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In this study, we used a rapid, highly-sensitive, single-cell biomass measurement method, Live Cell Interferometry (LCI), to measure biomass in populations of CD3 + T cells isolated from hematopoietic stem cell transplant (SCT) patients at various times pre- and post-transplant (days 0-100). CD3 + T cell 'mass spectra' were obtained from five autologous and 20 allogenic transplant recipients. We found a pronounced rise in median T cell biomass (+25%; p

Just as Bayes extensions of the frequentist optimal allocation design have been developed for the two-group case, we provide a Bayes extension of optimal allocation in the three-group case. We use the optimal allocations derived by Jeon and Hu [Optimal adaptive designs for binary response trials with three treatments. Statist Biopharm Res. 2010;2(3):310–318] and estimate success probabilities for each treatment arm using a Bayes estimator. We also introduce a natural lead-in design that allows adaptation to begin as early in the trial as possible. Simulation studies show that the Bayesian adaptive designs simultaneously increase the power and expected number of successfully treated patients compared to the balanced design. And compared to the standard adaptive design, the natural lead-in design introduced in this study produces a higher expected number of successes whilst preserving power.

The Patient Protection and Affordable Care Act (ACA) mandates the release of publicly available consumer reports to highlight differences in quality of care and reduce healthcare disparities. However, little is known about patient perceptions of the value of such reports. This study aims to identify whether vulnerable populations with type 2 diabetes perceive consumer reports as helpful in making decisions about diabetes care. We conducted a brief demographic survey and qualitative study of 18 focus groups: six each of African American, Hispanic, and non-Hispanic White consumers diagnosed with type 2 diabetes (n = 92). We analysed focus group transcripts to identify recurring themes, which were summarized and compared across population groups. Participants expressed minimal interest in currently available consumer reports. They instead listed personal referrals and interpersonal interactions among the most important factors when choosing a physician. Further, in place of information to aid in physician selection, participants articulated strong desires for more basic, straightforward disease-specific information that would promote diabetes self-management. This study’s results call into question the value of consumer reports as defined by the ACA. Participants reported little interest in comparative provider performance data. Instead, they were more interested in information to assist in diabetes self-management. This suggests that consumer reports may not be as important a tool to improve outcomes and reduce health disparities as policy makers imagine them to be.

A new method for simulating dependent binary data is presented. This methodology does not require specification of a parametric joint distribution, and instead uses desired dependence levels and marginal probabilities to construct a cumulative distribution function for the multinomial distribution of all possible combinations of binary outcomes. This method is simple to use and compute, and through simulation studies is found to be comparable with the gold-standard approach by Emrich and Piedmonte [A method for generating high-dimensional multivariate binary variates. Amer Statist. 1991;45(4):302–304].

Fourteen compounds representing ester derivatives of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl) propanoic and (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acids, expressing antiproliferative activity in vitro were examined. The objective of this study was to determinate their lipophilicity data, and also to ensure a mathematical model for prediction lipophilicity data of potential in vivo metabolites and new derivatives of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid, based on chromatographic parameters. Experimentally, lipophilicity data were obtained by a traditional shake flask procedure and an ultra-high performance liquid chromatographic tandem mass spectrometry (UHPLC-MS) method. A correlation between the partition coefficient n-octanol/water (logD7,4) and chromatographic data (CHI, 0), and also, between logD7,4 and retention time was investigated. A very good correlation (r2=0.8969) was found between lipophilicity parameters 0 and logD7,4 obtained using UHPLC-MS and shake flask methods: logD7,4 = (0.11±0.01)×0 + (1.25±0.20)×Nc - (9.19±1.18); statistical parameter F=47.84; significance of F = 3.74×10-6, Nc=number of C atoms between two amino groups (Nc=2 for 1,2-ethanediamine derivatives and Nc=3 for 1,3-propanediamine derivatives). The model predictivity power was determined by cross validation leave one out (LOO) technique, and expressed by the term Q2, was 0.89. The developed model has good predictivity power for prediction lipophilicity data of potential in vivo metabolites of the investigated compounds, such as novel 1,2-ethanediamine and 1,3-propanediamine N,N'-di-2-(3-cyclohexyl)propanoic acid derivatives. Also, the lipophilicity data obtained in the present study correlated with the antiproliferative activity of the investigated substances shown previously in in vitro studies.

A metric was developed to identify hospital proportion of carbapenem consumption (PoCC) among antipseudomonal antibiotics. The PoCC varied significantly among academic medical centers by Census Bureau geographic division after adjusting for patient mix. This metric may be useful in identifying disproportionate carbapenem use and potential carbapenem overuse.Infect Control Hosp Epidemiol 2018;39:229–232

Outcome- or response-adaptive allocation methods are used to adjust randomization probabilities in clinical trials based on observations from previously accrued patients. These methods aim to achieve one of several allocation goals, which have included maximizing statistical power, balancing for covariates, and maximizing treatment benefit. In the latter case, adaptive allocation strategies aim to treat patients as ethically as possible, often by minimizing the expected number of treatment failures. These “optimal designs” achieve this minimization through algorithms and functions of success probabilities in each group of subjects.

Over the two years following the 2012 introduction of CMS's National Partnership, combined rates of schizophrenia, Tourette's, and Huntington's in US long-stay residents increased 12%. We evaluated trends in reporting of these diagnoses for the subgroup of long-stay residents on antipsychotics.Retrospective analysis of Virginia Medicaid claims identified annual utilization rates of psychiatric diagnoses for long-stay seniors on antipsychotics. Chi-square analysis compared rates for the year before March, 2012 with the same 12-month period 1 year later. A 5-year pre-existing baseline rate was also obtained.Diagnosis rates for 2011 were unchanged from baseline. Comparing 2011 with 2013, diagnoses rates for schizophrenia, Tourette's, and Huntington's combined increased 40% (p .0001), primarily because schizophrenia reporting nearly doubled (p .0001).For long-stay seniors on antipsychotics, reporting of schizophrenia, Tourette's, and Huntington's began increasing in 2012 and at almost triple the rate CMS described for the general long-stay population. The increased reporting of these diagnoses described by CMS since 2012 appears to be new and concentrated in residents on antipsychotics Clinical Implications: Since antipsychotics prescribed for schizophrenia, Tourette's, and Huntington's are excluded from quality-measure auditing, apparent reductions in inappropriate long-stay antipsychotic use since the National Partnership may be exaggerated.

Introduction This study examines how improving curricular content and technical interface issues could make maintenance of certification activities more meaningful to American Board of Family Medicine diplomates completing Maintenance of Certification for Family Physicians (MC-FP) Program self-assessment modules (SAMs). Methods We used a sequential exploratory design to analyze quantitative and qualitative data from 320,500 surveys of family physicians who completed a SAM between January 2004 and April 2013. This included numeric rating scales and free text comments. Basic statistical rankings, template-based automated coding, and emergent coding were used to analyze SAM experience and identify thematic content. Results Across SAMs, numeric ratings were universally high and positive free text comments outnumbered negative comments two to one. When comparing feedback on the knowledge assessment and clinical simulation (CS) activities, SAMs were rated less favorably when the frequency of ideas identified by participants as most prevalent in one activity mismatched those identified as most prevalent in the companion activity. Participants were also critical of navigation issues, technical issues, and a lack of realness in the CS activity. Discussion Whether analyzed through quantitative data, qualitative data, or mixed methods, a large majority of participants rated their experience with SAMs highly. When individual SAMs were rated poorly, it seemed to be due to discordance in ideas emphasized between the knowledge assessment and CS components, or an opinion regarding the SAM topic that existed independent of the SAM process.

Purpose To accurately measure external auditory canal (EAC) dimensions by high resolution computed tomography (CT), and compare results with a traditional method of EAC measurement. Methods Using an advanced multidimensional open source digital imaging and communications in medicine (DICOM) analysis program (OsiriX, Pixmeo, Geneva, Switzerland) 91 adult EACs were analyzed on a previously obtained temporal bone CT scan. Tympanometric data were also recorded for each ear. The methods were compared using a linear mixed effect model. Results EAC volume was compared between tympanometrically calculated volumes and CT measured volumes. It was found that CT measured volumes are, on average, smaller (1.12 cm3, SE = 0.04) than tympanometry volumes (1.27 cm3, SE = 0.04 cm3). There was a significant difference in CT measured volume between genders (p = 0.0125), with males having larger measured volumes (1.23 cm3, SD = 0.28 cm3) than females (1.06 cm3, SD = 0.20 cm3). There was a significant difference in average circumference between ear laterality (p = 0.0071), with the right ear having a slightly larger average circumference (2.49 cm, SD = 0.23 cm) than the left ear (2.44 cm, SD = 0.50 cm).There was also a significant difference in minimum circumference between age groups (p = 0.0448), with patients younger than 60 years having larger minimum circumferences (1.89 cm, SD = 0.21 cm) than older patients (1.78 cm, SD = 0.25 cm). Conclusions This study demonstrates that CT analysis can provide more information about EAC dimensions than traditional techniques. Moreover, slight but statistically significant differences are associated with age, gender and laterality. Accurate estimation of EAC dimensions is important for the development of hearing aids and personal protective equipment and can also be helpful for surgical planning, specifically otoendoscopy. Future research will focus on simplifying computation, developing cross-cultural cohort comparisons, and application to otoendoscopic procedures.

Introduction Engaging patients to make informed choices is paramount but difficult in busy practices. This study sought to engage patients outside the clinical setting to better understand how they approach cancer screening decisions, including their primary concerns and their preferences for finalizing their decision. Methods Twelve primary care practices offering patients an online personal health record invited eligible patients to complete a 17-item online interactive module. Among 11,458 registered users, invitations to complete the module were sent to adults aged 50–74 years who were overdue for colorectal cancer screening and to women aged 40–49 years and men aged 55–69 who had not undergone a recent mammogram or prostate-specific antigen test, respectively. Results The module was started by 2,355 patients and completed by 903 patients. Most respondents (76.8%) knew they were eligible for screening. Preferred next steps were talking to the clinician (76.6%), reading/research (28.6%), and consulting trusted friends/family (16.4%). Priority topics included how much screening improves life expectancy, comparative test performance, and the prevalence/health risks of the cancer. Leading fears were getting cancer/delayed detection (79.2%), abnormal results (40.5%), and testing complications (39.1%), the last referring to false test results, medical complications, or unnecessary treatments. Men eligible for prostate-specific antigen screening were more likely than women eligible for mammography to express concerns about testing complications and to prioritize weighing pros and cons over gut feelings (p Conclusions Although this sample was predisposed to screening, most patients wanted help in finalizing their decision. Many wanted to weigh the pros and cons and expressed fears of potential harms from screening. Understanding how patients approach decisions may help design more effective engagement strategies.

PURPOSE To describe the frequency and patient-reported readiness to change, desire to discuss, and perceived importance of 13 health risk factors in a diverse range of primary care practices. METHODS Patients (n = 1,707) in 9 primary care practices in the My Own Health Report (MOHR) trial reported general, behavioral, and psychosocial risk factors (body mass index [BMI], health status, diet, physical activity, sleep, drug use, stress, anxiety or worry, and depression). We classified responses as “at risk” or “healthy” for each factor, and patients indicated their readiness to change and/or desire to discuss identified risk factors with providers. Patients also selected 1 of the factors they were ready to change as most important. We then calculated frequencies within and across these factors and examined variation by patient characteristics and across practices. RESULTS On average, patients had 5.8 (SD = 2.12; range, 0–13) unhealthy behaviors and mental health risk factors. About 55% of patients had more than 6 risk factors. On average, patients wanted to change 1.2 and discuss 0.7 risks. The most common risks were inadequate fruit/vegetable consumption (84.5%) and overweight/obesity (79.6%). Patients were most ready to change BMI (33.3%) and depression (30.7%), and most wanted to discuss depression (41.9%) and anxiety or worry (35.2%). Overall, patients rated health status as most important. CONCLUSIONS Implementing routine comprehensive health risk assessments in primary care will likely identify a high number of behavioral and psychosocial health risks. By soliciting patient priorities, providers and patients can better manage counseling and behavior change.

PURPOSE Guidelines recommend screening patients for unhealthy behaviors and mental health concerns. Health risk assessments can systematically identify patient needs and trigger care. This study seeks to evaluate whether primary care practices can routinely implement such assessments into routine care. METHODS As part of a cluster-randomized pragmatic trial, 9 diverse primary care practices implemented My Own Health Report (MOHR)—an electronic or paper- based health behavior and mental health assessment and feedback system paired with counseling and goal setting. We observed how practices integrated MOHR into their workflows, what additional practice staff time it required, and what percentage of patients completed a MOHR assessment (Reach). RESULTS Most practices approached (60%) agreed to adopt MOHR. How they implemented MOHR depended on practice resources, informatics capacity, and patient characteristics. Three practices mailed patients invitations to complete MOHR on the Web, 1 called patients and completed MOHR over the telephone, 1 had patients complete MOHR on paper in the office, and 4 had staff help patients complete MOHR on the Web in the office. Overall, 3,591 patients were approached and 1,782 completed MOHR (Reach = 49.6%). Reach varied by implementation strategy with higher reach when MOHR was completed by staff than by patients (71.2% vs 30.2%, P

Background Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia, and remains largely incurable with current therapies. The anti-apoptotic protein Bcl-2 is overexpressed in CLL patients, where it mediates survival and resistance to chemotherapy and targeted therapies. Venetoclax is the first-in-class BH3 mimetic to specifically target the Bcl-2 protein and has been recently approved in patients with relapsed CLL. In the MURANO trial, the combination of venetoclax and rituximab has demonstrated impressive clinical activity, including achievement of minimal residual disease (MRD) negativity in more than half of the patients treated with the combination, allowing a time limited therapy approach. The phosphatidylinositol -3-kinase (PI3K) pathway is activated in several cancers, especially lymphoid malignancies, where it mediates cell growth and survival. Unlike other isoforms, the PI3K delta isoform is expressed only in hematopoietic cells and plays a key role in B-cell homeostasis and function. Idelalisib is the first-in-class PI3K delta inhibitor to show impressive clinical activity in B-cell malignancies, and is approved in combination with rituximab in patients with relapsed/refractory CLL. Interestingly, venetoclax activity is limited by acquired and intrinsic resistance. In this regard, the anti-apoptotic proteins Mcl-1 and Bcl-xl mediate preclinical resistance to venetoclax that can be overcome by inhibition of the PI3K pathway through idelalisib, providing a strong rationale for this combination in several B-cell malignancies. We have shown potent synergistic interaction between venetoclax and idelalisib using CLL samples. Therefore, we are conducting a multi-institutional phase 1 clinical trial studying rituximab in combination with idelalisib and venetoclax in patients with relapsed/refractory CLL. Study Design The primary objectives of the RIVe-CLL (NCT03639324) are to determine the recommended phase 2 dose of idelalisib and venetoclax in combination with rituximab in patients with relapsed, refractory CLL and to determine the MRD negative complete response rate of the triple combination at 13 months. As secondary endpoints, we will assess safety, toxicity, MRD negativity, progression-free survival, overall survival, overall response rates, and pharmacokinetics/pharmacodynamics of the combination. Key eligibility criteria include: age ≥ 18; patients with R/R CLL who require therapy; Eastern Cooperative Oncology Group performance status ≤ 2; and adequate renal, bone marrow, and hepatic function. Patients must have no active infection, liver disorders, or autoimmune disease. Using the modified continual reassessment method (mCRM), and the escalation with overdose control (EWOC) process in order to identify the maximum tolerated dose (MTD), we are planning to treat 36 patients, and accounting for 15% drop-out or loss of follow-up, we anticipate enrolling a maximum of 42 patients. Comprehensive correlative science studies have been embedded in this trial, and include assessment of the level of MRD, mutation in the PI3K pathway, and bcl-2 protein, expression of the bcl-2 family protein, and alteration in the immune subsets particularly T cell subsets. The goal of this study is to evaluate the safety and efficacy of this triple combination using non-overlapping drugs with different mechanisms of action and to understand the underlying mechanisms of sensitivity and/or resistance to the combination. Disclosures Yazbeck: Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Background Although Web-based questionnaires are an efficient, increasingly popular mode of data collection, their utility is often challenged by high participant dropout. Researchers can gain insight into potential causes of high participant dropout by analyzing the dropout patterns. Objective This study proposed the application of and assessed the use of user-specified and existing hypothesis testing methods in a novel setting—survey dropout data—to identify phases of higher or lower survey dropout. Methods First, we proposed the application of user-specified thresholds to identify abrupt differences in the dropout rate. Second, we proposed the application of 2 existing hypothesis testing methods to detect significant differences in participant dropout. We assessed these methods through a simulation study and through application to a case study, featuring a questionnaire addressing decision-making surrounding cancer screening. Results The user-specified method set to a low threshold performed best at accurately detecting phases of high attrition in both the simulation study and test case application, although all proposed methods were too sensitive. Conclusions The user-specified method set to a low threshold correctly identified the attrition phases. Hypothesis testing methods, although sensitive at times, were unable to accurately identify the attrition phases. These results strengthen the case for further development of and research surrounding the science of attrition.

Introduction: Indolent B-Cell Non-Hodgkin’s Lymphoma (i-NHL) represents a heterogeneous group of lymphoproliferative malignancies, encompassing 40% of NHL, that remains largely incurable. The B-cell receptor signaling pathway is activated in B-cell malignancy and mediates its activity mainly through the Phosphoinositide 3-kinase (PI3K) pathway. Furthermore, novel PI3K inhibitors, such as idelalisib and copanlisib, have shown impressive clinical activity in several indolent lymphomas including marginal zone lymphoma (MZL). This further supports the important role of the PI3K pathway in these tumors. Methods We generated a genetically engineered mouse model carrying heterozygous knockout alleles of both the tumor suppressor genes Phosphatase and Tensin Homolog (PTEN) and Liver Kinase B1 (LKB1), leading to over-activation of the PI3K-mTOR pathway in all mouse tissues. We closely monitored these mice for tumor formation by at least weekly physical examinations for several months. Upon tumor detection, tumor size was recorded weekly using calipers, with an experimental endpoint of 15-20mm in any dimension. One half of the tumor was immediately preserved in a 4% paraformaldehyde solution and prepared for sectioning, H&E and immunohistochemical staining. Results: Thirty mice died or were sacrificed due to disease progression, defined as either lymph node enlargement and/or splenomegaly. All mice showed either abnormal lymphadenopathy or splenomegaly. By Kaplan-Meier analysis, we saw a steady decrease in both tumor-free and overall survival after 3 months of age. Utilizing the product limit method, the median survival time was 6 months (95% CI: 6, 8). A total of 51 lymph nodes were sent for IHC and pathological identification. Of the 51 nodes, 61.5% (N=32) showed indolent Non-Hodgkin’s Lymphoma, 25% (N=13) were atypical, and 11.5% (N=6) were reactive. All lymph nodes with indolent NHL were Marginal Zone subtype. In order to generate a more specific model of B cells, we used the Cre/LoxP system with CD19-Cre. We detected an increase in the average portion of MZL B cells in the spleen of the homozygous mice compared to wild type (38.3% vs 4.9%, p=0.0216). Conclusion: Nodal marginal zone lymphoma remains an incurable indolent lymphoma that lacks preclinical models. As novel agents become available, it is important to have a better understanding of the underlying pathogenesis of this malignancy and be able to model it in an immunocompetent mouse with a preserved microenvironment. Our data provides, for the first time, a proof of concept on the role of the PI3K-mTOR pathway in the pathogenesis of nodal marginal zone lymphoma and paves the way for future studies understanding the biology of this disease, and developing rational therapies for this incurable malignancy. Note: This abstract was not presented at the meeting. Citation Format: Victor Yazbeck, Ian McConnell, Joseph Lownik, Ariel Sindel, Roy Sabo, Alden Chesney, Guanhua Lai, Adolfo Mauro, Jamal Zweit, Rebecca Martin, Daniel Conrad, Steven Grant, Jolene Windle, Steven Grossman. Mouse model for nodal marginal zone lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4634.

Purpose Psychiatric history is known to be relevant to concussion outcomes, although less is known about the role of such factors or current mood ratings in adolescents. The aim of this study was to assess the role of premorbid psychiatric history (PPH) and current mood ratings (CMR) on overall sports-related concussion (SRC) symptomology and cognitive outcomes in adolescent and young adult athletes. Methods Participants age 12–25 years (M=14.8) diagnosed with SRC (n=560) were evaluated within 14 days of injury as part of the North Texas Concussion Registry (ConTex) using the Patient Health Questionnaire-8 Items (PHQ-8), General Anxiety Disorder-7 Item Scale (GAD-7), and ImPACT. Subjects were dichotomized into those with (PPH+) and without (PPH-) pre-existing reported psychiatric diagnoses, and CMR groups were determined by normal vs. elevated scores on the GAD-7 and PHQ-8. T-tests were used to compare groups. Results Significant differences in total symptom severity scores were found between both PPH (p=.01) and CMR (p Conclusion Findings suggest that PPH and elevated CMR are associated with greater self-reported symptom severity in adolescent SRC, but have little relationship to cognitive outcomes as assessed by ImPACT. Further research is needed to understand the interaction between PPH, CMR, and SRC recovery across the age spectrum.

Clinical outcomes following hematopoietic cell transplant (HCT) are considered stochastic with different outcomes despite uniformity in characteristics between patients. However, immune reconstitution following SCT has features of a dynamical system, making it likely that clinical outcomes are partially deterministic. We hypothesized that early cessation of mycophenolate mofetil (MMF) in reduced intensity conditioning (RIC) transplants will hasten T cell reconstitution without adversely impacting clinical outcomes. This idea is being tested in a randomized phase 2 clinical trial comparing GVHD prophylaxis using a regimen of tacrolimus & MMF 15 mg/kg q 12 h for 30 days in the control (MMF30) vs. 15 days in the study cohort (MMF15). The MMF15 patients received GM-CSF to promote early monocyte recovery; MMF 30 got G-CSF. All patients underwent reduced intensity conditioning with ATG 1.7 mg/kg/d given on days -9 thru -7 & 450 cGy total body irradiation on d-1 & 0. Patients were stratified based on diagnosis and donor type (8/8 or 7/8 HLA MRD or MUD). A response-adaptive randomization scheme was used to increase the probability that patients were allocated to the treatment regimen which yields superior donor-derived CD3+ (ddCD3) cell count by 8 weeks; primary endpoint is relapse free, DLI free survival. Preliminary results from the first 21 evaluable patients are presented. Patients baseline characteristics are summarized in table 1. Mean ddCD3 count at 8 weeks post HCT favored the MMF group (461 vs. 329), which led to more patients allocated to MMF15 cohort. Median myeloid engraftment at day 60 was 100% in both cohorts. Mean absolute lymphocyte count, CD3+ and CD4+ T-cell counts were higher in the MMF15 cohort on day 30 (500 vs 200/mL−1, P=0.005; 254 vs. 71/mL−1, P=0.0188; 107 vs. 25/mL−1, P=0.0036 respectively). There was a trend for higher ddCD3 cell count in the MMF15 cohort (Fig. 1). Despite this there were no significant differences noted on in lymphoid recovery at later time points. Despite a shorter course of MMF there was no significant difference in the rates of acute and chronic GVHD, relapse and patient survival between the two cohorts (Fig 2). In conclusion these early data demonstrate that a shorter 15-day course of MMF plus GM-CSF led to rapid, early T cell reconstitution post HCT without a significant increase in the risk of acute or chronic GVHD, or disease relapse. This effect is consistent with immune reconstitution post HCT being a dynamical rather than a stochastic process, which may be modified in real-time by adjustments in the intensity of GVHD prophylaxis.

Introduction Patients who receive HLA matched allogeneic hematopoietic cell transplant (HCT) from donors with killer immunoglobulin-like receptor (KIR) haplotype B have improved survival, decreased acute GVHD, and less CMV reactivation when compared with those transplanted with KIR haplotype A donors. However, the effect of NK cell (CD56+) reconstitution kinetics on clinical outcomes in patients with different KIR haplotypes is not well studied. Objectives Compare CD 56+ cell reconstitution kinetics in HCT patients with donor KIR Haplotypes A and B and its effect on clinical outcomes. Methods We assessed absolute NK and T cell counts at days +30, +60 and +100 in 10/10 allele level HLA matched unrelated HCT recipients with known donor KIR typing. KIR haplotype B was assigned when KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 or KIR3DS1 were present in the donor, and haplotype A in their absence. We also evaluated potential impact of NK cell and T cell count recovery on key post transplant outcomes in these patients. Results The study population consisted of 60 adult HCT patients with a median age of 52 years; 55% had lymphoid and 45% had myeloid disease; 57% received a reduced intensity conditioning regimen; 82% underwent T cell depletion with ATG; 88% received GCSF mobilized PBSCT. Recipients of donor haplotype A had a median absolute CD56+ cell count of 210mL−1 (±156) on day (d) +30; 189 (±225) on d+60, and 160 (±120) on d+100; recipients of haplotype B had median absolute CD56 cell counts of 286 (±276) on d+30, 196 (±194) on d+60, and 165 (±124) on d+100 (P=N.S. for haplotype B vs. A). As a whole, median CD56+ cell counts peaked at d+30 post HCT, a phenomenon more pronounced in haplotype B (fig. 1), and then declined at d+60 and d+100. There was no correlation between CD56 and CD3 at d+60. Survival was superior in patients who had CD56+ cell count > median for the entire cohort (227 µL−1) on d+60 (p= .039) (fig. 2); ROC-AUC analysis confirmed the deleterious effect of low NK cell counts, with a higher mortality rate observed in those with CD56+ cell count of Conclusions The magnitude of NK cells reconstitution at d+60 may override the effect of KIR Haplotype on survival in patients with myeloid and lymphoid malignancies, as well as play an important role in controlling viral reactivation. Our data demonstrates that poor NK cell recovery does not necessarily imply delayed T cell reconstitution; suggesting that the adverse survival effect may be NK cell mediated. Ongoing work is examining relationship between NK- and T-cell reconstitution as well as KIR-KIR ligand interactions, and clinical outcomes.

Increases in vector-host contact rates can enhance arbovirus transmission intensity. We investigated weekly fluctuations in contact rates between mosquitoes and nesting birds using the recently described Nest Mosquito Trap (NMT). The number of mosquitoes per nestling increased from < 1 mosquito per trap night to 36.2 in the final 2 wk of the nesting season. Our evidence suggests the coincidence of the end of the avian nesting season and increasing mosquito abundances may have caused a “host funnel,” concentrating host-seeking mosquitoes to the few remaining nestlings. The relative abundance of mosquitoes collected by the NMT suggests that significantly more Aedes albopictus (Skuse) and Culex pipiens (L.)/restuans (Theobald) sought nesting bird bloodmeals than were predicted by their relative abundances in CO2-baited Centers for Disease Control and Prevention light and gravid traps. Culex salinarius (Coquillett) and Culex erraticus Dyar and Knab were collected in NMTs in proportion to their relative abundances in the generic traps. Temporal host funnels and nesting bird host specificity may enhance arbovirus amplification and explain observed West Nile virus and St. Louis encephalitis virus amplification periods.

PURPOSE Technology could transform routine decision making by anticipating patients’ information needs, assessing where patients are with decisions and preferences, personalizing educational experiences, facilitating patient-clinician information exchange, and supporting follow-up. This study evaluated whether patients and clinicians will use such a decision module and its impact on care, using 3 cancer screening decisions as test cases. METHODS Twelve practices with 55,453 patients using a patient portal participated in this prospective observational cohort study. Participation was open to patients who might face a cancer screening decision: women aged 40 to 49 who had not had a mammogram in 2 years, men aged 55 to 69 who had not had a prostate-specific antigen test in 2 years, and adults aged 50 to 74 overdue for colorectal cancer screening. Data sources included module responses, electronic health record data, and a postencounter survey. RESULTS In 1 year, one-fifth of the portal users (11,458 patients) faced a potential cancer screening decision. Among these patients, 20.6% started and 7.9% completed the decision module. Fully 47.2% of module completers shared responses with their clinician. After their next office visit, 57.8% of those surveyed thought their clinician had seen their responses, and many reported the module made their appointment more productive (40.7%), helped engage them in the decision (47.7%), broadened their knowledge (48.1%), and improved communication (37.5%). CONCLUSIONS Many patients face decisions that can be anticipated and proactively facilitated through technology. Although use of technology has the potential to make visits more efficient and effective, cultural, workflow, and technical changes are needed before it could be widely disseminated.

This article presents an outcome-adaptive allocation method for dual-outcome clinical trials, where the allocation probabilities for each treatment depend on the relative performance of those treatments with respect to both outcomes. The method for computing such allocation weights is presented for cases where treatment performance is based on intertreatment comparisons, hypothetical standards, and a combination of the two. Simulation studies show that this method allocates patients away from inferior, ineffective, or harmful treatments and toward superior or otherwise beneficial treatments, at the cost of a moderate power loss when compared with balanced designs. This method also performs well in the presence of dependent outcomes. An example from a study of stem cell transplant patients with two objectives is presented to show how this method works in practice, where patients are allocated most frequently into the most efficacious treatment and away from those that do not work as well or are relatively ...

The anatomy of the glenoid is of critical importance when reconstructing the shoulder joint with arthroplasty. Over the past two decades, numerous techniques for measuring the orientation of the articular surface with respect to the rest of the scapula have been described. The present review examines these methods, as well as how they have evolved with technological advances, and how they can be applied to improve the restoration of normal anatomy with shoulder arthroplasty. The originally described technique has been widely accepted and applied to two- and three-dimensional computed tomography scans. Other new techniques have been described recently that use other landmarks entirely. Recent advances in computer-assisted surgery take these principles of measurement to allow more precise navigation and placement of glenoid components in simulation and in vivo.

A small body of evidence supports targeting adolescents who are heavy users of cannabis with brief interventions, yet more research is needed to confirm the effectiveness of these studies. We conducted a secondary analysis of our Peer Network Counseling (PNC) study (Mason et al., 2015), focusing on 46 adolescents of the sample of 119 who reported heavy cannabis use at baseline.Urban adolescents (91% African American) presenting for primary health care were randomized to intervention or control conditions and followed for 6 months. We selected cases (n = 46) to analyze based on heavy cannabis use reported at baseline (≥10 times in past month). The ordinal response data (cannabis use) were modeled using a mixed-effects proportional odds model, including fixed effects for treatment, time, and their interaction, and a subject-level random effect.In the subsample of adolescents with heavy cannabis use, those assigned to PNC had a 35.9% probability of being abstinent at 6 months, compared with a 13.2% probability in the control condition. Adolescents in the PNC condition had a 16.6% probability of using cannabis 10 or more times per month, compared with a 38.1% probability in the control condition. This differs from results of the full sample (N = 119), where no significant effects on cannabis use were found.PNC increased the probability of abstinence and reduced heavy cannabis use. These results provide initial support for PNC as a model for brief treatment with non-treatment seeking adolescents who are heavy users of cannabis.

Quantitative relationship between the magnitude of variation in minor histocompatibility antigens (mHA) and graft versus host disease (GVHD) pathophysiology in stem cell transplant (SCT) donor-recipient pairs (DRP) is not established. In order to elucidate this relationship, whole exome sequencing (WES) was performed on 27 HLA matched related (MRD), & 50 unrelated donors (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs). An average 2,463 SNPs were identified in MRD, and 4,287 in URD DRP (p

Background: Electronic surveys are convenient, cost effective, and increasingly popular tools for collecting information. While the online platform allows researchers to recruit and enroll more participants, there is an increased risk of participant dropout in Web-based research. Often, these dropout trends are simply reported, adjusted for, or ignored altogether. Objective: To propose a conceptual framework that analyzes respondent attrition and demonstrates the utility of these methods with existing survey data. Methods: First, we suggest visualization of attrition trends using bar charts and survival curves. Next, we propose a generalized linear mixed model (GLMM) to detect or confirm significant attrition points. Finally, we suggest applications of existing statistical methods to investigate the effect of internal survey characteristics and patient characteristics on dropout. In order to apply this framework, we conducted a case study; a seventeen-item Informed Decision-Making (IDM) module addressing how and why patients make decisions about cancer screening. Results: Using the framework, we were able to find significant attrition points at Questions 4, 6, 7, and 9, and were also able to identify participant responses and characteristics associated with dropout at these points and overall. Conclusions: When these methods were applied to survey data, significant attrition trends were revealed, both visually and empirically, that can inspire researchers to investigate the factors associated with survey dropout, address whether survey completion is associated with health outcomes, and compare attrition patterns between groups. The framework can be used to extract information beyond simple responses, can be useful during survey development, and can help determine the external validity of survey results. [J Med Internet Res 2016;18(11):e301]

Objective: Previous studies have shown associations between body mass index and cardiac structure in both childhood and adulthood. Using Fels Longitudinal Study measurements, we investigate the relationships between a curtailed juvenile state and both adult cardiac structure and function. Methods: A linear mixed-effect repeated measure analysis of variance model is used to test if there is a relationship between juvenile state and each echocardiographic measurement. Results: The curtailed juvenile state is significantly associated with adult left ventricular mass index for both males and females. It is also significantly associated with the interventricular septal wall thickness index and relative wall thickness index for females. In both cases, early juvenile states led to more abnormal structural estimates in adulthood than did late juvenile states. Among cardiac function measurements such as left ventricular ejection fraction and left ventricular shortening fraction, left ventricular ejection fraction is significantly associated with the juvenile state for females. Conclusion: The curtailed juvenile state at the childhood may have a long-term adverse effect on adult cardiac structure and function abnormalities.

Background The study aims to compare how work-to-rest ratio (W:R) influences insulin sensitivity (Si) and inflammatory responses following one session of sprint interval training (SIT). Methods Thirteen men and two women completed a cross-over comparison of two SIT interventions—Tabata (TAB), 10 × 20-s sprints/10-s rest, and Wingate (WIN), 5 × 30-s sprints with 270-s rest. IL-6, IL-10, and TNF-α were assessed at baseline, immediately following, and 1 h after SIT, as well as prior to the 24-h post-exercise oral glucose tolerance tests (OGTTs). Results Participants were 23.8 (±3.5) years old and 180.0 (±10.2) cm tall, weighed 78.5 (13.0) kg, and had 16.9 (±6.5) % body fat, with a mean VO2Peak of 42.0 (±7.9) ml kg−1 min−1. There were no differences in total work (kJ) between TAB (64.7 ± 12.0) and WIN (68.0 ± 15.0). Mean (±95 % CI) Si 24 h changed −2.8 (−5.1, −0.5) from baseline after TAB and −3.9 (−6.9, −0.9) after WIN. Cytokines were measured in pg ml−1 and expressed as mean change (±95 % CI). IL-6 increased significantly immediately following SIT for TAB 0.70 (0.23, 1.17), and WIN 1.11 (0.60, 1.62), and remained elevated 1 h post SIT for TAB 1.10 (0.37, 1.83), and WIN 0.95 (0.26, 1.65). IL-10 showed a significant positive change immediately following exercise for TAB 1.53 (0.77, 2.29) and WIN 1.59 (0.58, 2.59). TNF-α also increased immediately both TAB 3.26 (1.57, 4.96) and WIN 3.05 (0.56, 5.54) and was directly proportional to IL-10 (r = 0.64, p

The reference points for rotational orientation of the humeral component during elbow arthroplasty typically are on the articular surface or the humeral epicondyles. With bone loss, these landmarks may be compromised. Our purpose was to assess whether the flat posterior humeral cortex proximal to the olecranon fossa is a reliable landmark with which to orient the humeral component during elbow arthroplasty.Fifty cadaveric elbows (mean age [and standard deviation] at the time of death, 73 ± 12 years) underwent computed tomography (CT) scans. The flexion-extension axis (FEA) was determined by sphere-fitting the capitellar surface and circle-fitting the narrowest portion of the trochlea. The posterior humeral cortical line (PCL) was drawn on the flat posterior humeral cortex proximal to the olecranon fossa. The transepicondylar axis (TEA) was determined by a line between the most prominent points on the epicondyles. The angles between the PCL and FEA and the TEA and FEA were calculated and were compared by using two-tailed t tests.The PCL was externally rotated by a mean (and standard deviation) of 14.0° ± 4.2° (plt; 0.001) relative to the FEA (males: 12.6° ± 3.6°, females: 16.4° ± 5.2°; p = 0.002). The TEA was externally rotated by a mean of 2.8° ± 3.5° (plt; 0.001) relative to the FEA (males: 2.7° ± 3.4°, females: 2.6° ± 3.7°; p = 0.96). The intraobserver and interobserver reliability wasgt;0.98 for the capitellar and trochlear centers, while the cumulative intraobserver and interobserver reliability was 0.8 and 0.5 for the FEA-PCL angle and 0.4 and 0.3 for the FEA-TEA angle.The posterior humeral cortex is a reproducible landmark that is externally rotated with respect to the flexion-extension axis of the distal part of the humerus. The surgeon must be aware of the need for an internal rotation correction factor and consider the influence of the patient's sex on this correction when using the posterior humeral cortex as a landmark to avoid humeral component malrotation.While the PCL is better than the TEA as a reference point, neither is able to accurately identify the FEA because of considerable normal variation. Future studies are needed to evaluate the effectiveness of computer-assisted techniques or a preoperative CT scan of the contralateral, unaffected elbow in identifying rotational landmarks for the elbow undergoing arthroplasty.

Background: Evidence shows that some causes of the metabolic syndrome (MS) begin in childhood, which could indicate a familial association, through either genetic inheritance or cohabitation. Objective: This study examined associations between parents and adult offspring diagnoses of the MS and its risk factors. Design: Measurements were obtained from adult participants and their adult offspring enrolled in the Fels Longitudinal Study, with simultaneous waist circumference, systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, HDL, and glucose observations used for diagnosis. On the basis of repeated measurements (in some cases), adult participants were classified as having the MS at least once or as never having the MS. Chi-square tests, ORs, and mixed-effects models were used to study familial associations. Results: Maternal (OR: 2.5; 95% CI: 1.1, 5.5) and paternal (OR: 4.1; 95% CI: 1.4, 12.1) MS classifications were significantly associated with MS classification in sons. MS classification in mothers and daughters (OR: 2.7; 95% CI: 0.9, 8.7; P = 0.08) was similar to that in sons but was not significant, whereas fathers and daughters were not associated (OR: 1.1; 95% CI: 0.4, 3.5). Maternal MS diagnoses were significantly and positively associated with triglycerides in male offspring and were significantly associated with SBP, DBP, and triglycerides in females. Paternal diagnoses were significantly associated only with DBP and HDL in male offspring. Conclusions: Parental MS diagnosis is significantly associated with MS diagnosis in adult male offspring, and adverse levels of certain risk factors are associated between offspring and parents, although these associations vary across risk factors and child sex.

Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT.

The elbow joint is susceptible to osteochondral injuries related to complex fracture-dislocations, as well as to conditions such as osteochondritis dissecans. In many instances, the repair of fragments or fibrocartilage-stimulating techniques are sufficient to treat the defects but, in some patients, this is either not feasible or has failed. In these situations, osteochondral autografts provide reconstructive options. The present review discusses reconstructive options for the coronoid, radial head and capitellum using autografts.

While univariate instances of binomial data are readily handled with generalized linear models, cases of multivariate or repeated measure binomial data are complicated by the possibility of correlated responses. Likelihood-based estimation can be applied by using mixture distribution models, though this approach can present computational challenges. The logistic transformation can be used to bypass these concerns and allow for alternative estimating procedures. One popular alternative is the generalized estimating equation (GEE) method, though systematic errors can lead to infeasible correlation estimates or nonconvergence problems. Our approach is the coupling of quasileast squares (QLSs) method with a rarely used matrix factorization, which achieves a simplified estimation platform—as compared to the mixture model approach—and does not suffer from the convergence problems in GEE method. A noncontrived example is provided that shows the mechanical breakdown of GEE using several statistical software packages and highlights the usefulness of the QLS approach.

BACKGROUND In patients with hematologic malignancies who receive stem-cell transplantation, donors' T cells can recognize minor histocompatibility antigens on recipient cells and generate an objective response against the tumor. However, a major side effect of such therapy is graft-versus-host disease (GVHD). The purpose of this study was to characterize distinct T-cell clones that were frequently and exclusively involved in GVHD or graft-versus-tumor (GVT) effects. METHODS We hypothesized that distinct GVHD-associated T-cell clones can be identified during the disease progression. To test this, we conducted comparative analysis of T-cell receptor (TCR) Vβs in donor-recipient pairs of patients with GVHD versus those with GVHD-free and relapse-free survival using quantitative reverse-transcriptase polymerase chain reaction and spectratyping analyses. RESULTS We identified three sets of T-cell clones that were either frequently involved in GVHD (TCR Vβ4, 11, and 23) or GVT effect (TCR Vβ9, 16, and 20), or were increased at the time of GVHD and GVT effects in a patient-specific manner (TCR Vβ2, 3, 7, 12, 15, and 17). Spectratyping analysis showed restricted clonality of the identified TCR Vβs. Polymerase chain reaction analysis also confirmed the presence of GVHD-associated T-cell clones at the site of the disease. CONCLUSIONS These data suggest that GVHD- and GVT-associated clones can be distinguished by molecular analysis of TCR Vβ to develop targeted therapy for GVHD.

Rabbit anti-thymocyte globulin (ATG) is used as prophylaxis against GVHD following allogeneic hematopoietic cell transplantation (HCT). At our institution, ATG is exclusively used in the conditioning of matched unrelated donor (URD) transplant recipients. A total of 50 URD HCT recipients who received ATG (ATG group) were retrospectively compared with 48 matched related donor (MRD) HCT recipients who did not receive ATG (no ATG group). There were no significant differences between the groups in rates of day 100 mortality, acute GVHD or relapse. Chronic GVHD incidence was significantly lower in the ATG group (P = 0.007). At a median follow-up of 36 months in the entire cohort, 50% patients are alive in the ATG group and 63% of the patients are alive in the no ATG group (P = 0.13). We conclude that the administration of ATG to patients undergoing URD HCT preserves the anti-leukemia benefit of the transplant, while reducing the risk of developing GVHD, resulting in OS rates that are comparable to MRD HCT recipients.

Longitudinal instability of the forearm (the Essex-Lopresti injury, radioulnar dissociation) is uncommon and is often missed in the initial assessment of a patient with a radial head fracture. The present review outlines the anatomy and biomechanics of the forearm unit, as well as the current means of diagnosis and the range of treatment options avaailable for this challenging problem.

Objectives: To determine secular trends by birth decade in body mass index (BMI), waist circumference/height (W/Ht), percent body fat (PBF), and fat-free mass adjusted for height squared (FFM/Ht2) in children and adolescents aged 8–18 years. Methods: Serial data were analyzed from 628 boys and 591 girls aged 8–18 years who participated in the Fels Longitudinal Study. Subjects were stratified by birth decade from 1960 to 1999. Means and standard deviations were computed for all measurements by birth decade, age, and sex. A repeated-measures analysis of variance was used data to ascertain secular trends separately for boys and girls. Results: Boys and girls born in the 1990s had significantly higher mean BMI, W/Ht, and PBF than did children born in previous decades. Mean FFM/Ht2 was significantly smaller in boys born in the 1990s than boys of the same age born in earlier decades. No secular trend was noted in FFM/Ht2 in girls by decade of birth. Conclusion: Our analysis of serial data collected over 4 decades confirms the secular trend in childhood BMI previously observed in successive cross-sectional studies. Our analysis discloses significant positive secular trends in W/Ht and PBF in both boys and girls and a significant negative secular trend in FFM/Ht2 in boys over the last 4 decades of the 20th century. The secular changes presage increases in the prevalence of conditions associated with childhood and adolescent obesity—such as hypertension, glucose intolerance, and dyslipidemia—that may appear as early as the second decade of life. Am. J. Hum. Biol., 2012. © 2012 Wiley Periodicals, Inc.

OBJECTIVE: To document age- and sex-related differences in the 16 phenotypes of risk factors for the metabolic syndrome (MS) among adults in the Fels Longitudinal Study (FLS). METHODS: Data on risk factors for the MS were analyzed in 471 white men and 503 white women in the FLS. We used the Cochran-Armitage test to compare age- and sex-related differences in the prevalence of the 16 diagnostic clusters of positive risk factors. RESULTS: Of the 974 subjects, 238 were found to meet diagnostic criteria for 15 of a possible 16 phenotypes of the MS. The prevalence of the MS was four times greater in subjects older than 40 years than in subjects 20-40 years old. Older subjects had more risk factors exceeding criterion values than younger subjects. Among those who met three-to-five criteria for the MS, younger subjects were more likely to have dyslipidemia, less likely to have high blood pressure (HBP), and two times less likely to have impaired fasting plasma glucose (IFG) than subjects 40+ years old. Older men were more likely than older women to have HBP and IFG. . We found that if one of the five risk factors reaches a criterion value, the values for the other four risk factors move closer to their own diagnostic criterion values in apparent synchrony. CONCLUSIONS: Subjects 40+ years old are four times likelier to have the MS than younger subjects, and older men are at higher risk than older women. The mean values for each of the five risk factors get progressively worse as the number of risk factors meeting diagnostic criteria increases. Therefore, when one factor is found to meet its diagnostic criterion, levels of the other four risk factors should be measured. The different phenotypic patterns that comprise the MS should prompt clinicians to target specific risk factors for prevention or treatment. Certain phenotypes were found more commonly in women and certain others more commonly in men. Similarly, certain phenotypes were found more commonly in older than in younger age groups. These age- and sex-specific phenotypes should help clinicians to identify subjects at highest risk for certain risk factors and to initiate specifically tailored preventive and therapeutic interventions. Our observations should also stimulate clinical investigators and epidemiologists to ascertain what factors determine the sex and age specificity of certain phenotypes of the MS.

Objectives: While researchers are increasingly recognizing the importance of adjusting waist circumference (WC) for height, no standard has yet been established. In this study we contrast three standard methods for indexing WC by height (using height, root-height and height-squared) via comparisons with age-specific optimal indices. Study Design and Setting: Measurements from 722 male and 746 female Caucasian participants in the Fels Longitudinal Study were used. The three standard waist-circumference indices (as well as an optimal index) were determined for ages 2 through 18, and for every decade thereafter to 70 years of age. Pearson correlations were used to assess the suitability of all indices. Results: The three standard indices remain correlated with the original WC measures, though each was associ-ated with height at some ages. Waist-to-height ratio is suitable for some childhood ages (boys: 5 - 9, 13 - 16; girls: 4 - 7, 9, 11 - 14) but not for adult ages; Root-height works well mostly for older teenage children and adults but not in early childhood and adolescence; Height-squared is nowhere suitable. In both men and women, the optimal indexing factor ranged between root-height and height-squared in childhood, and is close to root-height in adulthood. Conclusions: No one index is most suitable, as WC indexed by root-height is suitable for use with measurements from teenage children and adults, while waist-to-height ratio is generally suitable for use in children. WC indexed by height-squared is nowhere suitable.

Studies have consistently shown that exposure to certain pesticides can be linked to adverse health conditions in both children and adults. These effects are complicated by exposure to multiple pesticides in the form of a chemical mixture. In this manuscript a methodology is presented that simultaneously summarizes the exposure profile into a representative value, yet maintains information on the individual constituents. An empirical Pseudo-Bayes (EB) approach is used to create a weighted-summation of the chemical concentrations, where Monte-Carlo methods are used to derive the weights from prior distributions based on information from the univariate relationships between each chemical and some response. This weighted summation is used to estimate a relationship between the set of chemicals and the response. A simulation study is used to compare the EB approach with two traditional approaches used in chemical exposure risk assessment, and an example is provided using pesticide data and metabolic hormone concentrations from the National Health and Nutrition Examination Survey. Copyright © 2011 John Wiley & Sons, Ltd.

Purpose Osteochondritis dissecans (OCD) of the capitellum most commonly affects adolescent pitchers and gymnasts, who present with pain and mechanical symptoms. Patients with larger lesions have poorer outcomes, possibly related to increased contact pressures on the surrounding articular surface with or without instability. The purpose of this in vitro study was to determine whether displaced OCD lesions of the capitellum lead to altered kinematics and stability of the elbow. Methods We mounted 9 fresh-frozen cadaveric arms in an upper extremity joint testing system, with cables attaching the tendons of the major muscles to motors and pneumatic actuators. An electromagnetic receiver on the ulna enabled quantification of the kinematics of the radius and ulna with respect to the humerus. We used 3-dimensional computed tomography scans and computer-assisted techniques to navigate sequential osteochondral defects ranging in size from 12.5% to 100% of the capitellum. The arms were subjected to active and passive flexion in both the vertical and valgus positions with the forearm in both pronation and supination. Results We found no significant differences in valgus angulation or ulnar rotation between any of the OCD lesions and the intact elbow during flexion, regardless of arm position or forearm rotation. Conclusions Osteochondritis dissecans lesions of the capitellum, both small and large, did not alter the ulnohumeral kinematics and stability with intact collateral ligaments. Therefore, excision of unfixable osteochondral fragments of the capitellum in the setting of intact collateral ligaments can be considered without the risk of creating instability.

Background: Primary Hepatobiliary Lymphoma (PHBL) is a rare disease. In review of the literature, there are only few retrospective studies. On prior studies, the median age at presentation was 62 years and was associated with a median overall survival of 162 months. In this study, we sought to characterize standard prognostic factors and their effects on overall survival utilizing the Surveillance, Epidemiology and End Results (SEER) database. Methods The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients diagnosed with PHBL between 1973 and 2014. B-Cell and T-Cell lymphomas of all stages were included. Patient characteristics and demographics are summarized. Overall survival (OS) was estimated using the Kaplan-Meier method for all patients and for sub-groups. Comparisons are made between the survival functions between the levels of these categorical measurements using the log-rank test, where we adjust the significance level to account for multiple comparisons using the Bonferroni correction. Results: A total of 1751 patients were included. The mean age was 64 years (2-97), with the majority of patients being male (n=1081, 62%) and Caucasian (n=1278, 73%). B-cell Non-Hodgkin's Lymphoma was the predominant lymphoma (n=1297, 75%), followed by Not Otherwise Specified (n=338, 19%), and T-cell NHL and Hodgkin's Lymphoma were nearly identical at n=54 and 50 respectively. Staging at presentation varied with the majority being 1 and 4 (n=703, 40% and n=698, 40%), this was followed by stage 2 (n=196, 11%). The median overall survival time was 16 months (95% CI; 12, 23). By diagnoses, the median survival time (Figure 1) for B-Cell NHL was 23 months (95% CI; 17, 33) and was significantly longer survival than patients with T-Cell NHL (1 month, 95% CI; 0, 8, p=0.0014) and NOS (9 months, 95% CI; 6, 12, p=0.0076) but was not significantly different than patients with Hodgkin's Lymphoma (12 months, 95% CI; 1, 71 p=0.15). By staging, patients with stage 1 (38 months, 95% CI; 24, 52) did not have a statistically significant difference in survival in comparison to stage 2 (15 months, 95% CI; 9, 48, p=0.85) or 3 (10 months, 95% CI; 2, 34, p=0.0173). Results were not statistically significant regarding gender nor ethnicity. On a multivariant analysis, surgery, chemotherapy, or radiation were all associated with better survival when adjusted for patient age, sex, race, disease type and cancer stage. However, there did not appear to be a statistical significance when compared to each other. Conclusion PHBL is a rare lymphoma affecting mostly elderly, Caucasian males. B-Cell NHL subtype and stage 1 were associated with a more favorable prognosis. However, compared to DLBCL, PHBL seem to have a poorer outcome. While treatment alone conferred a longer survival, the type of treatment option did not have an overall change to prognosis. Disclosures No relevant conflicts of interest to declare.

Introduction There are roughly 75,000 new cases of Non-Hodgkin's Lymphoma every year, representing almost 5% of all new cancer diagnoses. Indolent B-Cell Non-Hodgkin's Lymphoma (i-NHL) represents a heterogeneous group of lymphoproliferative malignancies, encompassing 40% of NHL, that remains largely incurable. Follicular lymphoma and marginal zone lymphoma (MZL) are the two most common subtypes of i-NHL. The B-cell receptor signaling pathway is activated in B-cell malignancy and mediates its activity mainly through the Phosphoinositide 3-kinase (PI3K) pathway. Furthermore, novel PI3K inhibitors, such as idelalisib and copanlisib, have shown impressive clinical activity in several indolent lymphomas including MZL. This further supports the important role of the PI3K pathway in these tumors. Therefore, we hypothesized that the PI3K-mTOR (mammalian target of rapamycin) pathway is sufficient for driving the pathogenesis of marginal zone lymphomas. Methods In order to test our hypothesis, we generated a genetically engineered mouse model carrying heterozygous knockout alleles of both the tumor suppressor genes Phosphatase and Tensin Homolog (PTEN) and Liver Kinase B1 (LKB1), leading to over-activation of the PI3K-mTOR pathway in all mouse tissues. We closely monitored these mice for tumor formation by at least weekly physical examinations for several months. Upon tumor detection, tumor size was recorded weekly using calipers, with an experimental endpoint of 15-20mm in any dimension. Upon reaching this endpoint, or if the surrounding area became necrotic/ulcerated, if the mouse's physical/behavioral condition deteriorated, or if there were any adverse conditions warranting mouse sacrifice, the mouse was euthanized and any existing tumors and any other tissues of interest were harvested. One half of the tumor was immediately preserved in a 4% paraformaldehyde solution and prepared for sectioning, H&E and immunohistochemical staining, with CD3 (T-cell marker), and PAX-5 (B-cell marker). The 2nd half of the tumor was processed using a "stomacher" machine to dissociate the tumor cells, which were then counted and frozen in accordance with cryopreservation guidelines suggested by the American Type Culture Collection (ATCC). Results We generated an initial cohort of 49 Pten+/-/Lkb1+/- mice. Among all mice, the average survival time was 6 months. Thirty mice died or were sacrificed due to disease progression, defined as either lymph node enlargement and/or splenomegaly. All mice showed either lymphadenopathy or splenomegaly (Figure 1). By Kaplan-Meier analysis, we see a steady decrease in both tumor-free and overall survival after 3 months of age. Utilizing the product limit method, the median survival time was 6 months (95% CI: 6, 8). A total of 51 lymph nodes were sent for IHC and pathological identification. Of the 51 nodes, 61.5% (N=32) showed indolent Non-Hodgkin's Lymphoma, 25% (N=13) were atypical, and 11.5% (N=6) were reactive. All lymph nodes with indolent NHL were Marginal Zone subtype (Figure 2), except one case that was suspicious for follicular lymphoma. We have not identified any large cell lymphoma or development of other malignancies. Discussion Marginal zone lymphoma remains an incurable indolent lymphoma that lacks preclinical models. As novel agents become available, it is important to have a better understanding of the underlying pathogenesis of this malignancy and be able to model it in a immunocompetent mouse with a preserved microenvironment. Our data provides, for the first time, a proof of concept on the role of the PI3K-mTOR pathway in the pathogenesis of marginal zone lymphoma and paves the way for future studies understanding the biology of this disease, and developing rational therapies for this incurable malignancy. Disclosures No relevant conflicts of interest to declare.

Objectives: Several studies have shown that causes of adult hypertension arise in childhood, and obesity may be a potential cause or at least a mitigating factor in this development. Body mass index is a well studied obesity metric, yet other potential adiposity measures such as percent body fat and waist circumference have been somewhat less considered. The purpose of this study is to determine associations between these alternative serial childhood adiposity measures and adulthood blood pressure. Methods: Measurements from participants in the Fels Longitudinal Study were used to summarize childhood adiposity, represented by childhood measurements of percent body fat and height-adjusted waist circumference. These subjects also provided systolic and diastolic blood pressure as adults. Childhood adiposity levels were categorized as high or low as compared to the respective upper quartile, and associations with adult blood pressure were measured using Poisson regression to estimate the number of expected occurrences of elevated adiposity during childhood. Adult lifestyle covariates and adiposity were accounted for using multiple linear regression. Results: Summary indices of the childhood adiposity measures were significantly associated with both adult blood pressure metrics in men and women, though some of these associations were altered or reduced in the presence of adult lifestyle characteristics and adult adiposity measures. Conclusions: Childhood measures of percent body fat and height-adjusted waist circumference have an effect on adult blood pressure, though the effect can be mitigated by adult lifestyles. Am. J. Hum. Biol., 2010. © 2010 Wiley-Liss, Inc.

In this article, we apply an autoregressive correlation structure to the analysis of balanced familial clustered data in the one-parent case with homogeneous intra-class variance. We use the quasi-least squares procedure to derive estimators of the correlation parameters and compare them with maximum likelihood and moment estimators. Asymptotically, the quasi-least squares estimators are nearly as efficient as the maximum likelihood estimators. The small-sample case is analyzed through simulation, and the quasi-least squares estimators are found to be more robust than the maximum likelihood estimators. To show the application of the estimation procedures, data provided in Katapa (1993) are re-analyzed. For non stationary unbalanced familial data, we outline general correlation models which are natural extensions of the structure studied in this article.

Summary Objective: To discuss generalized estimating equations as an extension of generalized linear models by commenting on the paper of Ziegler and Vens “Generalized Estimating Equations: Notes on the Choice of the Working Correlation Matrix”. Methods: Inviting an international group of experts to comment on this paper. Results: Several perspectives have been taken by the discussants. Econometricians have established parallels to the generalized method of moments (GMM). Statisticians discussed model assumptions and the aspect of missing data. Applied statisticians commented on practical aspects in data analysis. Conclusions: In general, careful modeling correlation is encouraged when considering estimation efficiency and other implications, and a comparison of choosing instruments in GMM and generalized estimating equations (GEE) would be worthwhile. Some theoretical drawbacks of GEE need to be further addressed and require careful analysis of data. This particularly applies to the situation when data are missing at random.