Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 34 Records) |
Query Trace: Lipscomb J[original query] |
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Acute hepatitis due to primary human immunodeficiency virus infection
Elliott EI , Smith D , Lipscomb J , Banini B , Meurer L , Vanderford TH , Johnson JA , Jain D , Achhra A . Open Forum Infect Dis 2024 11 (4) ofae170 The acute retroviral syndrome may present with diverse systemic manifestations and laboratory abnormalities. Here we present a rare case of primary human immunodeficiency virus (HIV) infection causing severe acute hepatitis. Liver histopathology demonstrated a pattern of lymphocytic inflammation consistent with acute hepatitis, high levels of HIV proviral DNA were detected within liver tissue, and immunofluorescence showed HIV p24 antigen within immune and parenchymal cells including hepatocytes. We review the literature pertaining to HIV infection of cell compartments within the liver and discuss the implications for HIV-associated acute liver disease. |
Weekly oral tenofovir alafenamide protects macaques from vaginal and rectal Simian HIV infection
Massud I , Nishiura K , Ruone S , Holder A , Dinh C , Lipscomb J , Mitchell J , Khalil GM , Heneine W , Garcia-Lerma JG , Dobard CW . Pharmaceutics 2024 16 (3) Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/10(6) cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/10(6) cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP. |
HIV immunocapture reveals particles expressed in semen under INSTI-based therapy are largely myeloid cell-derived and disparate from circulating provirus
Johnson JA , Li JF , Politch JA , Lipscomb JT , Santos Tino A , DeFelice J , Gelman M , Anderson DJ , Mayer KH . J Infect Dis 2024 As use of HIV integrase strand transfer inhibitors (INSTI) increases and formulations are being developed for maintenance therapies and chemoprophylaxis, assessing virus suppression under INSTI-based regimens in prevention-relevant biologic compartments, such as the male genital tract, is timely. We used cell-source marker virion immunocapture to examine amplification of particle RNA then assessed the phylogenetic relatedness of seminal and blood viral sequences from men with HIV who were prescribed INSTI-based regimens. Seminal plasma immunocaptures yielded amplifiable virion RNA from 13/24 (54%) men, and the sequences were primarily associated with markers indicative of macrophage and resident dendritic cell sources. Genetic distances were greatest (>2%) between seminal virions and circulating proviruses, pointing to ongoing low-level expression from tissue-resident cells. While the low levels in semen predict an improbable likelihood of transmission, viruses with large genetic distances are expressed under potent INSTI therapy and have implications for determining epidemiologic linkages if adherence is suboptimal. |
Extended post-exposure protection against vaginal SHIV infection with tenofovir alafenamide fumarate/elvitegravir inserts in macaques
Makarova N , Singletary T , Peet MM , Mitchell J , Bachman S , Holder A , Dinh C , Lipscomb J , Agrahari V , Mendoza M , Pan Y , Heneine W , Clark MR , García-Lerma JG , Doncel GF , Smith JM . J Infect Dis 2023 Vaginal inserts that can be used on demand before or after sex may be a desirable HIV prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF/20mg) and elvitegravir (EVG/16mg) were highly protective against repeated SHIV vaginal exposures when administered to macaques 4h before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8h or 24h after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women. |
Localized prostate cancer: An analysis of the CDC Breast and Prostate Cancer Data Quality and Patterns of Care study (CDC PoC-BP)
Celtik K , Wallis CJD , Lo M , Lim K , Lipscomb J , Fleming S , Wu XC , Anderson RT , Thompson TD , Farach A , Hamilton AS , Miles BJ , Satkunasivam R . Can Urol Assoc J 2022 16 (7) E391-E398 INTRODUCTION: Limited evidence exists on the comparative effectiveness of local treatments for prostate cancer (PCa) due to the lack of generalizability. Using granular national data, we sought to examine the association between radical prostatectomy (RP) and intensity-modulated radiation therapy (IMRT) treatment and survival. METHODS: Records were abstracted for localized PCa cases diagnosed in 2004 across seven state registries to identify patients undergoing RP (n=3019) or IMRT (n=667). Comorbidity was assessed by the Adult Comorbidity Evaluation-27 (ACE-27). Propensity score matching (PSM) was used to balance covariates between treatment groups. All-cause and PCa-specific mortality were primary endpoints. A subgroup analysis of patients with high-risk PCa (RP, n=89; IMRT, n=95) was conducted. RESULTS: Following PSM, matched patients (n=502 pairs) treated with either RP or IMRT were well-balanced with respect to covariates. With a median followup of 10.5 years (interquartile range [IQR] 9.9-11.0), the 11-year overall survival (OS) was 71.2% (95% confidence interval [CI] 66.9-75.8) for RP and 62.3% (95% CI 57.4-67.6) for IMRT. IMRT was associated with a 41% increased risk of all-cause mortality (hazard ratio [HR] 1.41, 95% CI 1.13-1.76) but not PCa-specific mortality (HR 1.75, 95% CI 0.84-3.64), as compared to RP. In patients with high-risk PCa, IMRT, as compared to RP, was not associated with statistically significant difference in all-cause (HR 1.53, 95% CI 0.97-2.42) or PCa-specific mortality (HR 1.92, 95% CI 0.69-5.36). CONCLUSIONS: Despite a low mortality rate at 10 years and possible residual confounding, we found a significantly increased risk of all-cause mortality, but no PCa-specific mortality associated with IMRT as compared to RP in this population-based study. |
A framework for cancer health economics research
Halpern MT , Shih YT , Yabroff KR , Ekwueme DU , Bradley CJ , Davidoff AJ , Sabik LM , Lipscomb J . Cancer 2020 127 (7) 994-996 Cancer has substantial economic impacts for patients, their families and/or caregivers, employers, and the health care system. However, there is only limited understanding of how economic issues can affect access to cancer care services and the receipt of high-quality cancer care. Health economics research in cancer is particularly timely due to the large and increasing number of patients with cancer and cancer survivors, but there are many factors that may create barriers to performing cancer health economics research. This commentary has identified important topics and questions in cancer health economics research and will assist in the development of this critical field. |
Cabotegravir long-acting protects macaques against repeated penile SHIV exposures
Dobard C , Makarova N , Nishiura K , Dinh C , Holder A , Sterling M , Lipscomb J , Mitchell J , Deyounks F , Garber D , Khalil G , Spreen W , Heneine W , Garcia-Lerma JG . J Infect Dis 2020 222 (3) 391-395 We used a novel penile simian HIV (SHIV) transmission model to investigate if cabotegravir long-acting (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once-weekly for 12 weeks. Of these, six received human-equivalent doses of CAB LA, six received oral FTC/TDF, and 10 were untreated. The efficacy of CAB LA was high (94.4% [95%CI=58.2%-99.3%]) and similar to that seen with oral FTC/TDF (94.0% [95%CI=55.1%-99.2%]). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA PrEP to heterosexual men. |
Improving Screening Uptake among Breast Cancer Survivors and Their First-Degree Relatives at Elevated Risk to Breast Cancer: Results and Implications of a Randomized Study in the State of Georgia.
Lipscomb J , Escoffery C , Gillespie TW , Henley SJ , Smith RA , Chociemski T , Almon L , Jiang R , Sheng X , Goodman M , Ward KC . Int J Environ Res Public Health 2020 17 (3) Women diagnosed with breast cancer at a relatively early age (</=45 years) or with bilateral disease at any age are at elevated risk for additional breast cancer, as are their female first-degree relatives (FDRs). We report on a randomized trial to increase adherence to mammography screening guidelines among survivors and FDRs. From the Georgia Cancer Registry, breast cancer survivors diagnosed during 2000-2009 at six Georgia cancer centers underwent phone interviews about their breast cancer screening behaviors and their FDRs. Nonadherent survivors and FDRs meeting all inclusion criteria were randomized to high-intensity (evidence-based brochure, phone counseling, mailed reminders, and communications with primary care providers) or low-intensity interventions (brochure only). Three and 12-month follow-up questionnaires were completed. Data analyses used standard statistical approaches. Among 1055 survivors and 287 FDRs who were located, contacted, and agreed to participate, 59.5% and 62.7%, respectively, reported breast cancer screening in the past 12 months and were thus ineligible. For survivors enrolled at baseline (N = 95), the proportion reporting adherence to guideline screening by 12 months post-enrollment was similar in the high and low-intensity arms (66.7% vs. 79.2%, p = 0.31). Among FDRs enrolled at baseline (N = 83), screening was significantly higher in the high-intensity arm at 12 months (60.9% vs. 32.4%, p = 0.03). Overall, about 72% of study-eligible survivors (all of whom were screening nonadherent at baseline) reported screening within 12 months of study enrollment. For enrolled FDRs receiving the high-intensity intervention, over 60% reported guideline screening by 12 months. A major conclusion is that using high-quality central cancer registries to identify high-risk breast cancer survivors and then working closely with these survivors to identify their FDRs represents a feasible and effective strategy to promote guideline cancer screening. |
Efficacy of oral tenofovir alafenamide/emtricitabine combination or single agent tenofovir alafenamide against vaginal SHIV infection in macaques
Massud I , Cong ME , Ruone S , Holder A , Dinh C , Nishiura K , Khalil G , Pan Y , Lipscomb J , Johnson R , Deyounks F , Rooney JF , Babusis D , Park Y , McCallister S , Callebaut C , Heneine W , Garcia-Lerma JG . J Infect Dis 2019 220 (11) 1826-1833 BACKGROUND: Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to SHIV to investigate if TAF alone or the combination of TAF and emtricitabine (FTC) can prevent vaginal infection. METHODS: Pigtail macaques were exposed vaginally to SHIV162p3 once a week for up to 15 weeks. Animals received clinical doses of FTC/TAF (n=6) or TAF (n=9) orally 24h before and 2h after each weekly virus exposure. Infection was compared with 21 untreated controls. RESULTS: Five of the 6 animals in the FTC/TAF and 4 of the 9 animals in the TAF alone group were protected against infection (p=0.001 and p=0.049, respectively). The calculated efficacy of FTC/TAF and TAF was 91% (95% CI=[34.9%, 98.8%]) and 57.8% [-8.7%, 83.6%]), respectively. Infection in FTC/TAF but not TAF-treated macaques was delayed relative to controls (p=0.005 and p=0.114). Median tenofovir diphosphate (TFV-DP) levels in PBMCs were similar among infected and uninfected macaques receiving TAF PrEP (351 and 143 fmols/106 cells, respectively; p=0.921). CONCLUSIONS: FTC/TAF provided a level of protection against vaginal challenge similar to FTC/tenofovir disoproxil fumarate combination in the macaque model. Our results support the clinical evaluation of FTC/TAF for PrEP in women. |
Obesity and mortality after locoregional breast cancer diagnosis
Moore AH , Trentham-Dietz A , Burns M , Gangnon RE , Greenberg CC , Vanness DJ , Hampton J , Wu XC , Anderson RT , Lipscomb J , Kimmick GG , Cress R , Wilson JF , Sabatino SA , Fleming ST . Breast Cancer Res Treat 2018 172 (3) 647-657 PURPOSE: Higher mortality after a breast cancer diagnosis has been observed among women who are obese. We investigated the relationships between body mass index (BMI) and all-cause or breast cancer-specific mortality after a diagnosis of locoregional breast cancer. METHODS: Women diagnosed in 2004 with AJCC Stage I, II, or III breast cancer (n = 5394) were identified from a population-based National Program of Cancer Registries (NPCR) patterns of care study (POC-BP) drawing from registries in seven U.S. states. Differences in overall and breast cancer-specific mortality were investigated using Cox proportional hazards regression models adjusting for demographic and clinical covariates, including age- and stage-based subgroup analyses. RESULTS: In women 70 or older, higher BMI was associated with lower overall mortality (HR for a 5 kg/m(2) difference in BMI = 0.85, 95% CI 0.75-0.95). There was no significant association between BMI and overall mortality for women under 70. BMI was not associated with breast cancer death in the full sample, but among women with Stage I disease; those in the highest BMI category had significantly higher breast cancer mortality (HR for BMI >/= 35 kg/m(2) vs. 18.5-24.9 kg/m(2) = 4.74, 95% CI 1.78-12.59). CONCLUSIONS: Contrary to our hypothesis, greater BMI was not associated with higher overall mortality. Among older women, BMI was inversely related to overall mortality, with a null association among younger women. Higher BMI was associated with breast cancer mortality among women with Stage I disease, but not among women with more advanced disease. |
Work-related injury and management strategies among certified athletic trainers
Kucera KL , Lipscomb HJ , Roos KG , Dement JM , Hootman JM . J Athl Train 2018 53 (6) 606-618 CONTEXT: Health care workers have high rates of musculoskeletal injuries, but many of these injuries go unreported to workers' compensation and national surveillance systems. Little is known regarding the work-related injuries of certified athletic trainers (ATs). OBJECTIVE: To determine the 12-month incidence and prevalence of work-related injuries and describe injury-reporting and -management strategies. DESIGN: Cross-sectional study. SETTING: Population-based online survey. PATIENTS OR OTHER PARTICIPANTS: Of the 29 051 ATs currently certified by the Board of Certification, Inc, who "opted in" to research studies, we randomly selected 10 000. Of these, 1826 (18.3%) ATs currently working in the clinical setting were eligible and participated in the baseline survey. MAIN OUTCOME MEASURES: An online survey was e-mailed in May of 2012. We assessed self-reported work-related injuries in the previous 12 months and management strategies including medical care, work limitations or modifications, and time off work. Statistics (frequencies and percentages) were calculated to describe injury rates per 200 000 work hours, injury prevalence, injury characteristics, and injury-reporting and -management strategies. RESULTS: A total of 247 ATs reported 419 work-related injuries during the previous 12 months, for an incidence rate of 21.6 per 200 000 hours (95% confidence interval [CI] = 19.6, 23.7) and injury prevalence of 13.5% (95% CI = 12.0%, 15.1%). The low back (26%), hand/fingers (9%), and knee (9%) were frequently affected body sites. Injuries were most often caused by bodily motion/overexertion/repetition (52%), contact with objects/equipment/persons (24%), or slips/trips/falls (15%). More than half of injured ATs (55.5%) sought medical care; 25% missed work, and most (77%) did not file a workers' compensation claim for their injury. Half of injured ATs were limited at work (n = 125), and 89% modified or changed their athletic training work as a result of the injury. CONCLUSIONS: More than half of AT work-related injuries required medical care or work limitations and were not reported for workers' compensation. Understanding how ATs care for and manage their work-related injuries is important given that few take time off work. |
Efficacy of vaginally administered gel containing emtricitabine and tenofovir against repeated rectal SHIV exposures in macaques
Dobard CW , Makarova N , West-Deadwyler R , Taylor A , Dinh C , Martin A , Lipscomb J , Mitchell J , Khalil G , Garcia-Lerma G , Heneine W . J Infect Dis 2018 218 (8) 1284-1290 Vaginal microbicides containing antiretrovirals (ARV) have shown to prevent vaginally acquired HIV but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs have shown to result in drug exposures in rectal tissues, thus raising the possibility of dual compartment protection. To test this concept, we investigated whether intravaginal dosing with emtricitabine (FTC)-tenofovir (TFV) gel, which fully protected macaques against repeated vaginal exposures to simian human immunodeficiency virus (SHIV), protects against rectal SHIV exposures. Pharmacokinetic (PK) studies revealed rapid distribution of FTC and TFV to rectal tissues and luminal fluids, albeit at concentrations 1-2 log10 lower than those in the vaginal compartment. Efficacy measurements against repeated rectal SHIV challenges demonstrated a 4.5-fold reduction in risk of infection in macaques that received intravaginal FTC/TFV compared to placebo gel (p=0.047; log-rank test). These data support the concept of dual compartment protection by vaginal dosing and warrants developing ARV-based vaginal products with improved bidirectional dosing. |
Risk of cancer death by comorbidity severity and use of adjuvant chemotherapy among women with locoregional breast cancer
Kimmick GG , Li X , Fleming ST , Sabatino SA , Wilson JF , Lipscomb J , Cress R , Bergom C , Anderson RT , Wu XC . J Geriatr Oncol 2017 9 (3) 214-220 OBJECTIVES: To examine the associations of comorbidity and chemotherapy with breast cancer- and non-breast cancer-related death. MATERIALS AND METHODS: Included were women with invasive locoregional breast cancer diagnosed in 2004 from seven population-based cancer registries. Data were abstracted from medical records and verified with treating physicians when there were inconsistencies and missing information on cancer treatment. Comorbidity severity was quantified using the Adult Comorbidity Evaluation 27. Treatment guideline concordance was determined by comparing treatment received with the National Comprehensive Cancer Network guidelines. Kaplan-Meier method and multivariable Cox proportional hazards regressions were employed for statistical analyses. RESULTS: Of 5852 patients, 76% were under 70years old and 69% received guideline concordant adjuvant chemotherapy. Comorbidity was more prevalent in women age 70 and older (79% vs. 51%; p<0.001). After adjusting for tumor characteristics and treatment, severe comorbidity burden was associated with significantly higher cancer-related mortality in older patients (Hazard Ratio [HR]=2.38, 95% CI 1.08-5.24), but not in younger patients (HR=1.78, 95% CI 0.87-3.64). Among patients receiving guideline adjuvant chemotherapy, cancer-related mortality was significantly higher in older patients (HR=2.35, 95% CI 1.52-3.62), and those with severe comorbidity (HR=3.79, 95% CI 1.72-8.33). CONCLUSIONS: Findings suggest that, compared to women with no comorbidity, patients with breast cancer age 70 and older with severe comorbidity are at increased risk of dying from breast cancer, even after adjustment for adjuvant chemotherapy and other tumor and treatment differences. This information adds to risk-benefit discussions and emphasizes the need for further study of the role for adjuvant chemotherapy in these patient groups. |
Topical tenofovir protects against vaginal SHIV infection in macaques co-infected with chlamydia trachomatis and trichomonas vaginalis
Makarova N , Henning T , Taylor A , Dinh C , Lipscomb J , Aubert R , Hanson D , Phillips C , Papp J , Mitchell J , McNicholl J , Garcia-Lerma GJ , Heneine W , Kersh E , Dobard C . AIDS 2017 31 (6) 745-752 BACKGROUND: Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV), two prevalent sexual transmitted infections, are known to increase HIV risk in women and could potentially diminish pre-exposure prophylaxis (PrEP) efficacy, particularly for topical interventions that rely on local protection. We investigated in macaques whether co-infection with CT/TV reduces protection by vaginal TFV gel. METHODS: Vaginal TFV gel dosing previously shown to provide 100% or 74% protection when applied either 30 minutes or 3 days before SHIV challenge was assessed in pigtailed macaques co-infected with CT/TV and challenged twice-weekly with SHIV162p3 for up to 10 weeks (2 menstrual cycles). Three groups of six macaques received either placebo or 1% TFV gel 30 minutes or 3 days before each SHIV challenge. We additionally assessed TFV and TFV-diphosphate (TFV-DP) concentrations in plasma and vaginal tissues in CT/TV co-infected (n = 4) and uninfected (n = 4) macaques. RESULTS: CT/TV co-infections were maintained during the SHIV challenge period. All macaques that received placebo gel were SHIV-infected after a median of 7 challenges (1 menstrual cycle). In contrast, no infections were observed in macaques treated with TFV gel 30 minutes before SHIV challenge (p < 0.001). Efficacy was reduced to 60% when TFV gel was applied 3 days before SHIV challenge (p = 0.07). Plasma TFV and TFV-DP concentrations in tissues and vaginal lymphocytes were significantly higher in CT/TV co-infected compared to CT/TV uninfected macaques. CONCLUSIONS: Our findings in this model suggest that CT/TV co-infection may have little or no impact on the efficacy of highly effective topical TFV modalities and highlight a significant modulation of TFV pharmacokinetics. |
Work-related illness and injury claims among nationally certified athletic trainers reported to Washington and California from 2001 to 2011
Kucera KL , Roos KG , Hootman JM , Lipscomb HJ , Dement JM , Silverstein BA . Am J Ind Med 2016 59 (12) 1156-1168 BACKGROUND: Little is known about the work-related injury and illnesses experienced by certified athletic trainers (AT). METHODS: The incidence and characteristics of injury/illness claims filed in two workers' compensation systems were described from 2001 to 2011. Yearly populations at risk were estimated from National Athletic Trainers' Association membership statistics. Incidence rate ratios (IRR) were reported by job setting. RESULTS: Claims were predominantly for traumatic injuries and disorders (82.7%: 45.7% sprains/strains, 12.0% open wounds, 6.5% bruises) and at these body sites (back 17.2%, fingers 12.3%, and knee 9.6%) and over half were caused by body motion and overexertion (51.5%). Compared with school settings, clinic/hospital settings had modestly higher claim rates (IRR = 1.29, 95% CI: 1.06-1.52) while other settings (e.g., professional or youth sport, nursing home) had lower claim rates (IRR = 0.63, 95% CI: 0.44-0.70). CONCLUSIONS: These first known estimates of work-related injuries/illnesses among a growing healthcare profession help identify occupational tasks and settings imposing injury risk for ATs. |
What predicts an advanced-stage diagnosis of breast cancer? sorting out the influence of method of detection, access to care and biological factors
Lipscomb J , Fleming ST , Trentham-Dietz A , Kimmick G , Wu XC , Morris CR , Zhang K , Smith RA , Anderson RT , Sabatino SA . Cancer Epidemiol Biomarkers Prev 2016 25 (4) 613-23 BACKGROUND: Multiple studies have yielded important findings regarding the determinants of an advanced-stage diagnosis of breast cancer. We seek to advance this line of inquiry through a broadened conceptual framework and accompanying statistical modeling strategy that recognize the dual importance of access-to-care and biological factors on stage. METHODS: The CDC-sponsored Breast and Prostate Cancer Data Quality and Patterns of Care Study yielded a 7-state, cancer registry-derived population-based sample of 9,142 women diagnosed with a first primary in situ or invasive breast cancer in 2004. The likelihood of advanced-stage cancer (AJCC IIIB, IIIIC, or IV) was investigated through multivariable regression modeling, with base-case analyses using the method of instrumental variables (IV) to detect and correct for possible selection bias. The robustness of base-case findings were examined through extensive sensitivity analyses. RESULTS: Advanced-stage disease was negatively associated with detection by mammography (p<0.001) and age<50 (p<0.001), and positively related to black race (p=0.066), not being privately insured [Medicaid (p=0.012), Medicare (p=0.036), uninsured (p=0.069)], being single (p=0.058), BMI>40 (p<0.001), a HER2 Type tumor (p<0.001), and tumor grade not well differentiated (p<0.001). This IV model detected and adjusted for significant selection effects associated with method of detection (p=0.017). Sensitivity analyses generally supported these base-case results. CONCLUSIONS: Through our comprehensive modeling strategy and multiple sensitivity analyses, we provide new estimates of the magnitude and robustness of the determinants of advanced-stage breast cancer. IMPACT: Statistical approaches frequently used to address observational data biases in treatment-outcome studies can be applied similarly in analyses of the determinants of stage-at-diagnosis. |
Influence of patient, physician, and hospital characteristics on the receipt of guideline-concordant care for inflammatory breast cancer
Denu RA , Hampton JM , Currey A , Anderson RT , Cress RD , Fleming ST , Lipscomb J , Sabatino SA , Wu XC , Wilson JF , Trentham-Dietz A . Cancer Epidemiol 2015 40 7-14 PURPOSE: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer for which treatments vary, so we sought to identify factors that affect the receipt of guideline-concordant care. METHODS: Patients diagnosed with IBC in 2004 were identified from the Breast and Prostate Cancer Data Quality and Patterns of Care Study, containing information from cancer registries in seven states. Variation in guideline-concordant care for IBC, based on National Comprehensive Cancer Network (NCCN) guidelines, was assessed according to patient, physician, and hospital characteristics. RESULTS: Of the 107 IBC patients in the study without distant metastasis at the time of diagnosis, only 25.8% received treatment concordant with guidelines. Predictors of non-concordance included patient age (≥70 years), non-white race, normal body mass index (BMI 18.5-25kg/m2), patients with physicians graduating from medical school >15 years prior, and smaller hospital size (<200 beds). IBC patients survived longer if they received guideline-concordant treatment based on either 2003 (p=0.06) or 2013 (p=0.06) NCCN guidelines. CONCLUSIONS: Targeting factors associated with receipt of care that is not guideline-concordant may reduce survival disparities in IBC patients. Prompt referral for neoadjuvant chemotherapy and post-operative radiation therapy is also crucial. |
Revisiting Pneumatic Nail Gun Trigger Recommendations
Albers J , Lowe BD , Lipscomb H , Hudock SD , Dement J , Evanoff B , Fullen M , Gillen M , Kaskutas V , Nolan J , Patterson D , Platner J , Pompeii L , Schoenfisch A . Prof Saf 2015 60 (3) 30-33 Pneumatic framing nail gun use is ubiquitous throughout the modern homebuilding industry. This tool has a safety device at the end of the gun muzzle that must be depressed before the fastener can be discharged. Generally, these devices have two types of trigger systems that then define how the nail gun fires in response to a trigger press: 1. The sequential actuation trigger requires that each nail can only be discharged when the safety tip is first depressed and, while held depressed, the trigger is squeezed. 2. The contact actuation trigger allows the operator to first squeeze the trigger and, while holding the trigger squeezed, repeatedly bump the safety tip on the workpiece to shoot multiple nails. In the authors' view, however, an unintended consequence of the recommendations published in (Baggs, et al, 1999) and (2001) has been the creation of the appearance of competing risks with nail gun trigger systems. |
Variations in guideline-concordant breast cancer adjuvant therapy in rural Georgia
Guy GP Jr , Lipscomb J , Gillespie TW , Goodman M , Richardson LC , Ward KC . Health Serv Res 2014 50 (4) 1088-108 OBJECTIVE: To examine factors associated with guideline-concordant adjuvant therapy among breast cancer patients in a rural region of the United States and to present an advancement in quality-of-care assessment in the context of multiple treatments. DATA SOURCES: Chart abstraction on initial therapy received by 868 women diagnosed with primary, invasive, early-stage breast cancer in a largely rural region of southwest Georgia. STUDY DESIGN: Using multivariable logistic regression, we examined predictors of adjuvant chemo-, radiation, and hormonal therapy regimens defined as guideline-concordant according to the 2000 National Institutes of Health Consensus Development Conference Statement. PRINCIPAL FINDINGS: Overall, 35.2 percent of women received guideline-concordant care for all three adjuvant therapies. Higher socioeconomic status was associated with receiving guideline-concordant care for all three adjuvant therapies jointly, and for chemotherapy. Compared with private insurance, having Medicaid was associated with guideline-concordant chemotherapy. Unmarried women were more likely to be nonconcordant for chemotherapy and radiation therapy. Increased age predicted nonconcordance for adjuvant therapies jointly, for chemotherapy, and for hormonal therapy. CONCLUSIONS: A number of factors were independently associated with receiving guideline-concordant adjuvant therapy. Identifying and addressing factors that lead to nonconcordance may reduce disparities in treatment and survival. |
HIV reverse-transcriptase drug resistance mutations during early infection reveal greater transmission diversity than in envelope sequences.
Lipscomb JT , Switzer WM , Li JF , Masciotra S , Owen SM , Johnson JA . J Infect Dis 2014 210 (11) 1827-37 BACKGROUND: Drug resistance mutations (DRMs) can serve as distinct, non-polymorphic markers for evaluating diversity of expressed HIV-1. We screened for resistance mutations during early-acute viremia and examined the diversity in reverse transcriptase (RT) relative to envelope (env) in cases of transmitted drug resistance. METHODS: We evaluated 111 longitudinal plasma samples collected every 2-7 days from 15 individuals who seroconverted for HIV-1 infection in 1994-2000. The samples were screened with sensitive PCR assays for the commonly transmitted M41 L and K70R mutations, and for K65R, which was undetected by bulk sequencing. Mutation-positive samples were further characterized by clonal sequencing of RT and env V1-V3. RESULTS: Resistance mutations were detected in 4 of 15 seroconverters at 5-50 days of viral nucleic acid expression; most mutations disappeared around the time of seroconversion. Clonal sequencing verified low-level K65R at frequencies of 0.4%-4.9%. In each case, K65R co-existed unlinked with variants carrying 2-5 thymidine analog mutations at frequencies of 1.6%-23.0%. In one seroconverter, variants with M184 V and NNRTI mutations were also identified at first RNA expression. Each seroconverter displayed a homogeneous V1-V3 env population. CONCLUSIONS: Reverse transcriptase DRMs demonstrate that the breadth of variants in transmission may be greater than what is reflected in envelope sequences. |
Postexposure protection of macaques from vaginal SHIV infection by topical integrase inhibitors
Dobard C , Sharma S , Parikh UM , West R , Taylor A , Martin A , Pau CP , Hanson DL , Lipscomb J , Smith J , Novembre F , Hazuda D , Garcia-Lerma JG , Heneine W . Sci Transl Med 2014 6 (227) 227ra35 Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P < 0.05, Fisher's exact test). Breakthrough infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure. |
Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy
Geretti AM , Fox Z , Johnson JA , Booth C , Lipscomb J , Stuyver LJ , Tachedjian G , Baxter J , Touloumi G , Lehmann C , Owen A , Phillips A . PLoS One 2013 8 (7) e69266 BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption. METHODS: Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography. RESULTS: Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04). CONCLUSIONS: Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs. |
Prostate cancer screening in men ages 75 and older fell by 8 percentage points after task force recommendation
Howard DH , Tangka FK , Guy GP , Ekwueme DU , Lipscomb J . Health Aff (Millwood) 2013 32 (3) 596-602 In 2008 the US Preventive Services Task Force recommended against screening men ages 75 and older for prostate cancer. Using Medicare Current Beneficiary Survey Access to Care files and linked claims, we compared trends in prostate-specific antigen (PSA) testing rates between men ages 75 and older and men ages 65-74. We estimate that the revised recommendation led to a 7.9-percentage-point decline in annual PSA testing rates over two years among men ages 75 and older. Although 42 percent of men in this age group continue to receive PSA tests, our results highlight the potential of guidelines with negative recommendations to reduce the use of low-value medical care. |
Application of an updated physiologically-based pharmacokinetic model for chloroform to evaluate CYP2E1-mediated renal toxicity in rats and mice
Sasso AF , Schlosser PM , Kedderis GL , Genter MB , Snawder J , Li Z , Rieth S , Lipscomb JC . Toxicol Sci 2012 131 (2) 360-74 Physiologically-based pharmacokinetic (PBPK) models are tools for interpreting toxicological data, and extrapolating observations across species and route of exposure. Chloroform (CHCl(3)) is a chemical for which there are PBPK models available in different species, and multiple sites of toxicity. Since chloroform induces toxic effects in the liver and kidneys via production of reactive metabolites, proper characterization of metabolism in these tissues is essential for risk assessment. While hepatic metabolism of chloroform is adequately described by these models, there is higher uncertainty for renal metabolism due to a lack of species-specific data and direct measurements of renal metabolism. Furthermore, models typically fail to account for regional differences in metabolic capacity within the kidney. Mischaracterization of renal metabolism may have a negligible effect on systemic chloroform levels, but it is anticipated to have a significant impact on the estimated site-specific production of reactive metabolites. In this paper, rate parameters for chloroform metabolism in the kidney are revised for rats, mice, and humans. New in vitro data were collected in mice and humans for this purpose and are presented here. The revised PBPK model is used to interpret data of chloroform-induced kidney toxicity in rats and mice exposed via inhalation and drinking water. Benchmark dose (BMD) modeling is used to characterize the dose-response relationship of kidney toxicity markers as a function of PBPK-derived internal kidney dose. Applying the PBPK model, it was also possible to characterize the dose-response for a recent dataset of rats exposed via multiple routes simultaneously. Consistent BMD modeling results were observed regardless of species or route of exposure. |
Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal
Van Rompay KK , Trott KA , Jayashankar K , Geng Y , Labranche CC , Johnson JA , Landucci G , Lipscomb J , Tarara RP , Canfield DR , Heneine W , Forthal DN , Montefiori D , Abel K . Retrovirology 2012 9 57 BACKGROUND: We reported previously that while prolonged tenofovir monotherapy of macaques infected with virulent simian immunodeficiency virus (SIV) resulted invariably in the emergence of viral mutants with reduced in vitro drug susceptibility and a K65R mutation in reverse transcriptase, some animals controlled virus replication for years. Transient CD8+ cell depletion or short-term tenofovir interruption within 1 to 5 years of treatment demonstrated that a combination of CD8+ cell-mediated immune responses and continued tenofovir therapy was required for sustained suppression of viremia. We report here follow-up data on 5 such animals that received tenofovir for 8 to 14 years. RESULTS: Although one animal had a gradual increase in viremia from 3 years onwards, the other 4 tenofovir-treated animals maintained undetectable viremia with occasional viral blips (≤ 300 RNA copies/ml plasma). When tenofovir was withdrawn after 8 to 10 years from three animals with undetectable viremia, the pattern of occasional episodes of low viremia (≤ 3600 RNA/ml plasma) continued throughout the 10-month follow-up period. These animals had low virus levels in lymphoid tissues, and evidence of multiple SIV-specific immune responses. CONCLUSION: Under certain conditions (i.e., prolonged antiviral therapy initiated early after infection; viral mutants with reduced drug susceptibility) a virus-host balance characterized by strong immunologic control of virus replication can be achieved. Although further research is needed to translate these findings into clinical applications, these observations provide hope for a functional cure of HIV infection via immunotherapeutic strategies that boost antiviral immunity and reduce the need for continuous antiretroviral therapy. |
Compared to subcutaneous tenofovir, oral tenofovir disoproxyl fumarate administration preferentially concentrates the drug into gut-associated lymphoid cells in simian immunodeficiency virus-infected macaques
Van Rompay KK , Babusis D , Abbott Z , Geng Y , Jayashankar K , Johnson JA , Lipscomb J , Heneine W , Abel K , Ray AS . Antimicrob Agents Chemother 2012 56 (9) 4980-4 To compare tissue-based pharmacokinetics and efficacy of oral tenofovir disoproxyl fumarate (TDF) versus subcutaneous tenofovir (TFV), macaques were treated for 2 weeks starting 1 week after simian immunodeficiency virus inoculation. Despite lower plasma TFV levels in the oral TDF arm, similar TFV diphosphate levels and antiviral activities were measured in lymphoid cells of most tissues. In intestinal tissues, however, oral TDF resulted in higher active drug levels, associated with lower virus levels and better immune preservation. |
Black-white differences in receipt and completion of adjuvant chemotherapy among breast cancer patients in a rural region of the US
Lipscomb J , Gillespie TW , Goodman M , Richardson LC , Pollack LA , Ryerson AB , Ward KC . Breast Cancer Res Treat 2012 133 (1) 285-96 Recent breast cancer treatment studies conducted in large urban settings have reported racial disparities in the appropriate use of adjuvant chemotherapy. This article presents the first focused evaluation of black-white differences in receipt and completion of chemotherapy for breast cancer in a primarily rural region of the United States. We performed chart abstraction on initial therapy received by 868 women diagnosed with Stages I, IIA, IIB, or IIIA breast cancer in 2001-2003 in southwest Georgia (SWGA). For chemotherapy, information collected included treatment plan, dates of delivery, concordance between therapy planned and received, and date and reasons for end of treatment. The patient's age at diagnosis, race, marital status, insurance coverage, hormone receptor status, comorbidities, socioeconomic status, urban/rural status, treatment site, and distance to the site were also collected. Following univariate analyses, we used multivariable logistic regression modeling to examine the impact of race on the likelihood of (1) receiving chemotherapy and (2) completing planned chemotherapy. For patients terminating chemotherapy prematurely, the reasons were documented. The results showed that the unadjusted black-white difference in receipt of chemotherapy (48.3 vs. 36.0%) was significant, but in the multivariable analysis the black-white odds ratio (OR = 1.18) was not. While the unadjusted black-white difference (92.0 vs. 87.8%) in completing chemotherapy was not significant, in multivariable models black race was positively associated with completing care (p ranging from 0.032 to 0.087 and OR, correspondingly, from 2.16 to 2.64). The impact of race on completing chemotherapy was influenced by marital status, with a significant black-white difference for patients not married (OR = 4.67), but no difference for those married (OR = 1.06). We find compelling racial differences in this largely rural region-with black breast cancer patients receiving or completing chemotherapy at rates that equal or exceed white patients. Further investigation is warranted, both in SWGA and in other rural regions. |
Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue
Dobard C , Sharma S , Martin A , Pau CP , Holder A , Kuklenyik Z , Lipscomb J , Hanson DL , Smith J , Novembre FJ , Garcia-Lerma JG , Heneine W . J Virol 2012 86 (2) 718-25 A vaginal gel containing 1% tenofovir (TFV) was found to be safe and effective in reducing HIV infection in women when used pericoitally. Because of the long intracellular half-life of TFV and high drug exposure in vaginal tissues, we hypothesized that a vaginal gel containing TFV may provide long-lasting protection. Here, we performed delayed-challenge experiments and showed that vaginal 1% TFV gel protected 4/6 macaques against vaginal simian-human immunodeficiency virus (SHIV) exposures occurring 3 days after gel application, demonstrating long-lasting protection. Despite continued gel dosing postinfection, neither breakthrough infection had evidence of drug resistance by ultrasensitive testing of SHIV in plasma and vaginal lavage. Analysis of the active intracellular tenofovir diphosphate (TFV-DP) in vaginal lymphocytes collected 4 h to 3 days after gel dosing persistently showed high TFV-DP levels (median, 1,810 fmol/10(6) cells) between 4 and 24 h that exceed the 95% inhibitory concentration (IC(95)), reflecting rapid accumulation and long persistence. In contrast to those in peripheral blood mononuclear cells (PBMCs) following oral dosing, TFV-DP levels in vaginal lymphocytes decreased approximately 7-fold by 3 days, exhibiting a much higher rate of decay. We observed a strong correlation between intracellular TFV-DP in vaginal lymphocytes, in vitro antiviral activity, and in vivo protection, suggesting that TFV-DP above the in vitro IC(95) in vaginal lymphocytes is a good predictor of high efficacy. Data from this model reveal an extended window of protection by TFV gel that supports coitus-independent use. The identification of protective TFV-DP concentrations in vaginal lymphocytes may facilitate the evaluation of improved delivery methods of topical TFV and inform clinical studies. |
Influence of race, insurance, socioeconomic status, and hospital type on receipt of guideline-concordant adjuvant systemic therapy for locoregional breast cancers
Wu XC , Lund MJ , Kimmick GG , Richardson LC , Sabatino SA , Chen VW , Fleming ST , Morris CR , Huang B , Trentham-Dietz A , Lipscomb J . J Clin Oncol 2011 30 (2) 142-50 PURPOSE: For breast cancer, guidelines direct the delivery of adjuvant systemic therapy on the basis of lymph node status, histology, tumor size, grade, and hormonal receptor status. We explored how race/ethnicity, insurance, census tract-level poverty and education, and hospital Commission on Cancer (CoC) status were associated with the receipt of guideline-concordant adjuvant systemic therapy. METHODS: Locoregional breast cancers diagnosed in 2004 (n = 6,734) were from the National Program of Cancer Registries-funded seven-state Patterns of Care study of the Centers for Disease Control and Prevention. Predictors of guideline-concordant (receiving/not receiving) adjuvant systemic therapy, according to National Comprehensive Cancer Network Guidelines, were explored by logistic regression. RESULTS: Overall, 35% of women received nonguideline chemotherapy, 12% received nonguideline regimens, and 20% received nonguideline hormonal therapy. Significant predictors of nonguideline chemotherapy included Medicaid insurance (odds ratio [OR], 0.66; 95% CI, 0.50 to 0.86), high-poverty areas (OR, 0.77; 95% CI, 0.62 to 0.96), and treatment at non-CoC hospitals (OR, 0.69; 95% CI, 0.56 to 0.85), with adjustment for age, registry, and clinical variables. Predictors of nonguideline regimens among chemotherapy recipients included lack of insurance (OR, 0.47; 95% CI, 0.25 to 0.92), high-poverty areas (OR, 0.71; 95% CI, 0.51 to 0.97), and low-education areas (OR, 0.65; 95% CI, 0.48 to 0.89) after adjustment. Living in high-poverty areas (OR, 0.78; 95% CI, 0.64 to 0.96) and treatment at non-CoC hospitals (OR, 0.68; 95% CI, 0.55 to 0.83) predicted nonguideline hormonal therapy after adjustment. ORs for poverty, education, and insurance were attenuated in the full models. CONCLUSION: Sociodemographic and hospital factors are associated with guideline-concordant use of systemic therapy for breast cancer. The identification of modifiable factors that lead to nonguideline treatment may reduce disparities in breast cancer survival. |
Detection of low-level K65R variants in nucleoside reverse transcriptase inhibitor-naive chronic and acute HIV-1 subtype C infections.
Li JF , Lipscomb JT , Wei X , Martinson NA , Morris L , Heneine W , Johnson JA . J Infect Dis 2011 203 (6) 798-802 To substantiate reports of greater emergence of the K65R nucleoside reverse transcriptase inhibitor (NRTI) mutation in human immunodeficiency virus type 1 (HIV-1) subtype C, we examined natural low-level K65R expression in subtype C relative to subtypes B and AE. We used allele-specific polymerase chain reaction to screen HIV-1 amplified by reverse-transcription high-fidelity polymerase chain reaction from subtype C-infected South African women and infants and CRF01(subtype AE) from Thailand; all subjects were NRTI naive. We found low-level K65R of unknown clinical significance in NRTI-naive subtype C-infected women and infants at frequencies above the natural occurrence in subtypes B and AE. The frequent appearance of subtype C frameshift deletions at codon 65 supports a propensity for transcription error in this region. |
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