HbA1c), lipid control, and resource use. Key differences appear to be at the patient level. Of the patient level factors, consistent differences between African Americans and American Whites with T2DM have been found in diabetes knowledge, self-management skills, empowerment, and perceived control. A variety of interventions to improve diabetes self-management have been tested including: 1) knowledge interventions; 2) lifestyle interventions; 3) skills training interventions; and 4) patient activation and empowerment interventions. Most of these interventions have been tested individually, but rarely have they been tested in combination, especially among African Americans who have the greatest burden of diabetes related complications. This study provides a unique opportunity to address this gap in the literature.
We describe an ongoing four-year randomized clinical trial, using a 2 × 2 factorial design, which will test the efficacy of separate and combined telephone-delivered, diabetes knowledge/information and motivation/behavioral skills training interventions in high risk African Americans with poorly controlled T2DM (HbA1c ≥ 9%). Two-hundred thirty-two (232) male and female African-American participants, 18 years of age or older and with an HbA1c ≥ 9%, will be randomized into one of four groups for 12-weeks of phone interventions: (1) an education group, (2) a motivation/skills group, (3) a combined group or (4) a usual care/general health education group. Participants will be followed for 12-months to ascertain the effect of the interventions on glycemic control. Our primary hypothesis is that among African Americans with poorly controlled T2DM, patients randomized to the combined diabetes knowledge/information and motivation/behavioral skills training intervention will have significantly greater reduction in HbA1c at 12 months of follow-up compared to the usual care/general health education group.
Results from this study will provide important insight into how best to deliver diabetes education and skills training in ethnic minorities and whether combined knowledge/information and motivation/behavioral skills training is superior to the usual method of delivering diabetes education for African Americans with poorly controlled T2DM.
Trial registration
National Institutes of Health Clinical Trials Registry ( identifier# NCT00929838).
PMCID: PMC2855561  PMID: 20350322
9.  Could living unrelated renal transplantation ameliorate the actual shortage of organs in the Balkan region? 
Hippokratia  2013;17(3):243-245.
Background: Despite the efforts for more transplants performed with organs from deceased donors, the living renal transplantation is still the predominant transplant activity in the Balkan region. In order to adress the severe organ shortage, we started accepting unrelated (emotionally related) living donors (LURD). Here we present our 10-year experience with living unrelated renal transplantation (LURT).
Methods: Twenty four LURT were performed in our center in the last 10 years. The mean recipients and donors age was 41.7 and 47.2 years, respectively. As LURD spouses (n=17) and extended family members (n=7) were accepted predominantly. All donors went through careful psychological evaluation in order to confirm emotional relationship. The final decision was taken after both the recipient and the donor signed a consent in front of a judge. A quadruple sequential immunosuppressive protocol was used in all recipients. The 5-year Kaplan Meier graft survival rate, HLA mismatch, rejection episodes, delayed graft function, serum creatinine and Glomerular filtration rate-Modification of the diet in renal disease (GFR-MDRD) were analyzed. The results were compared with 30 living related renal transplants (LRT) performed during the same time with mean recipients and donors age of 35.9 and 58.5 years, respectively.
Results: The mean follow up for LURT and LRT recipients were 81.4 and 79.6 months, respectively. There was a significant difference regarding recipients and donors age, HLA mismatch (5.07 and 2.9) and rejection episodes (16% vs. 11%) in LURT and LRT recipients. The 5 years graft survival rate was excellent in both groups (83 and 81%, respectively). There was no significant difference in 5 years serum creatinine (129.3 vs 121.1 μmol/lit) and 5 years GFR-MDRD (56.6 and 58.6 ml/min).
Conclusion: The authors present an excellent 5-year graft survival rate in both LURT and LRT recipients. Therefore, LURT could ameliorate the severe organ shortage in the region and could be recommended as a valuable source of organs in the countries with developed and underdeveloped deceased donor donation.
PMCID: PMC3872461  PMID: 24470735
Kidney unrelated transplantation; Kaplan-Meier surviving curves; glomerular filtration rate
10.  The RaDIANT community study protocol: community-based participatory research for reducing disparities in access to kidney transplantation 
BMC Nephrology  2014;15(1):171.
The Southeastern United States has the lowest kidney transplant rates in the nation, and racial disparities in kidney transplant access are concentrated in this region. The Southeastern Kidney Transplant Coalition (SEKTC) of Georgia, North Carolina, and South Carolina is an academic and community partnership that was formed with the mission to improve access to kidney transplantation and reduce disparities among African American (AA) end stage renal disease (ESRD) patients in the Southeastern United States.
We describe the community-based participatory research (CBPR) process utilized in planning the Reducing Disparities In Access to kidNey Transplantation (RaDIANT) Community Study, a trial developed by the SEKTC to reduce health disparities in access to kidney transplantation among AA ESRD patients in Georgia, the state with the lowest kidney transplant rates in the nation. The SEKTC Coalition conducted a needs assessment of the ESRD population in the Southeast and used results to develop a multicomponent, dialysis facility-randomized, quality improvement intervention to improve transplant access among dialysis facilities in GA. A total of 134 dialysis facilities are randomized to receive either: (1) standard of care or “usual” transplant education, or (2) the multicomponent intervention consisting of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients within dialysis facilities. The primary outcome is change in facility-level referral for kidney transplantation from baseline to 12 months; the secondary outcome is reduction in racial disparity in transplant referral.
The RaDIANT Community Study aims to improve equity in access to kidney transplantation for ESRD patients in the Southeast.
Trial registration number NCT02092727.
PMCID: PMC4230631  PMID: 25348614
Kidney transplantation; Dialysis facility; Randomized trial; Education; Staff; Community-based participatory research
11.  Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review 
PLoS Medicine  2010;7(11):e1000368.
Patrina Caldwell and colleagues performed a systematic review of randomized studies that compared methods of recruiting individual study participants into trials, and found that strategies that focus on increasing potential participants' awareness of the specific health problem, and that engaged them, appeared to increase recruitment.
Recruitment of participants into randomised controlled trials (RCTs) is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions) were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs.
Methods and Findings
A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies). Strategies that increased people's awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR) 1.48, 95% confidence interval (CI) 1.00–2.18], attendance at an education session [RR 1.14, 95% CI 1.01–1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14–1.66]), or a video about the health condition (RR 1.75, 95% CI 1.11–2.74), and also monetary incentives (RR1.39, 95% CI 1.13–1.64 to RR 1.53, 95% CI 1.28–1.84) improved recruitment. Increasing patients' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study's main limitation was the necessity of modifying the search strategy with subsequent search updates because of changes in MEDLINE definitions. The abstracts of previous versions of this systematic review were published in 2002 and 2007.
Recruitment strategies that focus on increasing potential participants' awareness of the health problem being studied, its potential impact on their health, and their engagement in the learning process appeared to increase recruitment to clinical studies. Further trials of recruitment strategies that target engaging participants to increase their awareness of the health problems being studied and the potential impact on their health may confirm this hypothesis.
Please see later in the article for the Editors' Summary
Editors' Summary
Before any health care intervention—a treatment for a disease or a measure such as vaccination that is designed to prevent an illness—is adopted by the medical community, it undergoes exhaustive laboratory-based and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments or preventive methods, and test these interventions in animals. New interventions that look hopeful are then investigated in clinical trials—studies that test these interventions in people by following a strict trial protocol or action plan. Phase I trials test interventions in a few healthy volunteers or patients to evaluate their safety and to identify possible side effects. In phase II trials, a larger group of patients receives an intervention to evaluate its safety further and to get an initial idea of its effectiveness. In phase III trials, very large groups of patients (sometimes in excess of a thousand people) are randomly assigned to receive the new intervention or an established intervention or placebo (dummy intervention). These “randomized controlled trials” or “RCTs” provide the most reliable information about the effectiveness and safety of health care interventions.
Why Was This Study Done?
Patients who participate in clinical trials must fulfill the inclusion criteria laid down in the trial protocol and must be given information about the trial, its risks, and potential benefits before agreeing to participate (informed consent). Unfortunately, many RCTs struggle to enroll the number of patients specified in their trial protocol, which can reduce a trial's ability to measure the effect of a new intervention. Inadequate recruitment can also increase costs and, in the worst cases, prevent trial completion. Several strategies have been developed to improve recruitment but it is not clear which strategy works best. In this study, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) of “recruitment trials”—studies that have randomly divided potential RCT participants into groups, applied different strategies for recruitment to each group, and compared recruitment rates in the groups.
What Did the Researchers Do and Find?
The researchers identified 37 randomized trials of recruitment strategies into real and mock RCTs (where no actual trial occurred). In all, 18,812 people agreed to participate in an RCT in these recruitment trials out of at least 59,354 people approached. Some of these trials investigated novel strategies for recruitment, such as changes in how patients are randomized. Others looked at the effect of recruiter differences (for example, increased contact between the health care professionals doing the recruiting and the trial investigators), the effect of offering monetary incentives to participants, and the effect of giving more information about the trial to potential participants. Recruitment strategies that improved people's awareness of the health problem being studied—provision of an interactive computer program or a video about the health condition, attendance at an educational session, or inclusion of a health questionnaire in the recruitment process—improved recruitment rates, as did monetary incentives. Increasing patients' understanding about the trial process itself, recruiter differences, and alterations in consent design and randomization generally had no effect on recruitment rates although consent rates were higher when patients knew the treatment to which they had been randomly allocated before consenting. However, differential losses among the patients in different treatment groups in such nonblinded trials may jeopardize study findings.
What Do These Findings Mean?
These findings suggest that trial recruitment strategies that focus on increasing the awareness of potential participants of the health problem being studied and its possible effects on their health, and that engage potential participants in the trial process are likely to increase recruitment to RCTs. The accuracy of these findings depends on whether the researchers identified all the published research on recruitment strategies and on whether other research on recruitment strategies has been undertaken and not published that could alter these findings. Furthermore, because about half of the recruitment trials identified by the researchers were undertaken in the US, the successful strategies identified here might not be generalizable to other countries. Nevertheless, these recruitment strategies should now be investigated further to ensure that the future evaluation of new health care interventions is not hampered by poor recruitment into RCTs.
Additional Information
Please access these Web sites via the online version of this summary at
The Web site is a searchable register of federally and privately supported clinical trials in the US and around the world, providing information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials
The UK National Health Service Choices Web site has information for patients about clinical trials and medical research
The UK Medical Research Council Clinical Trials Units also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
The Australian Government's National Health and Medical Research Council has information about clinical trials
WHO International Clinical Trials Registry Platform aims to ensure that all trials are publicly accessible to those making health care decisions
The Star Child Health International Forum of Standards for Research is a resource center for pediatric clinical trial design, conduct, and reporting
PMCID: PMC2976724  PMID: 21085696
12.  ACCISS study rationale and design: activating collaborative cancer information service support for cervical cancer screening 
BMC Public Health  2009;9:444.
High-quality cancer information resources are available but underutilized by the public. Despite greater awareness of the National Cancer Institute's Cancer Information Service among low-income African Americans and Hispanics compared with Caucasians, actual Cancer Information Service usage is lower than expected, paralleling excess cancer-related morbidity and mortality for these subgroups. The proposed research examines how to connect the Cancer Information Service to low-income African-American and Hispanic women and their health care providers. The study will examine whether targeted physician mailing to women scheduled for colposcopy to follow up an abnormal Pap test can increase calls to the Cancer Information Service, enhance appropriate medical follow-up, and improve satisfaction with provider-patient communication.
The study will be conducted in two clinics in ethnically diverse low-income communities in Chicago. During the formative phase, patients and providers will provide input regarding materials planned for use in the experimental phase of the study. The experimental phase will use a two-group prospective randomized controlled trial design. African American and Hispanic women with an abnormal Pap test will be randomized to Usual Care (routine colposcopy reminder letter) or Intervention (reminder plus provider recommendation to call the Cancer Information Service and sample questions to ask). Primary outcomes will be: 1) calls to the Cancer Information Service; 2) timely medical follow-up, operationalized by whether the patient keeps her colposcopy appointment within six months of the abnormal Pap; and 3) patient satisfaction with provider-patient communication at follow-up.
The study examines the effectiveness of a feasible, sustainable, and culturally sensitive strategy to increase awareness and use of the Cancer Information Service among an underserved population. The goal of linking a public service (the Cancer Information Service) with real-life settings of practice (the clinics), and considering input from patients, providers, and Cancer Information Service staff, is to ensure that the intervention, if proven effective, can be incorporated into existing care systems and sustained. The approach to study design and planning is aimed at bridging the gap between research and practice/service.
Trial Registration
PMCID: PMC2790457  PMID: 19951443
13.  Selecting renal replacement therapies: what do African American and non-African American patients and their families think others should know? A mixed methods study 
BMC Nephrology  2013;14:9.
Little is known regarding the types of information African American and non-African American patients with chronic kidney disease (CKD) and their families need to inform renal replacement therapy (RRT) decisions.
In 20 structured group interviews, we elicited views of African American and non-African American patients with CKD and their families about factors that should be addressed in educational materials informing patients’ RRT selection decisions. We asked participants to select factors from a list and obtained their open-ended feedback.
Ten groups of patients (5 African American, 5 non-African American; total 68 individuals) and ten groups of family members (5 African American, 5 non-African American; total 62 individuals) participated. Patients and families had a range (none to extensive) of experiences with various RRTs. Patients identified morbidity or mortality, autonomy, treatment delivery, and symptoms as important factors to address. Family members identified similar factors but also cited the effects of RRT decisions on patients’ psychological well-being and finances. Views of African American and non-African American participants were largely similar.
Educational resources addressing the influence of RRT selection on patients’ morbidity and mortality, autonomy, treatment delivery, and symptoms could help patients and their families select RRT options closely aligned with their values. Including information about the influence of RRT selection on patients’ personal relationships and finances could enhance resources’ cultural relevance for African Americans.
PMCID: PMC3565884  PMID: 23317336
Decision-making; Renal replacement therapy; Family members; African American
14.  Depression in African-American patients with kidney disease. 
Journal of the National Medical Association  2002;94(8 Suppl):92S-103S.
There are few data on the epidemiology, consequences and treatment of depression in African-American patients with kidney disease in the US, even though such patients disproportionately bear the burden of this illness. This paper reviews data on the diagnosis and pathogenesis of depression and its consequences in patients with and without kidney disease, in addition to work on the epidemiology of depression in the African-American population and in the US End-stage Renal Disease (ESRD) program. African Americans are thought to have similar susceptibility to the development of depression as other populations in the US, but diminished access to care for this group of patients may be associated with differential outcomes. Data are presented from longitudinal studies of psychosocial outcomes in a population comprising primarily African-American patients with ESRD, and is reviewed the treatment of depression in patients with and without kidney disease. There are few studies of the management of depression that focus on minority populations. The authors agree with recommendations that treatment trials should include minority patients, patients with medical comorbidities, and the elderly, and assess function and quality of life as outcomes. The relationships between age, marital status and satisfaction, ethnicity, and perception of quality of life and depressive affect level and diagnosis of depression, and medical outcomes have not been determined in ESRD patients, or in African-American patients with ESRD. There are few studies of drugs for the treatment of depression in ESRD patients, and only one small randomized controlled trial. These have shown that therapy with selective serotonin reuptake inhibitors appears to be a safe treatment option for patients with ESRD. The long-term effectiveness of therapy, and its association with clinically important outcomes such as perception of quality of life, compliance, and survival have not been evaluated in ESRD patients. Also, therapeutic effectiveness and outcomes have not been assessed in minority populations with ESRD. These issues need to be addressed to optimize the management of depression in African Americans with kidney disease.
PMCID: PMC2594165  PMID: 12152919
15.  Study protocol for improving asthma outcomes through cross-cultural communication training for physicians: a randomized trial of physician training 
BMC Medical Education  2014;14:118.
Massive resources are expended every year on cross-cultural communication training for physicians. Such training is a focus of continuing medical education nationwide and is part of the curriculum of virtually every medical school in America. There is a pressing need for evidence regarding the effects on patients of cross-cultural communication training for physicians. There is a need to understand the added benefit of such training compared to more general communication. We know of no rigorous study that has assessed whether cross-cultural communication training for physicians results in better health outcomes for their patients. The current study aims to answer this question by enhancing the Physician Asthma Care Education (PACE) program to cross cultural communication (PACE Plus), and comparing the effect of the enhanced program to PACE on the health outcomes of African American and Latino/Hispanic children with asthma.
A three-arm randomized control trial is used to compare PACE Plus, PACE, and usual care. Both PACE and PACE Plus are delivered in two, two-hour sessions over a period of two weeks to 5–10 primary care physicians who treat African American and Latino/Hispanic children with asthma. One hundred twelve physicians and 1060 of their pediatric patients were recruited who self-identify as African American or Latino/Hispanic and experience persistent asthma. Physicians were randomized into receiving either the PACE Plus or PACE intervention or into the control group. The comparative effectiveness of PACE and PACE Plus on clinician’s therapeutic and communication practices with the family/patient, children’s urgent care use for asthma, asthma control, and quality of life, and parent/caretaker satisfaction with physician performance will be assessed. Data are collected via telephone survey and medical record review at baseline, 9 months following the intervention, and 21 months following the intervention.
This study aims to reduce disparities in asthma outcomes among African American and Latino/Hispanic children through cross-cultural communication training of their physicians and assessing the added value of this training compared to general communication. The results of this study will provide important information about the value of cross-cultural training in helping to address persistent racial disparities in outcomes.
Trial registration NCT01251523 December 1, 2010
PMCID: PMC4070340  PMID: 24935221
Asthma; Randomized controlled trials; Physicians; Communication; Health disparities
16.  Trial Publication after Registration in ClinicalTrials.Gov: A Cross-Sectional Analysis 
PLoS Medicine  2009;6(9):e1000144.
Joseph Ross and colleagues examine publication rates of clinical trials and find low rates of publication even following registration in
Background is a publicly accessible, Internet-based registry of clinical trials managed by the US National Library of Medicine that has the potential to address selective trial publication. Our objectives were to examine completeness of registration within and to determine the extent and correlates of selective publication.
Methods and Findings
We examined reporting of registration information among a cross-section of trials that had been registered at after December 31, 1999 and updated as having been completed by June 8, 2007, excluding phase I trials. We then determined publication status among a random 10% subsample by searching MEDLINE using a systematic protocol, after excluding trials completed after December 31, 2005 to allow at least 2 y for publication following completion. Among the full sample of completed trials (n = 7,515), nearly 100% reported all data elements mandated by, such as intervention and sponsorship. Optional data element reporting varied, with 53% reporting trial end date, 66% reporting primary outcome, and 87% reporting trial start date. Among the 10% subsample, less than half (311 of 677, 46%) of trials were published, among which 96 (31%) provided a citation within of a publication describing trial results. Trials primarily sponsored by industry (40%, 144 of 357) were less likely to be published when compared with nonindustry/nongovernment sponsored trials (56%, 110 of 198; p<0.001), but there was no significant difference when compared with government sponsored trials (47%, 57 of 122; p = 0.22). Among trials that reported an end date, 75 of 123 (61%) completed prior to 2004, 50 of 96 (52%) completed during 2004, and 62 of 149 (42%) completed during 2005 were published (p = 0.006).
Reporting of optional data elements varied and publication rates among completed trials registered within were low. Without greater attention to reporting of all data elements, the potential for to address selective publication of clinical trials will be limited.
Please see later in the article for the Editors' Summary
Editors' Summary
People assume that whenever they are ill, health care professionals will make sure they get the best available treatment. But how do clinicians know which treatment is most appropriate? In the past, clinicians used their own experience to make treatment decisions. Nowadays, they rely on evidence-based medicine—the systematic review and appraisal of the results of clinical trials, studies that investigate the efficacy and safety of medical interventions in people. However, evidence-based medicine can only be effective if all the results from clinical trials are published promptly in medical journals. Unfortunately, the results of trials in which a new drug did not perform better than existing drugs or in which it had unwanted side effects often remain unpublished or only appear in the public domain many years after the drug has been approved for clinical use by the US Food and Drug Administration (FDA) and other governmental bodies.
Why Was This Study Done?
The extent of this “selective” publication, which can impair evidence-based clinical practice, remains unclear but is thought to be substantial. In this study, the researchers investigate the problem of selective publication by systematically examining the extent of publication of the results of trials registered in, a Web-based registry of US and international clinical trials. was established in 2000 by the US National Library of Medicine in response to the 1997 FDA Modernization Act. This act required preregistration of all trials of new drugs to provide the public with information about trials in which they might be able to participate. Mandatory data elements for registration in initially included the trial's title, the condition studied in the trial, the trial design, and the intervention studied. In September 2007, the FDA Amendments Act expanded the mandatory requirements for registration in by making it necessary, for example, to report the trial start date and to report primary and secondary outcomes (the effect of the intervention on predefined clinical measurements) in the registry within 2 years of trial completion.
What Did the Researchers Do and Find?
The researchers identified 7,515 trials that were registered within after December 31, 1999 (excluding phase I, safety trials), and whose record indicated trial completion by June 8, 2007. Most of these trials reported all the mandatory data elements that were required by before the FDA Amendments Act but reporting of optional data elements was less complete. For example, only two-thirds of the trials reported their primary outcome. Next, the researchers randomly selected 10% of the trials and, after excluding trials whose completion date was after December 31, 2005 (to allow at least two years for publication), determined the publication status of this subsample by systematically searching MEDLINE (an online database of articles published in selected medical and scientific journals). Fewer than half of the trials in the subsample had been published, and the citation for only a third of these publications had been entered into Only 40% of industry-sponsored trials had been published compared to 56% of nonindustry/nongovernment-sponsored trials, a difference that is unlikely to have occurred by chance. Finally, 61% of trials with a completion date before 2004 had been published, but only 42% of trials completed during 2005 had been published.
What Do These Findings Mean?
These findings indicate that, over the period studied, critical trial information was not included in the registry. The FDA Amendments Act should remedy some of these shortcomings but only if the accuracy and completeness of the information in is carefully monitored. These findings also reveal that registration in does not guarantee that trial results will appear in a timely manner in the scientific literature. However, they do not address the reasons for selective publication (which may be, in part, because it is harder to publish negative results than positive results), and they are potentially limited by the methods used to discover whether trial results had been published. Nevertheless, these findings suggest that the FDA, trial sponsors, and the scientific community all need to make a firm commitment to minimize the selective publication of trial results to ensure that patients and clinicians have access to the information they need to make fully informed treatment decisions.
Additional Information
Please access these Web sites via the online version of this summary at
PLoS Medicine recently published two related articles on selected publication by Ida Sim and colleagues and by Lisa Bero and colleagues and an editorial discussing the FDA Amendments Act provides information about the US National Institutes of Health clinical trial registry, including background information about clinical trials, and a fact sheet detailing the requirements of the FDA Amendments Act 2007 for trial registration
The US Food and Drug Administration provides further information about drug approval in the US for consumers and health care professionals
PMCID: PMC2728480  PMID: 19901971
17.  Diabetes mellitus and hypertension: key risk factors for kidney disease. 
The incidence of end-stage renal disease (ESRD) in the US is rising at an alarming rate, with the largest increase among African-American populations. The key risk factors for kidney disease are hypertension and diabetes, which are both becoming more prevalent in the US, and particularly in African Americans. Although African Americans make up 12.6% of the US population, the incidence of diabetes-related ESRD is four times higher than for whites, and the prevalence of ESRD due to hypertension is twice that of white patients. Approximately 30 to 40% of all patients with diabetes will develop nephropathy and many will progress to ESRD, necessitating dialysis or kidney transplantation. Recent studies in patients with type 2 diabetes indicate a significant delay in progression or development of diabetic nephropathy following blockade of the renin-angiotensin-aldosterone system with the use of angiotensin receptor antagonists. Early intervention in patients with hypertension is necessary to prevent kidney damage, and data from the African American Study of Kidney Disease and Hypertension suggest that angiotensin-converting enzyme inhibitors are effective in this population. Although African-American patients receiving hemodialysis appear to have increased survival compared with whites, racial factors and poor access to medical care contribute to the increased risk of kidney disease in minorities. A concerted effort is necessary to raise awareness in minority populations and provide strategies for prevention and early treatment thereby attenuating the increasing prevalence of kidney failure in these groups.
PMCID: PMC2594170  PMID: 12152917
18.  A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes 
PLoS Medicine  2011;8(3):e1000422.
Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
Methods and Findings
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49–1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21–0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65–1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53–1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
Trial registration
ClinicalTrials gov NCT00273780
Please see later in the article for the Editors' Summary
Editors' Summary
Adherence to HIV treatment programs in poor countries has long been cited as an important public health concern, especially as poor adherence can lead to drug resistance and inadequate treatment of HIV. However, two factors have recently cast doubt on the poor adherence problem: (1) recent studies have shown that adherence is high in African HIV treatment programs and often better than in Western HIV clinics. For example, in a meta-analysis of 27 cohorts from 12 African countries, adequate adherence was noted in 77% of subjects compared to only 55% among 31 North America cohorts; (2) choice of antiretroviral regimens may impact on the development of antiretroviral resistance. In poor countries, most antiretroviral regimens contain non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine or efavirenz, which remain in the patient's circulation for weeks after single-dose administration. This situation means that such patients may not experience antiretroviral resistance unless they drop below 80% adherence—contrary to the more stringent 95% plus adherence levels needed to prevent resistance in regimens based on unboosted protease inhibitors—ultimately, off-setting some treatment lapses in resource-limited settings where NNRTI-based regimens are widely used.
Why Was This Study Done?
Given that adherence may not be as crucial an issue as previously thought, antiretroviral treatment programs in sub-Saharan Africa may be spending scarce resources to promote adherence to the detriment of some potentially more effective elements of HIV treatment and management programs. Although many treatment programs currently include adherence interventions, there is limited quality evidence that any of these methods improve long-term adherence to HIV treatment. Therefore, it is necessary to identify adherence interventions that are inexpensive and proven to be effective in resource-limited settings. As adherence counseling is already widely implemented in African HIV treatment programs and inexpensive alarm devices are thought to also improve compliance, the researchers compared the impact of adherence counseling and the use of an alarm device on adherence and biological outcomes in patients enrolled in HIV programs in rural Kenya.
What Did the Researchers Do and Find?
The researchers enrolled 400 eligible patients (newly diagnosed with HIV, never before taken antiretroviral therapy, aged over 18 years) to four arms: (1) adherence counseling alone; (2) alarm device alone; (3) both adherence counseling and alarm device together; and (4) a control group that received neither adherence counseling nor alarm device. The patients had blood taken to record baseline CD4 count and HIV-1 RNA and after starting HIV treatment, returned to the study clinic every month with their pill bottles for the study pharmacist to count and recorded the number of pills remaining in the bottle, and to receive another prescription. Patients were followed up for 18 months and had their CD4 count and HIV-1 RNA measured at 6, 12, and 18 months.
Patients receiving adherence counseling were 29% less likely to experience poor adherence compared to those who received no counseling. Furthermore, those receiving intensive early adherence counseling were 59% less likely to experience viral failure. However, there was no significant difference in mortality or significant differences in CD4 counts at 18 months follow-up between those who received counseling and those who did not. There were no significant differences in adherence, time to viral failure, mortality, or CD4 counts in patients who received alarm devices compared to those who did not.
What Do These Findings Mean?
The results of this study suggest that intensive adherence counseling around the time of HIV treatment initiation significantly reduces poor adherence and virologic treatment failure, while using an alarm device has no effect. Therefore, investment in careful counseling based on individual needs at the onset of HIV treatment initiation, appears to have sustained benefit, possibly through strengthening the relationship between the health care provider and patient through communication, education, and trust. Interactive adherence counseling supports the bond between the clinic and the patient and may result in fewer patients needing to switch to expensive second-line medications and, possibly, may help to decrease the spread of resistant HIV. These findings define an adherence counseling protocol that is effective and are highly relevant to other HIV clinics caring for large numbers of patients in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at
UNAIDS provides information about HIV treatment strategies
The American Public Health Association has information about adherence to HIV treatment regimens
The US Department of Health and Human Services has information for patients about adherence to HIV treatment
The World Health Organization provides information about HIV treatment pharmacovigilance
PMCID: PMC3046986  PMID: 21390262
19.  The spino-bulbar-cerebellar pathway: organization and neurochemical properties of spinal cells that project to the lateral reticular nucleus in the rat 
In addition to classical spinocerebellar pathways, the cerebellum receives information from the spinal cord indirectly via spino-bulbar-cerebellar systems. One of the structures in this pathway is the lateral reticular nucleus (LRt). We performed series of experiments to investigate the organization and neurotransmitter content of spinoreticular tract (SRT) neurons in the lumbar spinal cord that project to the LRt. Three rats received injections of the b subunit of Cholera toxin (CTb) or Fluorogold (FG) within the left and right LRt. The majority of SRT cells (56–61%) were found within the contralateral medial intermediate gray matter where small numbers (7–10%) of double-labeled cells were also present on both sides of the cord. Six rats received unilateral spinal injections of CTb to label spinal projections to the LRt. Injections of FG were made also into the anterior lobe of the cerebellum to label LRt pre-cerebellar neurons. Terminals were found mainly ipsilateral to spinal injection sites within the central and ventrolateral regions of the LRt. Immunocytochemical analysis of SRT terminals revealed that the majority (75%) were contained vesicular glutamate transporter 2 but a minority (20%) contained the vesicular GABA transporter. The inhibitory subpopulation was found to be GABAergic, glycinergic, or contained both transmitters. Inhibitory and excitatory terminals were present within overlapping regions of the nucleus. Most CTb terminals contacting LRt pre-cerebellar neurons were excitatory (80%) whereas a minority were inhibitory and most cells (88%) received contacts from both inhibitory and excitatory terminals. This study shows that SRT axons in the LRt have the capacity to exert direct excitatory and inhibitory actions on LRt pre-cerebellar neurons. Thus spinal cord input has the capacity to facilitate or depress the activity of individual LRt cells which in turn adjust activity in the cerebellum to produce coordinated motor behaviors.
PMCID: PMC4303139  PMID: 25657619
spinal cord; motor control; cerebellum; neurotransmitters; neuroanatomy
20.  Rare Variants Detection with Kernel Machine Learning Based on Likelihood Ratio Test 
PLoS ONE  2014;9(3):e93355.
This paper mainly utilizes likelihood-based tests to detect rare variants associated with a continuous phenotype under the framework of kernel machine learning. Both the likelihood ratio test (LRT) and the restricted likelihood ratio test (ReLRT) are investigated. The relationship between the kernel machine learning and the mixed effects model is discussed. By using the eigenvalue representation of LRT and ReLRT, their exact finite sample distributions are obtained in a simulation manner. Numerical studies are performed to evaluate the performance of the proposed approaches under the contexts of standard mixed effects model and kernel machine learning. The results have shown that the LRT and ReLRT can control the type I error correctly at the given α level. The LRT and ReLRT consistently outperform the SKAT, regardless of the sample size and the proportion of the negative causal rare variants, and suffer from fewer power reductions compared to the SKAT when both positive and negative effects of rare variants are present. The LRT and ReLRT performed under the context of kernel machine learning have slightly higher powers than those performed under the context of standard mixed effects model. We use the Genetic Analysis Workshop 17 exome sequencing SNP data as an illustrative example. Some interesting results are observed from the analysis. Finally, we give the discussion.
PMCID: PMC3968153  PMID: 24675868
21.  Determining electrically evoked compound action potential thresholds: A comparison of computer versus human analysis methods 
Ear and hearing  2013;34(1):96-109.
Current cochlear implants (CIs) have telemetry capabilities for measuring the electrically evoked compound action potential (ECAP). Neural Response Telemetry (NRT™; Cochlear) and Neural Response Imaging (NRI; Advanced Bionics [AB]) can measure ECAP responses across a range of stimulus levels to obtain an amplitude growth function. Software-specific algorithms automatically mark the leading negative peak, N1, and the following positive peak/plateau, P2, and apply linear regression to estimate ECAP threshold. Alternatively, clinicians may apply expert judgments to modify the peak markers placed by the software algorithms, and/or use visual detection to identify the lowest level yielding a measurable ECAP response. The goals of this study were to: (1) assess the variability between human and computer decisions for (a) marking N1 and P2, and (b) determination of linear regression threshold (LRT) and visual detection threshold (VDT); and (2) compare LRT and VDT methods within and across human and computer decision methods.
ECAP amplitude growth functions were measured for three electrodes in each of 20 ears (10 Cochlear Nucleus® 24RE/CI512, and 10 AB CII/90K). LRT, defined as the current level yielding an ECAP with zero amplitude, was calculated for both computer- (C-LRT) and human-picked peaks (H-LRT). VDT, defined as the lowest level resulting in a measurable ECAP response, was also calculated for both computer- (C-VDT) and human-picked peaks (H-VDT). Because NRI assigns peak markers to all waveforms but does not include waveforms with amplitudes less than 20 μV in its regression calculation, C-VDT for AB subjects was defined as the lowest current level yielding an amplitude ≥20 μV.
Overall, there were significant correlations between human and computer decisions for peak-marker placement, LRT, and VDT for both manufacturers (r = 0.78 to 1.00, p < 0.001). For Cochlear devices, LRT and VDT correlated equally well for both computer- and human-picked peaks (r = 0.98 to 0.99, p < 0.001), which likely reflects the well-defined NRT algorithm and the lower noise floor in the 24RE and CI512 devices. For AB devices, correlations between LRT and VDT for both peak-picker methods were weaker than for Cochlear devices (r = 0.69 to 0.85, p < 0.001), which likely reflect the higher noise floor of the system. Disagreement between computer and human decisions regarding the presence of an ECAP response occurred for 5.0 % of traces for Cochlear devices and 2.1 % of traces for AB devices.
Results indicate that human and computer peak-picking methods can be used with similar accuracy for both Cochlear and AB devices. Either C-VDT or C-LRT can be used with equal confidence for Cochlear 24RE and CI512 recipients because both methods are strongly correlated with human decisions. However for AB devices, greater variability exists between different threshold determination methods. This finding should be considered in the context of using ECAP measures to assist with programming CIs.
PMCID: PMC3511653  PMID: 22885406
cochlear implant; electrically evoked compound action potential; threshold; Neural Response Telemetry; Neural Response Imaging
22.  Study protocol for Women of Color and Asthma Control: A randomized controlled trial of an asthma-management intervention for African American women 
BMC Public Health  2012;12:76.
Among adults in the United States, asthma prevalence is disproportionately high among African American women; this group also experiences the highest levels of asthma-linked mortality and asthma-related health care utilization. Factors linked to biological sex (e.g., hormonal fluctuations), gender roles (e.g., exposure to certain triggers) and race (e.g., inadequate access to care) all contribute to the excess asthma burden in this group, and also shape the context within which African American women manage their condition. No prior interventions for improving asthma self-management have specifically targeted this vulnerable group of asthma patients. The current study aims to evaluate the efficacy of a culturally- and gender-relevant asthma-management intervention among African American women.
A randomized controlled trial will be used to compare a five-session asthma-management intervention with usual care. This intervention is delivered over the telephone by a trained health educator. Intervention content is informed by the principles of self-regulation for disease management, and all program activities and materials are designed to be responsive to the specific needs of African American women. We will recruit 420 female participants who self-identify as African American, and who have seen a clinician for persistent asthma in the last year. Half of these will receive the intervention. The primary outcomes, upon which the target sample size is based, are number of asthma-related emergency department visits and overnight hospitalizations in the last 12 months. We will also assess the effect of the intervention on asthma symptoms and asthma-related quality of life. Data will be collected via telephone survey and medical record review at baseline, and 12 and 24 months from baseline.
We seek to decrease asthma-related health care utilization and improve asthma-related quality of life in African American women with asthma, by offering them a culturally- and gender-relevant program to enhance asthma management. The results of this study will provide important information about the feasibility and value of this program in helping to address persistent racial and gender disparities in asthma outcomes.
Trial Registration NCT01117805
PMCID: PMC3317437  PMID: 22272780
Asthma; randomized controlled trials; women; African Americans; chronic disease management; self-regulation; behavioral interventions
23.  Combining an Evolution-guided Clustering Algorithm and Haplotype-based LRT in Family Association Studies 
BMC Genetics  2011;12:48.
With the completion of the international HapMap project, many studies have been conducted to investigate the association between complex diseases and haplotype variants. Such haplotype-based association studies, however, often face two difficulties; one is the large number of haplotype configurations in the chromosome region under study, and the other is the ambiguity in haplotype phase when only genotype data are observed. The latter complexity may be handled based on an EM algorithm with family data incorporated, whereas the former can be more problematic, especially when haplotypes of rare frequencies are involved. Here based on family data we propose to cluster long haplotypes of linked SNPs in a biological sense, so that the number of haplotypes can be reduced and the power of statistical tests of association can be increased.
In this paper we employ family genotype data and combine a clustering scheme with a likelihood ratio statistic to test the association between quantitative phenotypes and haplotype variants. Haplotypes are first grouped based on their evolutionary closeness to establish a set containing core haplotypes. Then, we construct for each family the transmission and non-transmission phase in terms of these core haplotypes, taking into account simultaneously the phase ambiguity as weights. The likelihood ratio test (LRT) is next conducted with these weighted and clustered haplotypes to test for association with disease. This combination of evolution-guided haplotype clustering and weighted assignment in LRT is able, via its core-coding system, to incorporate into analysis both haplotype phase ambiguity and transmission uncertainty. Simulation studies show that this proposed procedure is more informative and powerful than three family-based association tests, FAMHAP, FBAT, and an LRT with a group consisting exclusively of rare haplotypes.
The proposed procedure takes into account the uncertainty in phase determination and in transmission, utilizes the evolutionary information contained in haplotypes, reduces the dimension in haplotype space and the degrees of freedom in tests, and performs better in association studies. This evolution-guided clustering procedure is particularly useful for long haplotypes containing linked SNPs, and is applicable to other haplotype-based association tests. This procedure is now implemented in R and is free for download.
PMCID: PMC3118131  PMID: 21592403
24.  The Effect of Light Rail Transit on Body Mass Index and Physical Activity 
The built environment can constrain or facilitate physical activity. Most studies of the health consequences of the built environment suffer from problems of selection bias associated with confounding effects of residential choice and transportation decisions.
To examine the cross-sectional associations between objective and perceived measures of the built environment, BMI, obesity (BMI>30 kg/m2), and meeting weekly recommended physical activity (RPA) levels through walking and vigorous exercise. To assess effect of using light rail transit system (LRT) on changes in BMI, obesity, and meeting weekly RPA levels.
Data were collected on individuals before (July 2006–February of 2007) and after (March 2008–July 2008) completion of a light rail system in Charlotte, NC. BMI, obesity, and physical activity levels were calculated for a comparison of these factors pre- and post-LRT construction. A propensity score weighting approach adjusted for differences in baseline characteristics among LRT and non-LRT users. Data were analyzed in 2009.
More positive perceptions of one’s neighborhood at baseline were associated with a −0.36 (p<.05) lower BMI, 15% lower odds (95% CI=0.77, 0.94) of obesity, 9% higher odds (95% CI = 0.99, 1.20) of meeting weekly RPA through walking, and 11% higher odds (95% CI= 1.01, 1.22) of meeting RPA levels of vigorous exercise. The use of light rail transit to commute to work was associated with an average −1.18 reduction in BMI (p<0.05) and an 81% reduced odds (95% CI= 0.04, 0.92) of becoming obese over time.
The results of this study suggest that improving neighborhood environments and increasing the public’s use of LRT systems could provide improvements in health outcomes for millions of individuals.
PMCID: PMC2919301  PMID: 20621257
25.  Evidence for the Selective Reporting of Analyses and Discrepancies in Clinical Trials: A Systematic Review of Cohort Studies of Clinical Trials 
PLoS Medicine  2014;11(6):e1001666.
In a systematic review of cohort studies, Kerry Dwan and colleagues examine the evidence for selective reporting and discrepancies in analyses between journal publications and other documents for clinical trials.
Please see later in the article for the Editors' Summary
Most publications about selective reporting in clinical trials have focussed on outcomes. However, selective reporting of analyses for a given outcome may also affect the validity of findings. If analyses are selected on the basis of the results, reporting bias may occur. The aims of this study were to review and summarise the evidence from empirical cohort studies that assessed discrepant or selective reporting of analyses in randomised controlled trials (RCTs).
Methods and Findings
A systematic review was conducted and included cohort studies that assessed any aspect of the reporting of analyses of RCTs by comparing different trial documents, e.g., protocol compared to trial report, or different sections within a trial publication. The Cochrane Methodology Register, Medline (Ovid), PsycInfo (Ovid), and PubMed were searched on 5 February 2014. Two authors independently selected studies, performed data extraction, and assessed the methodological quality of the eligible studies. Twenty-two studies (containing 3,140 RCTs) published between 2000 and 2013 were included. Twenty-two studies reported on discrepancies between information given in different sources. Discrepancies were found in statistical analyses (eight studies), composite outcomes (one study), the handling of missing data (three studies), unadjusted versus adjusted analyses (three studies), handling of continuous data (three studies), and subgroup analyses (12 studies). Discrepancy rates varied, ranging from 7% (3/42) to 88% (7/8) in statistical analyses, 46% (36/79) to 82% (23/28) in adjusted versus unadjusted analyses, and 61% (11/18) to 100% (25/25) in subgroup analyses. This review is limited in that none of the included studies investigated the evidence for bias resulting from selective reporting of analyses. It was not possible to combine studies to provide overall summary estimates, and so the results of studies are discussed narratively.
Discrepancies in analyses between publications and other study documentation were common, but reasons for these discrepancies were not discussed in the trial reports. To ensure transparency, protocols and statistical analysis plans need to be published, and investigators should adhere to these or explain discrepancies.
Please see later in the article for the Editors' Summary
Editors' Summary
In the past, clinicians relied on their own experience when choosing the best treatment for their patients. Nowadays, they turn to evidence-based medicine—the systematic review and appraisal of trials, studies that investigate the benefits and harms of medical treatments in patients. However, evidence-based medicine can guide clinicians only if all the results from clinical trials are published in an unbiased and timely manner. Unfortunately, the results of trials in which a new drug performs better than existing drugs are more likely to be published than those in which the new drug performs badly or has unwanted side effects (publication bias). Moreover, trial outcomes that support the use of a new treatment are more likely to be published than those that do not support its use (outcome reporting bias). Recent initiatives—such as making registration of clinical trials in a trial registry (for example, a prerequisite for publication in medical journals—aim to prevent these biases, which pose a threat to informed medical decision-making.
Why Was This Study Done?
Selective reporting of analyses of outcomes may also affect the validity of clinical trial findings. Sometimes, for example, a trial publication will include a per protocol analysis (which considers only the outcomes of patients who received their assigned treatment) rather than a pre-planned intention-to-treat analysis (which considers the outcomes of all the patients regardless of whether they received their assigned treatment). If the decision to publish the per protocol analysis is based on the results of this analysis being more favorable than those of the intention-to-treat analysis (which more closely resembles “real” life), then “analysis reporting bias” has occurred. In this systematic review, the researchers investigate the selective reporting of analyses and discrepancies in randomized controlled trials (RCTs) by reviewing published studies that assessed selective reporting of analyses in groups (cohorts) of RCTs and discrepancies in analyses of RCTs between different sources (for example, between the protocol in a trial registry and the journal publication) or different sections of a source. A systematic review uses predefined criteria to identify all the research on a given topic.
What Did the Researchers Do and Find?
The researchers identified 22 cohort studies (containing 3,140 RCTs) that were eligible for inclusion in their systematic review. All of these studies reported on discrepancies between the information provided by the RCTs in different places, but none investigated the evidence for analysis reporting bias. Several of the cohort studies reported, for example, that there were discrepancies in the statistical analyses included in the different documents associated with the RCTs included in their analysis. Other types of discrepancies reported by the cohort studies included discrepancies in the reporting of composite outcomes (an outcome in which multiple end points are combined) and in the reporting of subgroup analyses (investigations of outcomes in subgroups of patients that should be predefined in the trial protocol to avoid bias). Discrepancy rates varied among the RCTs according to the types of analyses and cohort studies considered. Thus, whereas in one cohort study discrepancies were present in the statistical test used for the analysis of the primary outcome in only 7% of the included studies, they were present in the subgroup analyses of all the included studies.
What Do These Findings Mean?
These findings indicate that discrepancies in analyses between publications and other study documents such as protocols in trial registries are common. The reasons for these discrepancies in analyses were not discussed in trial reports but may be the result of reporting bias, errors, or legitimate departures from a pre-specified protocol. For example, a statistical analysis that is not specified in the trial protocol may sometimes appear in a publication because the journal requested its inclusion as a condition of publication. The researchers suggest that it may be impossible for systematic reviewers to distinguish between these possibilities simply by looking at the source documentation. Instead, they suggest, it may be necessary for reviewers to contact the trial authors. However, to make selective reporting of analyses more easily detectable, they suggest that protocols and analysis plans should be published and that investigators should be required to stick to these plans or explain any discrepancies when they publish their trial results. Together with other initiatives, this approach should help improve the quality of evidence-based medicine and, as a result, the treatment of patients.
Additional Information
Please access these websites via the online version of this summary at
Wikipedia has pages on evidence-based medicine, on systematic reviews, and on publication bias (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) provides information about the US National Institutes of Health clinical trial registry, including background information about clinical trials
The Cochrane Collaboration is a global independent network of health practitioners, researchers, patient advocates, and others that aims to promote evidence-informed health decision-making by producing high-quality, relevant, accessible systematic reviews and other synthesized research evidence; the Cochrane Handbook for Systematic Reviews of Interventions describes the preparation of systematic reviews in detail
PLOS Medicine recently launched a Reporting Guidelines Collection, an open-access collection of reporting guidelines, commentary, and related research on guidelines from across PLOS journals that aims to help advance the efficiency, effectiveness, and equitability of the dissemination of biomedical information
PMCID: PMC4068996  PMID: 24959719

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