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1.  Geographic Variability in Human Papillomavirus Vaccination Among U.S. Young Women 
Background
Little information is available on geographic disparity of human papillomavirus (HPV) vaccination among women aged 18–26 years in the U.S. Genital HPV is the most common sexually transmitted infection in the U.S. Persistent HPV infection with oncogenic types can cause cervical cancer.
Purpose
This study utilized data collected from the 2010 National Health Interview Survey (NHIS). It identified geographic variability and other factors contributing to the disparities in HPV vaccine series initiation in a nationally representative sample of women aged 18–26 years.
Methods
The study utilized data collected from 1867 women who participated in the Cancer Control Module Supplement of the 2012 NHIS. A multivariable logistic regression model was used to assess characteristics associated with initiation of the HPV series. Analyses were performed in 2012.
Results
After adjusting for other characteristics, women living in the West and North Central/Midwest had 54% and 20% greater odds of initiating the HPV series, respectively, compared with those living in the Northeast. Other factors associated with HPV series initiation were: younger age, Hispanic background, being single/never married, childlessness, a history of HPV, and current alcohol use. Factors correlated with failure to initiate the HPV series were: not having insurance, living below the 200% poverty level, not being a high school graduate, not currently using hormone-based birth control, most recent Pap >1 year ago, no regular provider, last clinic visit ≥12 months ago, and never having received the hepatitis B vaccine
Conclusions
Results demonstrate disparity in HPV vaccine uptake by region of residence in the U.S. among young women. Further research is needed to understand the factors contributing to this geographic disparity. Evaluation of vaccination policies and practices associated with higher coverage regions might help characterize effective methods to improve HPV vaccination among women aged 18–26 years.
doi:10.1016/j.amepre.2012.09.061
PMCID: PMC3552249  PMID: 23332332
2.  The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells 
PLoS ONE  2013;8(12):e82860.
Background/Purpose
Acyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR.
Methodology/Principal Findings
NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5′-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively).
Conclusions/Significance
The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in this study will be important targets of the anti-cancer activity of ACR.
doi:10.1371/journal.pone.0082860
PMCID: PMC3871542  PMID: 24376596
3.  Falls in the community: state of the science 
Falls and fall-related injuries among older community-dwelling adults continue to be a major health concern in the US. Falls are the leading cause of disability and trauma-related death in persons over 65 years of age. This article discusses current approaches in community fall management and challenges with these approaches, and offers some insight for community providers regarding this issue.
doi:10.2147/CIA.S44996
PMCID: PMC3681268  PMID: 23776331
community falls; patient care planning; risk assessment; aged
4.  A most stubborn bias: No adjustment method fully resolves confounding by indication in observational studies 
Objective
To evaluate the effectiveness of methods that control for confounding by indication, we compared breast cancer recurrence rates among women receiving adjuvant chemotherapy versus those who did not.
Study Design and Setting
In a medical record review-based study of breast cancer treatment in older women (n=1798) diagnosed 1990-1994, our crude analysis suggested adjuvant chemotherapy was positively associated with recurrence [hazard ratio (HR)=2.6 (95% confidence interval (CI)=1.9, 3.5)]. We expected a protective effect, so postulated that the crude association was confounded by indications for chemotherapy. We attempted to adjust for this confounding by restriction, multivariable regression, propensity scores [PS], and instrumental variable [IV] methods.
Results
After restricting to women at high-risk for recurrence (n=946), chemotherapy was not associated with recurrence [HR=1.1 (95% CI=0.7, 1.6)] using multivariable regression. PS adjustment yielded similar results [HR=1.3 (95% CI=0.8, 2.0)]. The IV-like method yielded a protective estimate [HR=0.9; (95% CI=0.2, 4.3)]; however imbalances of measured factors across levels of the IV suggested residual confounding.
Conclusion
Conventional methods do not control for unmeasured factors, which often remain important when addressing confounding by indication. PS and IV analysis methods can be useful under specific situations, but neither method adequately controlled confounding by indication in this study.
doi:10.1016/j.jclinepi.2009.03.001
PMCID: PMC2789188  PMID: 19457638
confounding by indication; propensity score; instrumental variable; non-randomized studies; breast cancer; chemotherapy
5.  Breast cancer recurrence in older women five to ten years after diagnosis 
Little is known about the risk of recurrence more than five years after diagnosis among older breast cancer survivors. A community-based population of women ≥65 years diagnosed with early stage breast cancer who survived disease-free for five years was followed for five additional years or until a diagnosis of breast cancer recurrence, second primary, death or loss to follow-up. These five-year disease-free survivors (N=1277) had primary breast cancers that were node negative (77%) and estrogen receptor positive or unknown (86%). Five percent (N=61) developed a recurrence between five and ten years after diagnosis; 25% local, 9.8% regional, and 66% distant. Women who were node positive (Hazard Ratio [HR]=3.9; 95% Confidence Interval [CI]=1.5,10); had poorly differentiated tumors (HR=2.5; 95% CI=0.9, 6.6); or who received breast conserving surgery without radiation therapy (HR=2.4; 95%CI=1.0, 5.8) had higher recurrence rates compared with node negative, well differentiated, and receipt of mastectomy, respectively. Not receiving adjuvant tamoxifen, compared with receiving adjuvant tamoxifen, was also positively associated with late recurrence among women with estrogen receptor positive/unknown tumors. While relatively few women experience a late recurrence, most recurrences present as advanced disease, which is difficult to treat in older women. This study of late recurrence emphasizes that the risk, although small, is not negligible even in this group at high risk for death due to competing causes.
doi:10.1158/1055-9965.EPI-09-0607
PMCID: PMC2784208  PMID: 19843686
Breast cancer; recurrence; primary therapy; cancer survivorship; older women
6.  Referral, Receipt, and Completion of Chemotherapy in Patients With Early-Stage Breast Cancer Older Than 65 Years and at High Risk of Breast Cancer Recurrence 
Journal of Clinical Oncology  2009;27(27):4508-4514.
Purpose
Some women with early-stage breast cancer are at higher risk of recurrence and can benefit from chemotherapy. We describe patterns of referral, receipt, and completion of chemotherapy among older women at high risk of recurrence.
Patients and Methods
A total of 2,124 women age 65 years or older who were diagnosed with early-stage breast cancer between 1990 and 1994 and 1996 to 1999 were included; 1,090 of these were at high risk of recurrence. We reviewed medical records to categorize chemotherapy outcomes as follows: did not discuss or were not referred to a medical oncologist (n = 133); discussed and/or referred to a medical oncologist but received no chemotherapy (n = 742); received an incomplete chemotherapy course (n = 29), or received a completed chemotherapy course (n = 186).
Results
Overall, 19.7% of high-risk women received any chemotherapy, and 86.5% of these women completed their chemotherapy courses. Just greater than 10% of high-risk women did not have a discussion about chemotherapy as part of breast cancer treatment documented in the medical record; these women also received fewer diagnostic assessments of their initial tumors.
Conclusion
Individuals who receive chemotherapy for early-stage breast cancer are a select subgroup of patients at high risk of recurrence. This study identifies characteristics of women who were referred for and who received chemotherapy, and this study plays an important role in understanding generalizability of studies that examine chemotherapy treatment effectiveness. Outcomes after breast cancer could continue to be improved with increased receipt of chemotherapy among older women at high risk of breast cancer recurrence.
doi:10.1200/JCO.2008.18.3459
PMCID: PMC2754903  PMID: 19687341
7.  Delayed radiotherapy for breast cancer patients in integrated delivery systems 
Objective
To identify factors associated with delayed radiotherapy (RT) in older women with early stage breast cancer.
Methods
We studied 541 women ages 65+ diagnosed with early stage breast cancer from 1990–1994 at five integrated healthcare delivery systems and treated with breast conserving surgery and RT, but not chemotherapy. We examined whether demographic, tumor, or treatment characteristics were associated with RT delays of >8 weeks post-surgery using chi-square tests and multivariable logistic regression.
Results
Seventy-six women (14%) had delayed RT, with a median delay of 14 weeks. Non-white and Hispanic women were much more likely than White women to have delayed RT (OR=3.3, 95%CI: 1.7, 10) in multivariable analyses that controlled for demographic and clinical variables.
Conclusions
Of women receiving BCS and radiation in this cohort, 14% experienced delayed RT, even though they had insurance and access to care in integrated delivery systems. Women receiving delayed care were more likely to be non-White and Hispanic. Timely RT should be facilitated through physician and patient education, navigation, and notification programs to improve quality of care. Future research should examine modifiable barriers to RT timeliness and whether delays impact long-term outcomes.
PMCID: PMC2916649  PMID: 19895182
breast cancer; radiotherapy; socioeconomic status; integrated delivery system
8.  Potential misinterpretations caused by collapsing upper categories of comorbidity indices: An illustration from a cohort of older breast cancer survivors 
Clinical epidemiology  2009;1:93-100.
Background:
Comorbidity indices summarize complex medical histories into concise ordinal scales, facilitating stratification and regression in epidemiologic analyses. Low subject prevalence in the highest strata of a comorbidity index often prompts combination of upper categories into a single stratum (‘collapsing’).
Objective:
We use data from a breast cancer cohort to illustrate potential inferential errors resulting from collapsing a comorbidity index.
Methods:
Starting from a full index (0, 1, 2, 3, and ≥4 comorbidities), we sequentially collapsed upper categories to yield three collapsed categorizations. The full and collapsed categorizations were applied to analyses of (1) the association between comorbidity and all-cause mortality, wherein comorbidity was the exposure; (2) the association between older age and all-cause mortality, wherein comorbidity was a candidate confounder or effect modifier.
Results:
Collapsing the index attenuated the association between comorbidity and mortality (risk ratio, full versus dichotomized categorization: 4.6 vs 2.1), reduced the apparent magnitude of confounding by comorbidity of the age/mortality association (relative risk due to confounding, full versus dichotomized categorization: 1.14 vs 1.09), and obscured modification of the association between age and mortality on both the absolute and relative scales.
Conclusions:
Collapsing categories of a comorbidity index can alter inferences concerning comorbidity as an exposure, confounder and effect modifier.
PMCID: PMC2943165  PMID: 20865090
epidemiology; breast neoplasms; comorbidity; confounding factors (epidemiologic); bias (epidemiologic); statistical models
9.  Identification and characteristics of vaccine refusers 
BMC Pediatrics  2009;9:18.
Background
This study evaluated the utility of immunization registries in identifying vaccine refusals among children. Among refusers, we studied their socioeconomic characteristics and health care utilization patterns.
Methods
Medical records were reviewed to validate refusal status in the immunization registries of two health plans. Racial, education, and income characteristics of children claiming refusal were collected based on the census tract of each child. Health care utilization was identified using both electronic medical record and insurance claims. Within the immunization registries of two HMOs in the study, some providers use refusal and medical contraindication interchangeably, and some providers tend to always use "ever refusal." Therefore, we combined medical contraindication and refusal together and treated them all as "refusal" in this study.
Results
The immunization registry, compared to chart review, had negative predictive values of 85–92% and 90–97% for 2- and 6-year olds, and positive predictive values of only 52–74% and 59–62% to identify vaccine refusals. Refusers were more likely to reside in well-educated, higher income areas than non-refusers. Refusers had not opted out of health care system and continued, although less frequently for the age 2 and under group, to use services.
Conclusion
Without enhancements to immunization registries, identifying children with immunization refusal would be time consuming. Since communities where refusers live are well educated, interventions should target these communities to communicate vaccine adverse events and consequences of vaccine preventable diseases.
doi:10.1186/1471-2431-9-18
PMCID: PMC2667392  PMID: 19261196
10.  Under Utilization of Surveillance Mammography among Older Breast Cancer Survivors 
Background
Annual surveillance mammography is recommended for follow-up of women with a history of breast cancer. We examined surveillance mammography among breast cancer survivors who were enrolled in integrated healthcare systems.
Methods
Women in this study were 65 or older when diagnosed with early stage invasive breast cancer (N = 1,762). We assessed mammography use during 4 years of follow-up, using generalized estimating equations to account for repeated measurements.
Results
Eighty-two percent had mammograms during the first year after treatment; the percentage declined to 68.5% in the fourth year of follow-up. Controlling for age and comorbidity, women who were at higher risk of recurrence by being diagnosed at stage II or receiving breast-conserving surgery (BCS) without radiation therapy were less likely to have yearly mammograms (compared to stage I, odds ratio [OR] for stage IIA 0.72, confidence interval [CI] 0.59, 0.87, OR for stage IIB 0.75, CI 0.57, 1.0; compared to BCS with radiation, OR 0.58, CI 0.43, 0.77). Women with visits to a breast cancer surgeon or oncologist were more likely to receive mammograms (OR for breast cancer surgeon 6.0, CI 4.9, 7.4, OR for oncologist 7.4, CI 6.1, 9.0).
Conclusions
Breast cancer survivors who are at greater risk of recurrence are less likely to receive surveillance mammograms. Women without a visit to an oncologist or breast cancer surgeon during a year have particularly low rates of mammography. Improvements to surveillance care for breast cancer survivors may require active participation by primary care physicians and improvements in cancer survivorship programs by healthcare systems.
doi:10.1007/s11606-007-0471-2
PMCID: PMC2359172  PMID: 18060463
breast cancer; surveillance; mammography; survivors
11.  Breast Cancer Treatment among Older Women in Integrated Health Care Settings 
Purpose
A substantial literature describes age-dependent variations in breast cancer treatment, showing that older women are less likely to receive standard treatment than are younger women. We sought to identify patient and tumor characteristics associated with the non-receipt of standard primary tumor and systemic adjuvant therapies.
Methods
We studied 1,859 women aged 65 years or older with stage I and II breast cancer diagnosed between 1990 and 1994 who were cared for in six geographically dispersed community-based health care systems. We collected demographic, tumor, treatment, and comorbidity data from electronic data sources, including cancer registry, administrative, and clinical databases, and from subjects’ medical records.
Results
Women 75 years of age or older and those with higher comorbidy indices were more likely to receive non-standard primary tumor therapy; to not receive axillary lymph node dissection; and to not receive radiation therapy following breast conserving surgery. Asian women were less likely to receive breast conserving surgery and African American women were less likely to be prescribed tamoxifen. Although non-receipt of most therapies was associated with a lower baseline risk of recurrence, an important minority of high risk women (16–30%) did not received guideline therapies.
Conclusions
Age is an independent risk factor for non-receipt of effective cancer therapies, even when comorbidity and risk of recurrence are taken into account. Information regarding treatment effectiveness in this age group and tools that allow physicians and patients to estimate the benefits versus the risks of therapies, taking into account age and comorbidity burden, are critically needed.
doi:10.1200/JCO.2006.06.3065
PMCID: PMC1913483  PMID: 16983106
breast cancer; older women; patterns of care
12.  Automated inter-rater reliability assessment and electronic data collection in a multi-center breast cancer study 
Background
The choice between paper data collection methods and electronic data collection (EDC) methods has become a key question for clinical researchers. There remains a need to examine potential benefits, efficiencies, and innovations associated with an EDC system in a multi-center medical record review study.
Methods
A computer-based automated menu-driven system with 658 data fields was developed for a cohort study of women aged 65 years or older, diagnosed with invasive histologically confirmed primary breast cancer (N = 1859), at 6 Cancer Research Network sites. Medical record review with direct data entry into the EDC system was implemented. An inter-rater and intra-rater reliability (IRR) system was developed using a modified version of the EDC.
Results
Automation of EDC accelerated the flow of study information and resulted in an efficient data collection process. Data collection time was reduced by approximately four months compared to the project schedule and funded time available for manuscript preparation increased by 12 months. In addition, an innovative modified version of the EDC permitted an automated evaluation of inter-rater and intra-rater reliability across six data collection sites.
Conclusion
Automated EDC is a powerful tool for research efficiency and innovation, especially when multiple data collection sites are involved.
doi:10.1186/1471-2288-7-23
PMCID: PMC1919388  PMID: 17577410
13.  Variation in hepatitis B immunization coverage rates associated with provider practices after the temporary suspension of the birth dose 
BMC Pediatrics  2006;6:31.
Background
In 1999, the American Academy of Pediatrics and U.S. Public Health Service recommended suspending the birth dose of hepatitis B vaccine due to concerns about potential mercury exposure. A previous report found that overall national hepatitis B vaccination coverage rates decreased in association with the suspension. It is unknown whether this underimmunization occurred uniformly or was associated with how providers changed their practices for the timing of hepatitis B vaccine doses. We evaluate the impact of the birth dose suspension on underimmunization for the hepatitis B vaccine series among 24-month-olds in five large provider groups and describe provider practices potentially associated with underimmunization following the suspension.
Methods
Retrospective cohort study of children enrolled in five large provider groups in the United States (A-E). Logistic regression was used to evaluate the association between the birth dose suspension and a child's probability of being underimmunized at 24 months for the hepatitis B vaccine series.
Results
Prior to July 1999, the percent of children who received a hepatitis B vaccination at birth varied widely (3% to 90%) across the five provider groups. After the national recommendation to suspend the hepatitis B birth dose, the percent of children who received a hepatitis B vaccination at birth decreased in all provider groups, and this trend persisted after the policy was reversed. The most substantial decreases were observed in the two provider groups that shifted the first hepatitis B dose from birth to 5–6 months of age. Accounting for temporal trend, children in these two provider groups were significantly more likely to be underimmunized for the hepatitis B series at 24 months of age if they were in the birth dose suspension cohort compared with baseline (Group D OR 2.7, 95% CI 1.7 – 4.4; Group E OR 3.1, 95% CI 2.3 – 4.2). This represented 6% more children in Group D and 9% more children in Group E who were underimmunized in the suspension cohort compared with baseline. Children in the reversal cohort in these groups remained significantly more likely to be underimmunized compared with baseline. In contrast, in a third provider group where the typical timing of the third dose was unchanged and in two other provider groups whose hepatitis B vaccination schedules were unaffected by the birth dose suspension, hepatitis B vaccination coverage either was maintained or improved.
Conclusion
When the hepatitis B birth dose was suspended, provider groups that moved the first dose of vaccination to 5–6 months of age or later had decreases in hepatitis B vaccine coverage at 24 months. These findings suggest that as vaccine policy changes occur, providers could attempt to minimize underimmunization by adopting vaccination schedules that minimize delays in the recommended timing of vaccine doses.
doi:10.1186/1471-2431-6-31
PMCID: PMC1657005  PMID: 17101052
14.  The Impact of Comorbidities on Hormone Use 
OBJECTIVE
Determine the impact of fracture, coronary disease, and diabetes on changes in rates of discontinuation and initiation of estrogen therapy with (EPT) and without (ET) progestin, before (September 1, 1999 to June 30, 2002, baseline) versus 5 months after (follow-up) release of the Women's Health Initiative EPT trial results (WHI).
DESIGN, SETTING, AND PARTICIPANTS
Observational cohort; 169,586 women 40 to 80 years old from 5 U.S. HMOs.
METHODS
We used pharmacy data to identify ET and EPT users. A woman was a user any month she filled ≥1 estrogen prescription and in subsequent months based upon the number of pills/patches dispensed. We used inpatient and outpatient claims to identify fracture January 1, 1999 to June 30, 2002 and pharmacy data to identify disease-based groups of medications for diabetes and cardiovascular disease.
MEASURES
EPT/ET prevalence, initiation, and discontinuation rates.
RESULTS
Baseline to follow-up EPT and ET prevalence declined 45% and 22%, respectively, with no difference by comorbidity. Follow-up EPT initiation was half the baseline rate irrespective of comorbidity. Compared to baseline, follow-up EPT discontinuation rates increased among women with diabetes (relative risk [RR], 6.9; 95% confidence interval [CI], 5.6 to 8.4), cardiovascular disease (RR, 5.5; 95% CI, 4.9 to 6.2), fracture (RR, 3.8; 95% CI, 2.4 to 5.7), and no comorbidity (RR, 4.4; 95% CI, 3.9 to 4.9). The RRs for follow-up versus baseline EPT discontinuation were higher among women with diabetes (P <.01) and cardiovascular disease (P <.01) versus women without these comorbidities. ET discontinuation rates among these same groups were elevated 2- to 2.8-fold.
CONCLUSIONS
Diabetes and cardiovascular disease were associated with higher EPT discontinuation rates post-WHI compared to women without comorbidity; comorbidity had little impact on changes in prevalence or initiation of ET/EPT after release of the WHI.
doi:10.1111/j.1525-1497.2005.04059.x
PMCID: PMC1490092  PMID: 15857493
hormone therapy; women; menopause; estrogen; fracture
15.  Impact of the introduction of pneumococcal conjugate vaccine on immunization coverage among infants 
BMC Pediatrics  2005;5:43.
Background
The introduction of pneumococcal conjugate vaccine (PCV) to the U.S. recommended childhood immunization schedule in the year 2000 added three injections to the number of vaccinations a child is expected to receive during the first year of life. Surveys have suggested that the addition of PCV has led some immunization providers to move other routine childhood vaccinations to later ages, which could increase the possibility of missing these vaccines. The purpose of this study was to evaluate whether introduction of PCV affected immunization coverage for recommended childhood vaccinations among 13-month olds in four large provider groups.
Methods
In this retrospective cohort study, we analyzed computerized data on vaccinations for 33,319 children in four large provider groups before and after the introduction of PCV. The primary outcome was whether the child was up to date for all non-PCV recommended vaccinations at 13 months of age. Logistic regression was used to evaluate the association between PCV introduction and the primary outcome. The secondary outcome was the number of days spent underimmunized by 13 months. The association between PCV introduction and the secondary outcome was evaluated using a two-part modelling approach using logistic and negative binomial regression.
Results
Overall, 93% of children were up-to-date at 13 months, and 70% received all non-PCV vaccinations without any delay. Among the entire study population, immunization coverage was maintained or slightly increased from the pre-PCV to post-PCV periods. After multivariate adjustment, children born after PCV entered routine use were less likely to be up-to-date at 13 months in one provider group (Group C: OR = 0.5; 95% CI: 0.3 – 0.8) and were less likely to have received all vaccine doses without any delay in two Groups (Group B: OR = 0.4, 95% CI: 0.3 – 0.6; Group C: OR = 0.5, 95% CI: 0.4 – 0.7). This represented 3% fewer children in Group C who were up-to-date and 14% (Group C) to 16% (Group B) fewer children who spent no time underimmunized at 13 months after PCV entered routine use compared to the pre-PCV baseline. Some disruptions in immunization delivery were also observed concurrent with temporary recommendations to suspend the birth dose of hepatitis B vaccine, preceding the introduction of PCV.
Conclusion
These findings suggest that the introduction of PCV did not harm overall immunization coverage rates in populations with good access to primary care. However, we did observe some disruptions in the timely delivery of other vaccines coincident with the introduction of PCV and the suspension of the birth dose of hepatitis B vaccine. This study highlights the need for continued vigilance in coming years as the U.S. introduces new childhood vaccines and policies that may change the timing of existing vaccines.
doi:10.1186/1471-2431-5-43
PMCID: PMC1314888  PMID: 16313673

Results 1-15 (15)