Motivation: Proteomics presents the opportunity to provide novel insights about the global biochemical state of a tissue. However, a significant problem with current methods is that shotgun proteomics has limited success at detecting many low abundance proteins, such as transcription factors from complex mixtures of cells and tissues. The ability to assay for these proteins in the context of the entire proteome would be useful in many areas of experimental biology.
Results: We used network-based inference in an approach named SNIPE (Software for Network Inference of Proteomics Experiments) that selectively highlights proteins that are more likely to be active but are otherwise undetectable in a shotgun proteomic sample. SNIPE integrates spectral counts from paired case–control samples over a network neighbourhood and assesses the statistical likelihood of enrichment by a permutation test. As an initial application, SNIPE was able to select several proteins required for early murine tooth development. Multiple lines of additional experimental evidence confirm that SNIPE can uncover previously unreported transcription factors in this system. We conclude that SNIPE can enhance the utility of shotgun proteomics data to facilitate the study of poorly detected proteins in complex mixtures.
Availability and Implementation: An implementation for the R statistical computing environment named snipeR has been made freely available at http://genetics.bwh.harvard.edu/snipe/.
Supplementary information: Supplementary data are available at Bioinformatics online.
HIV risk is disproportionately high among incarcerated individuals. Corrections agencies have been slow to implement evidence-based guidelines and interventions for HIV prevention, testing, and treatment. The emerging field of implementation science focuses on organizational interventions to facilitate adoption and implementation of evidence-based practices. A survey of among CJ-DATS correctional agency partners revealed that HIV policies and practices in prevention, detection and medical care varied widely, with some corrections agencies and facilities closely matching national guidelines and/or implementing evidence-based interventions. Others, principally attributed to limited resources, had numerous gaps in delivery of best HIV service practices. A brief overview is provided of a new CJ-DATS cooperative research protocol, informed by the survey findings, to test an organization-level intervention to reduce HIV service delivery gaps in corrections.
Corrections; Implementation; Staff survey; HIV policies; inmates
We tested if good parole officer (PO)–parolee relationships reduce HIV risk behaviors during parole, as they do for risk of rearrest. Analyses used data from 374 parolees enrolled in a randomized clinical trial. Past month HIV risk behaviors were assessed by interview at baseline, 3- and 9-months after parole initiation. The Working Alliance Inventory and the Dual-Role Relationships Inventory measured PO relationship. Gender-stratified multivariate regressions tested associations of PO–parolee relationship with sex with multiple partners, unprotected sex with risky partner(s), and drug injection. Women parolees (n = 65) who reported better PO relationship characteristics were less likely to report having multiple sex partners [adjusted odds ratio: 0.82 (0.69, 0.98) at 3-months, 0.89 (0.80, 0.99) at 9-months], and, among those reporting multiple sex partners, had fewer partners on average [adjusted relative risk 0.98 (0.96, 0.99)]. These effects were not found among men. PO–parolee relationship quality can influence sexual risk behaviors among women parolees.
Parole; Community supervision; Working alliance; HIV risk behaviors; Women
To determine whether collaborative behavioral management (CBM) reduces substance use, crime and re-arrest among drug-involved parolees.
Step’n Out was a randomized behavioral trial of CBM versus standard parole (SP) during 2004-2008. CBM adapted evidence-based role induction, behavioral contracting, and contingent reinforcement to provide parole officer/treatment counselor dyads with positive tools in addition to sanctions to manage parolees’ behavior over 12 weeks.
Six parole offices in five states in the U.S.A.
Parolee volunteers with a mandate for addiction treatment and a minimum of three months of parole (N=476). Follow-up was 94% at 3- and 86% at 9-months.
Drug use and crime in a given month from calendar interviews 3- and 9-months after parole initiation, and re-arrests from criminal justice administrative data.
The CBM group had fewer months in which they used their primary drug (adjusted risk ratio (ARR) 0.20, 95% CI: 0.05, 0.78, p = .02) and alcohol (ARR 0.38, 95% CI: 0.22, 0.66, p=.006) over follow-up. CBM had its greatest effects among parolees who reported marijuana or another “non-hard” drug as their primary drug; parolees who preferred stimulants or opiates did not benefit. No differences were seen in total crime, re-arrests or parole revocations.
Collaborative behavioral management may reduce substance use among primary marijuana or other “non-hard” drug-using parolees without increasing revocations. Since the majority of drug violation arrests in the U.S. are for marijuana, these findings have important implications for the management of a substantial proportion of the U.S. community correctional population.
To investigate how incarceration may affect risk of acquiring HIV and other sexually transmitted infections, we tested associations of ex-offenders’ sexual risk behavior with the male-female sex ratio and the male incarceration rate.
Longitudinal data from 1287 drug-involved persons on probation and parole as part of the Criminal Justice Drug Abuse Treatment Studies were matched by county of residence with population factors, and stratified by race/ethnicity and gender. Generalized estimating equations assessed associations of having unprotected sex with a partner who had HIV risk factors, and having more than 1 sex partner in the past month.
Among non-Hispanic Black men and women, low sex ratios were associated with greater risk of having unprotected sex with a risky partner (Adjusted relative risk (ARR) = 1.76, 95% confidence interval (CI) = 1.29, 2.42; ARR = 2.48, 95% CI = 1.31, 4.73, respectively). Among non-Hispanic Black and non-Hispanic White women, low sex ratios were associated with having more than 1 sex partner (ARR = 2.00, 95% CI = 1.02, 3.94; ARR = 1.71, 95% CI = 1.06, 2.75, respectively). High incarceration rates were associated with greater risk of having a risky partner for all men (non-Hispanic Black: ARR= 2.14, 95% CI=1.39, 3.30; non-Hispanic White: ARR= 1.39, 95% CI: 1.05, 1.85; Hispanic: ARR = 3.99, 95% CI =1.55, 10.26) and having more than one partner among non-Hispanic White men (ARR= 1.92, 95% CI = 1.40, 2.64).
Low sex ratios and high incarceration rates may influence the number and risk characteristics of sex partners of ex-offenders. HIV-prevention policies and programs for ex-offenders could be improved by addressing structural barriers to safer sexual behavior.
criminal justice; racial/ethnic health disparities; sex ratios; parole/probation; social determinants; HIV/AIDS
Treatment for advanced stage oropharyngeal squamous cell carcinoma (OPSCC) includes combined chemoradiation therapy or surgery followed by radiation therapy alone or in combination with chemotherapy. The goal of this study was to utilize available evidence to examine survival outcome differences in patients with advanced stage OPSCC treated with these different modalities.
Patients with advanced stage OPSCC were identified. Primary outcome measurements were disease specific and overall survival rates with differences examined via Kaplan-Meier and logistic regression analysis.
344 patients were enrolled. 94 patients underwent triple modality therapy inclusive of surgery followed by adjuvant combined chemotherapy and radiation therapy (S-CRT). 131 had surgery and radiation therapy (S-RT), while 56 had chemoradiation (CRT) therapy as their primary treatment. A total of 63 patients had single modality radiation therapy and were excluded from analysis due to the large number of palliative patients.
Kaplan-Meier overall survival analysis showed that therapy with S-CRT had the highest disease specific survival at five years (71.1%). This is contrasted against S-RT and CRT, with five year survival rates at 53.9%, and 48.6%, respectively.
Cox regression showed that the comparison of S-CRT vs. S-RT, and CRT is associated with statistically significant increased hazard ratios of 1.974, and 2.785, indicating that both S-RT and CRT are associated with a reduced likelihood of survival at 5 years when compared to S-CRT.
In this population based cohort study S-CRT is associated with a 17–22% 5 year disease specific survival benefit compared to CRT or S-RT.
The oral cavity is the most common site for head and neck squamous cell carcinoma. Treatment of advanced stage oral cavity squamous cell carcinoma (OCSCC) has classically involved surgical resection with postoperative adjuvant radiotherapy (S-RT).Despite this aggressive dual modality therapy, the disease outcomes have remained poor. The treatment options expanded in 2004 when two international trials showed the addition of postoperative chemotherapy to radiation improved outcomes. These trials were, however not oral cavity site specific.
To assess survival outcomes of advanced OCSCC treated by differing modalities. The primary goal was to determine if the addition of postoperative chemotherapy (S-CRT) improves survival compared to other treatment regimens.
Demographic, pathologic, treatment, and survival data was obtained from patients diagnosed with OCSCC from 1998–2010 in Alberta, Canada. 222 patients were included in the final analysis from 895 OCSCC patients. Actuarial overall, disease-specific, disease-free, and metastasis-free survivals were estimated with Kaplan-Meier and Cox regression analyses. Patients were grouped by treatment.
Patients receiving S-CRT had improved overall, disease-specific, disease-free, and metastasis-free survival compared to S-RT, CRT or RT(p < 0.05). Two and five year estimated overall survival was significantly higher in the S-CRT group at 77 and 58% (p < 0.05), versus S-RT with 55 and 40% rates(p < 0.05). Results were similar for disease-specific, disease-free, and metastasis free survival with S-CRT being favoured. Patients with extracapsular spread (ECS) treated with S-CRT versus S-RT had 55% survival advantage at 5 years (p < 0.05).
This study shows that adding adjuvant chemotherapy to S-RT improves survival outcomes in advanced OCSCC, especially in patients with ECS.
To evaluate any disparity in clinical versus pathological TNM staging in oral cavity squamous cell carcinoma (OCSCC) patients and any impact of this on survival.
Demographic, survival, staging, and pathologic data on all patients undergoing surgical treatment for OCSCC in Alberta between 1998 and 2006 was collected. Clinical and pathological TNM staging data were compared. Patients were stratified as pathologically downstaged, upstaged or unchanged.
Tertiary care centers in Alberta, Canada.
Main outcome measures
Survival differences between groups were analyzed using Kaplan-Meier and Cox regression models.
Patients with clinically early stage tumors were pathologically upstaged in 21.9% of cases and unchanged in 78.1% of cases. Patients with clinically advanced stage tumors were pathologically downstaged in 7.9% of cases and unchanged in 92.1% of cases. Univariate and multivariate estimates of disease-specific survival showed no statistically significant differences in survival when patients were either upstaged or downstaged.
Some disparity exists in clinical versus pathological staging in OCSCC, however, this does not have any significant impact on disease specific survival.
Finding brief effective treatments for criminal justice populations is a major public need. The CJ-DATS Targeted Intervention for Corrections (TIC), which consists of six brief interventions (Communication, Anger, Motivation, Criminal Thinking, Social Networks, and HIV/Sexual Health), were tested in separate federally-funded randomized control studies. In total, 1,573 criminal justice-involved individuals from 20 correction facilities participated (78% males; 54% white). Multi-level repeated measures analyses found significant gains in knowledge, attitudes, and psychosocial functioning (criteria basic to Knowledge, Attitude, and Practices (KAP) and TCU Treatment Process Models). While improvements were less consistent in criminal thinking, overall evidence supported efficacy for the TIC interventions.
adaptive treatment; brief interventions; CJ-DATS; criminal justice treatment; TCU Treatment Model; tier one treatment
Medication-assisted treatment (MAT) is underutilized in the treatment of drug-dependent, criminal justice populations. This study surveyed criminal justice agencies affiliated with the Criminal Justice Drug Abuse Treatment Studies (CJ-DATS) to assess use of MAT and factors influencing use of MAT. A convenience sample (N=50) of criminal justice agency respondents (e.g., jails, prisons, parole/probation, and drug courts) completed a survey on MAT practices and attitudes. Pregnant women and individuals experiencing withdrawal were most likely to receive MAT for opiate dependence in jail or prison, while those re-entering the community from jail or prison were the least likely to receive MAT. Factors influencing use of MAT included criminal justice preferences for drug-free treatment, limited knowledge of the benefits of MAT, security concerns, regulations prohibiting use of MAT for certain agencies, and lack of qualified medical staff. Differences across agency type in the factors influencing use and perceptions of MAT were also examined.
MAT use is largely limited to detoxification and maintenance of pregnant women in criminal justice settings. Use of MAT during the community reentry period is minimal. Addressing inadequate knowledge and negative attitudes about MAT may increase its adoption, but better linkages to community pharmacotherapy during the reentry period might overcome other issues, including security, liability, staffing and regulatory concerns. The CJ-DATS collaborative MAT implementation study to address inadequate knowledge, attitudes and linkage will be described.
Modern desistance research has examined many facets of desistance, in terms of theoretical predictors of desistance and recidivism, and in terms of differing types of offending. Though predicting desistance from illegal drug use is among these topics, no research to date has examined the predictors of desisting from prescription opioid abuse. This study uses longitudinal data from 318 prescription opioid users to analyze the effects of various predictors of desistance on declining nonmedical prescription opioid use, with an emphasis on gender differences among participants. Results indicate that theoretical and demographic characteristics correspond with differing rates of decline and further vary by gender.
Prescription drug abuse; opioids; desistance
Defects of the scalp and lateral temporal bone (LTB) represent a unique challenge to the reconstructive surgeon. Simple reconstructive methods such as skin grafts, locoregional flaps, or tissue expanders are often not feasible due to a myriad of reasons. Vascularized free tissue transfer coverage offers distinct advantages in managing these defects. A retrospective case series was performed on all patients at the University of Washington Medical Center who had scalp or LTB defects reconstructed with free tissue transfer from May 1996 to July 2009. Cases were analyzed for defect characteristics, flap type, vessel selection, radiation status, dural exposure, complications, and outcomes. Sixty-eight free flaps were performed in 65 patients with scalp or LTB defects. Twenty-two resections included craniotomy, and 48 patients had pre- or postoperative radiation. Defects ranged from 6 to 836 cm2. All flaps (46 latissimus, 11 rectus, 4 radial forearm, 6 anterolateral thigh, and 1 omental) were transferred successfully. Vein grafts were required in five cases. Complications included delayed flap failure requiring secondary reconstruction, neck hematoma, venous thrombosis, skull base infection, large wound dehiscence, small wound dehiscence, donor site hematoma and seroma, and cerebrospinal fluid leak. Cosmetic results were consistent and durable. Microvascular free tissue transfer is a safe, reliable method of reconstructing scalp and LTB defects and offers favorable cosmetic results. We favor the use of latissimus muscle-only flap with skin graft coverage for large scalp defects and rectus or anterolateral thigh free flaps for lateral temporal bone defects.
Scalp reconstruction; lateral temporal bone reconstruction; scalp neoplasms; scalp defects; microvascular reconstruction; free tissue transfer
Based on mouse lens gene expression profiling, a systems tool was developed for identification of genes associated with human congenital cataract. iSyTE ranked 88% of known isolated congenital cataract–associated genes within the top two of all candidates in the originally mapped genomic intervals.
To facilitate the identification of genes associated with cataract and other ocular defects, the authors developed and validated a computational tool termed iSyTE (integrated Systems Tool for Eye gene discovery; http://bioinformatics.udel.edu/Research/iSyTE). iSyTE uses a mouse embryonic lens gene expression data set as a bioinformatics filter to select candidate genes from human or mouse genomic regions implicated in disease and to prioritize them for further mutational and functional analyses.
Microarray gene expression profiles were obtained for microdissected embryonic mouse lens at three key developmental time points in the transition from the embryonic day (E)10.5 stage of lens placode invagination to E12.5 lens primary fiber cell differentiation. Differentially regulated genes were identified by in silico comparison of lens gene expression profiles with those of whole embryo body (WB) lacking ocular tissue.
Gene set analysis demonstrated that this strategy effectively removes highly expressed but nonspecific housekeeping genes from lens tissue expression profiles, allowing identification of less highly expressed lens disease–associated genes. Among 24 previously mapped human genomic intervals containing genes associated with isolated congenital cataract, the mutant gene is ranked within the top two iSyTE-selected candidates in approximately 88% of cases. Finally, in situ hybridization confirmed lens expression of several novel iSyTE-identified genes.
iSyTE is a publicly available Web resource that can be used to prioritize candidate genes within mapped genomic intervals associated with congenital cataract for further investigation. Extension of this approach to other ocular tissue components will facilitate eye disease gene discovery.
To elucidate the transcriptional regulation of Bmp4 expression during organogenesis, we used phylogenetic footprinting and transgenic reporter analyses to identify Bmp4 cis-regulatory modules (CRMs). These analyses identified a regulatory region located ∼46 kb upstream of the mouse Bmp4 transcription start site that had previously been shown to direct expression in lateral plate mesoderm. We refined this regulatory region to a 396-bp minimal enhancer, and show that it recapitulates features of endogenous Bmp4 expression in developing mandibular arch ectoderm and incisor epithelium during the initiation-stage of tooth development. In addition, this enhancer directs expression in the apical ectodermal ridge (AER) of the developing limb and in anterior and posterior limb mesenchyme. Transcript profiling of E11.5 mouse incisor dental lamina, together with protein binding microarray (PBM) analyses, allowed identification of a conserved DNA binding motif in the Bmp4 enhancer for Pitx homeoproteins, which are also expressed in the developing mandibular and incisor epithelium. In vitro electrophoretic mobility shift assays (EMSA) and in vivo transgenic reporter mutational analyses revealed that this site supports Pitx binding and that the site is necessary to recapitulate aspects of endogenous Bmp4 expression in developing craniofacial and limb tissues. Finally, Pitx2 chromatin immunoprecipitation (ChIP) demonstrated direct binding of Pitx2 to this Bmp4 enhancer site in a dental epithelial cell line. These results establish a direct molecular regulatory link between Pitx family members and Bmp4 gene expression in developing incisor epithelium.
A common HIV/AIDS risk reduction strategy among men who have sex with men (MSM) is to limit their unprotected sex partners to those who are of the same HIV status, a practice referred to as serosorting. Decisions to serosort for HIV risk reduction are based on personal impressions and beliefs, and there is limited guidance offered on this community derived strategy from public health services. This paper reviews research on serosorting for HIV risk reduction and offers an evidence-based approach to serosorting guidance. Following a comprehensive electronic and manual literature search, we reviewed 51 studies relating to the implications of serosorting. Studies showed that HIV negative MSM who select partners based on HIV status are inadvertently placing themselves at risk for HIV. Infrequent HIV testing, lack of HIV status disclosure, co-occurring STIs, and acute HIV infection impede the potential protective benefits of serosorting. Public health messages should continue to encourage reductions in numbers of sexual partners and increases in condom use. Risk reduction messages should also highlight the limitations of relying on one’s own and partner’s HIV status in making sexual risk decisions.
serosorting; acute infection; HIV testing; prevention messages
Brief interventions to reduce harmful or problem behaviors have become increasingly popular in a variety of health fields, including HIV and hepatitis risk reduction. A central issue in intervention research involves the evaluation of what constitutes an effective “dose” of an intervention. This research examines the relative effectiveness of three alternative brief interventions of varying intensity designed to change the risk behaviors of inmates who are reentering society: a DVD-based, peer delivered intervention; the NIDA Standard HIV Intervention; and a standard practice condition (HIV educational video). All participants randomly received one of the interventions and were tested for HIV and HCV prior to release from custody. Thirty and ninety-day follow-ups examined changes in high-risk behaviors. Results reported here for 343 subjects who have completed the 90–day follow up indicate significant reductions in reported sexual risk behaviors for those participating the DVD intervention, compared to the other two brief interventions. This study is among the first to report any positive impacts on sexual behaviors among a population of inmates returning to the community.
drug abuse; HIV; inmates; intervention; prison
This article describes the rationale, study design, and implementation for the Step'n Out study of the Criminal Justice Drug Abuse Treatment Studies. Step'n Out tests the relative effectiveness of collaborative behavioral management of drug-involved parolees. Collaborative behavioral management integrates the roles of parole officers and treatment counselors to provide role induction counseling, contract for pro-social behavior, and deliver contingent reinforcement of behaviors consistent with treatment objectives. The Step'n Out study will randomize 450 drug-involved parolees to collaborative behavioral management or usual parole. Follow-up at 3-and 9-months will assess primary outcomes of rearrest, crime and drug use. If collaborative behavioral management is effective, its wider adoption could improve the outcomes of community reentry of drug-involved ex-offenders.
Community corrections; community reinforcement; contingency management; drug abusear; graduated sanctions; parole
Dual expression of chemokine receptor CCR4 and E-selectin ligand is characteristic of skin-tropic CD4 T cells from blood, lymphoid organs, and the skin itself. A strong and specific correlation exists among CCR4, its ligand CCL17/TARC, and the cutaneous lymphocyte-homing process. Nevertheless, whether CCR4 function is required for skin-specific trafficking remains an open question, which we address in this study. We developed an Ag-specific, TCR-transgenic, murine CD4 T cell adoptive transfer model that induces a mixed Th1 and Th17 cutaneous response. Within the hosts, both CCR4+/+and CCR4−/− donor CD4 T cells contribute equally well to the circulating E-selectin ligand+ pool in response to Ag. However, only CCR4+/+ donor cells accumulate efficiently within the skin. CCR4−/− cells home normally to the peritoneum, showing that they do not have a general defect in lymphocyte trafficking. We conclude that under physiological conditions, CCR4 is a nonredundant, necessary component of skin-specific lymphocyte trafficking.
A series of polymers of polyglutamic acid have been tested as plasma volume expanders. The results indicate that those polymers prepared from backbones of 40,000 molecular weight or over and side chains of 3,000 molecular weight or over, will have plasma volume retention half-life of 15 hours or longer. Measurements of the oncotic efficiency of these polymers in vivo indicated a blood stream fluid retention of approximately 51 ml./gm. of polymer. Similar measurements of polymer-serum albumin solutions in vitro showed a retention of 52 ml./gm. of polymer. The clinical response to infusion of solutions of these polymers indicated no untoward pharmacological properties. Although the number of trials presented is too small for ultimate conclusion regarding either the physiological or clinical effects of these polymers, they do provide a strong indication of the desirability of further clinical testing of this polymer and a sound basis on which to plan the larger scale preparation of polymer. Both measures are currently under way.