Improved automated spot counting and modeling with bias correction.

A complete workflow was presented for estimating the concentration of microorganisms in biological samples by automatically counting spots that represent viral plaque forming units (PFU) bacterial colony forming units (CFU), or spot forming units (SFU) in images, and modeling the counts. The workflow was designed for processing images from dilution series but can also be applied to stand-alone images. The accuracy of the methods was greatly improved by adding a newly developed bias correction method. When the spots in images are densely populated, the probability of spot overlapping increases, leading to systematic undercounting. In this paper, this undercount issue was addressed in an empirical way. The proposed empirical bias correction method utilized synthetic images with known spot sizes and counts as a training set, enabling the development of an effective bias correction function using a thin-plate spline model. Its application focused on the bias correction for the automated spot counting algorithm LoST proposed by Lin et al. Simulation results demonstrated that the empirical bias correction significantly improved spot counts, reducing bias for both fixed and random spot sizes and counts.

The partnership between statisticians and the Institutional Animal Care and Use Committee (IACUC).

In this tutorial we explore the valuable partnership between statisticians and Institutional Animal Care and Use Committees (IACUCs) in the context of animal research, shedding light on the critical role statisticians play in ensuring the ethical and scientifically rigorous use of animals in research. Pharmaceutical statisticians have increasingly become vital members of these committees, contributing expertise in study design, data analysis, and interpretation, and working more generally to facilitate the integration of good statistical practices into experimental procedures. We review the "3Rs" principles (Replacement, Reduction, and Refinement) which are the foundation for the humane use of animals in scientific research, and how statisticians can partner with IACUC to help ensure robust and reproducible research while adhering to the 3Rs principles. We also highlight emerging areas of interest, such as the use of virtual control groups.

Musculoskeletal Effects of 2 Functional Electrical Stimulation Cycling Paradigms Conducted at Different Cadences for People With Spinal Cord Injury: A Pilot Study.

OBJECTIVE: To compare the musculoskeletal effects of low cadence cycling with functional electrical stimulation (FES) with high cadence FES cycling for people with spinal cord injury (SCI). DESIGN: Randomized pre-post design. SETTING: Outpatient rehabilitation clinic. PARTICIPANTS: Participants (N=17; 14 men, 3 women; age range, 22-67y) with C4-T6 motor complete chronic SCI were randomized to low cadence cycling (n=9) or high cadence cycling (n=8). INTERVENTIONS: Low cadence cycling at 20 revolutions per minute (RPM) and high cadence cycling at 50 RPM 3 times per week for 6 months. Cycling torque (resistance per pedal rotation) increased if targeted cycling cadence was maintained. MAIN OUTCOME MEASURES: Dual-energy x-ray absorptiometry was used to assess distal femur areal bone mineral density, magnetic resonance imaging was used to assess to assess trabecular bone microarchitecture and cortical bone macroarchitecture and thigh muscle volume, and biochemical markers were used to assess bone turnover. It was hypothesized that subjects using low cadence cycling would cycle with greater torque and therefore show greater musculoskeletal improvements than subjects using high cadence cycling. RESULTS: A total of 15 participants completed the study. Low cadence cycling obtained a maximal average torque of 2.9±2.8Nm, and high cadence cycling obtained a maximal average torque of 0.8±0.2Nm. Low cadence cycling showed greater decreases in bone-specific alkaline phosphatase, indicating less bone formation (15.5% decrease for low cadence cycling, 10.7% increase for high cadence cycling). N-telopeptide decreased 34% following low cadence cycling, indicating decreased resorption. Both groups increased muscle volume (low cadence cycling by 19%, high cadence cycling by 10%). Low cadence cycling resulted in a nonsignificant 7% increase in apparent trabecular number (P=.08) and 6% decrease in apparent trabecular separation (P=.08) in the distal femur, whereas high cadence cycling resulted in a nonsignificant (P>.3) 2% decrease and 3% increase, respectively. CONCLUSIONS: This study suggests that the greater torque achieved with low cadence cycling may result in improved bone health because of decreased bone turnover and improved trabecular bone microarchitecture. Longer-term outcome studies are warranted to identify the effect on fracture risk.

Cost-effectiveness of a standard intervention versus a navigated intervention on colorectal cancer screening use in primary care.

BACKGROUND: Colorectal cancer (CRC) screening is cost-effective but underused. The objective of this study was to determine the cost-effectiveness of a mailed standard intervention (SI) and tailored navigation interventions (TNIs) to increase CRC screening use in the context of a randomized trial among primary care patients. METHODS: Participants (n = 945) were randomized either to a usual care control group (n = 317), to an SI group (n = 316), or to a TNI group (n = 312). The SI group was sent both colonoscopy instructions and stool blood tests irrespective of baseline preference. TNI group participants were sent instructions for scheduling a colonoscopy, a stool blood test, or both based on their test preference, as determined at baseline; then, they received a navigation telephone call. Activity cost estimation was used to determine the cost of each intervention and to compute incremental cost-effectiveness ratios. Statistical uncertainty within the base case was assessed with 95% confidence intervals derived from net benefit regression analysis. The effects of uncertain parameters, such as the cost of planning, training, and involvement of those receiving "investigator salaries," were assessed with sensitivity analyses. RESULTS: Program costs of the SI were $167 per participant. The average cost of the TNI was $289 per participant. CONCLUSIONS: The TNI was more effective than the SI but substantially increased the cost per additional individual screened. Decision-makers need to consider cost structure, level of planning, and training required to implement these 2 intervention strategies and their willingness to pay for additional individuals screened to determine whether a tailored navigation would be justified and feasible.

Pain characteristics and age-related pain trajectories in infants and young children with sickle cell disease.

BACKGROUND: The epidemiology of painful episodes in infants and younger children with SCD has not been well studied, particularly for pain managed at home. PROCEDURE: SCD infants identified by newborn screening were enrolled in a longitudinal observational study of pain symptoms requiring parents to report the presence or absence of pain daily. When sickle cell related-pain events occurred, pain occurrence, location, associated symptoms and the treatment provided also were reported. RESULTS: 103 children were enrolled at a median age of 7.2 months; 50 had an SS genotype, 32 SC, 6 SB(0)thalassemia, and 15 SB(+)thalassemia. Parents/guardians reported for a median of 3.8 years (range 0.3-7.6 years) assessing pain for a total of 141,197 days, excluding any period of recurrent transfusions, with an additional 28,079 days of missing data (16%). Children had pain reported on 2,288 days (1.6%), representing 768 distinct episodes of pain, of which 108 required hospitalizations (14%). Pain locations and symptoms consistent with dactylitis were most prevalent (80%) in the 0-12 month age group, and became progressively less prevalent thereafter. Group-based trajectory modeling of pain episode or pain day frequency identified several trajectory groups with progressively older ages of peak pain frequency, which included 40-45% of SS/SB(0)thalassemia and 10-12% of SC/SB(+)thalassemia children. CONCLUSIONS: Pain is relatively infrequent in SCD infants and young children and commonly managed at home. Analyses of longitudinal pain trajectories suggest several different pain trajectories, differing in their frequency, age of onset, and age at peak pain frequency with clinical implications for hydroxyurea management.

Noninferiority of 16-Week vs 8-Week Guselkumab Dosing in Super Responders for Maintaining Control of Psoriasis: The GUIDE Randomized Clinical Trial.

Importance: Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies. Objective: To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis. Design, Setting, and Participants: The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively. Interventions: In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks. Main Outcomes and Measures: Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood. Results: Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and ß defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified. Conclusions and Relevance: Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity. Trial Registration: ClinicalTrials.gov Identifier: NCT03818035.

Differential expression of cytochrome P450 omega-hydroxylase isoforms and their association with clinicopathological features in pancreatic ductal adenocarcinoma.

BACKGROUND: The cytochrome P450 (CYP) superfamily consists of enzymes that catalyze the oxidation of lipids, steroids, and drugs. In particular, the CYP4 family plays an essential role in lipid metabolism by the ω-hydroxylation of terminal ends of fatty acids. Disturbance of this system has been associated with increased angiogenesis, proliferation, and metastasis of several cancers. This study aimed to detect the expression of CYP4 isoforms (CYP4A11, CYP4F2, CYP4F3) in pancreatic ductal adenocarcinoma (PDA) and their association with clinicopathological features. METHODS: Pancreatic specimens were collected from 73 patients who underwent surgical resection at the Thomas Jefferson University Hospital. Quantitative polymerase chain reaction was used to examine the cytochrome P450 isoforms in PDA (n = 62), adjacent-normal (n = 30), and benign tissues (n = 11). Logistic regression models were used to analyze gene expression among tissue types. Spearman rank correlations were calculated for isoform expression and for age. Differences in expression by gender were assessed via t test. Other clinicopathological variables (diabetes, smoking, obesity, T stage, perineural invasion, nodal status) were analyzed by Wilcoxon rank sum. RESULTS: CYP4 expression for isoforms was significantly higher in PDA tissues versus matched-adjacent tissues (p < 0.01). PDA tumors expressed significantly higher levels of CYP4F2 and CYP4F3 when compared to benign lesions (p < 0.01). Significant associations were found between low levels of CYP4F2 and CYP4F3 and increased age of PDA patients. Interestingly, all isoforms were expressed at higher levels in male patients. CONCLUSIONS: Transcriptional upregulation of cytochrome P450 ω-hydroxylase suggests that these enzymes have the potential to be used as distinguishing markers in pancreatic pathology.

Targeted cyst wall puncture and aspiration during EUS-FNA increases the diagnostic yield of premalignant and malignant pancreatic cysts.

BACKGROUND: Characterization of pancreatic cysts by using EUS-FNA includes chemical and cytologic analysis. OBJECTIVE: To evaluate whether material obtained from FNA of the cyst wall increases diagnostic yield. DESIGN: Prospective series. SETTING: Tertiary referral center. PATIENTS: Consecutive patients with pancreatic cysts referred for EUS-FNA between March 2010 and March 2011. INTERVENTION: FNA was performed with aspiration of cyst fluid for carcinoembryonic antigen (CEA) and cytology, followed by cyst wall puncture (CWP). CWP is defined as puncturing the far wall of the cyst and moving the needle back and forth through the wall to sample the wall epithelium. MAIN OUTCOME MEASUREMENTS: The diagnostic yield for mucinous cystic pancreatic neoplasms by CEA and cytology obtained from cyst fluid compared with cytology obtained from CWP. CEA ≥192 ng/mL was considered mucinous. RESULTS: A total of 69 pancreatic cysts from 66 patients were included. Adequate amounts of fluid were aspirated for CEA, amylase, and cytology in 60 cysts (81%). Cellular material adequate for cytologic assessment from CWP was obtained in 56 cysts (81%). Ten (30%) of 33 cysts with CEA <192 ng/mL and negative results of cyst fluid cytology had a mucinous diagnosis from CWP; 6 of 9 (67%) cysts with an insufficient amount of fluid for CEA analysis and cyst fluid cytology had a mucinous diagnosis from CWP. Furthermore, 4 malignant cysts were independently diagnosed by CWP cytology. The incremental diagnostic yield of CWP for mucinous or malignant cysts was therefore 29% (20 of 69 cysts, P = .0001). An episode of pancreatitis (1.45%) occurred. LIMITATION: Lack of surgical criterion standard. CONCLUSIONS: CWP during EUS-FNA is a safe and effective technique for improving the diagnostic yield for premalignant and malignant pancreatic cysts.

Discovery and pharmacological characterization of cetrelimab (JNJ-63723283), an anti-programmed cell death protein-1 (PD-1) antibody, in human cancer models.

PURPOSE: Preclinical characterization of cetrelimab (JNJ-63723283), a fully humanized immunoglobulin G4 kappa monoclonal antibody targeting programmed cell death protein-1 (PD-1), in human cancer models. METHODS: Cetrelimab was generated by phage panning against human and cynomolgus monkey (cyno) PD-1 extracellular domains (ECDs) and affinity maturation. Binding to primate and rodent PD-1 ECDs, transfected and endogenous cell-surface PD-1, and inhibition of ligand binding were measured. In vitro activity was evaluated using cytomegalovirus recall, mixed lymphocyte reaction, staphylococcal enterotoxin B stimulation, and Jurkat-PD-1 nuclear factor of activated T cell reporter assays. In vivo activity was assessed using human PD-1 knock-in mice implanted with MC38 tumors and a lung patient-derived xenograft (PDX) model (LG1306) using CD34 cord-blood-humanized NSG mice. Pharmacodynamics, toxicokinetics, and safety were assessed in cynos following single and/or repeat intravenous dosing. RESULTS: Cetrelimab showed high affinity binding to human (1.72 nM) and cyno (0.90 nM) PD-1 and blocked binding of programmed death-ligand 1 (PD-L1; inhibitory concentration [IC] 111.7 ng/mL) and PD-L2 (IC 138.6 ng/mL). Cetrelimab dose-dependently increased T cell-mediated cytokine production and stimulated cytokine expression. Cetrelimab 10 mg/kg reduced mean MC38 tumor volume in PD-1 knock-in mice at Day 21 (P < 0.0001) versus control. In a PDX lung model, 10 mg/kg cetrelimab (every 5 days for six cycles) increased frequency of peripheral T cells and reduced (P < 0.05) mean tumor volume versus control. Activity was consistent with that of established PD-1 inhibitors. Cetrelimab dosing was well tolerated in cynos and mean drug exposure increase was dose-dependent. CONCLUSION: Cetrelimab potently inhibits PD-1 in vitro and in vivo, supporting its clinical evaluation.

Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.

Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM.

Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis.

Small molecule inhibitors targeting mutant EGFR are standard of care in non-small cell lung cancer (NSCLC), but acquired resistance invariably develops through mutations in EGFR or through activation of compensatory pathways such as cMet. Amivantamab (JNJ-61186372) is an anti-EGFR and anti-cMet bispecific low fucose antibody with enhanced Fc function designed to treat tumors driven by activated EGFR and/or cMet signaling. Potent in vivo antitumor efficacy is observed upon amivantamab treatment of human tumor xenograft models driven by mutant activated EGFR, and this activity is associated with receptor downregulation. Despite these robust antitumor responses in vivo, limited antiproliferative effects and EGFR/cMet receptor downregulation by amivantamab were observed in vitro Interestingly, in vitro addition of isolated human immune cells notably enhanced amivantamab-mediated EGFR and cMet downregulation, leading to antibody dose-dependent cancer cell killing. Through a comprehensive assessment of the Fc-mediated effector functions, we demonstrate that monocytes and/or macrophages, through trogocytosis, are necessary and sufficient for Fc interaction-mediated EGFR/cMet downmodulation and are required for in vivo antitumor efficacy. Collectively, our findings represent a novel Fc-dependent macrophage-mediated antitumor mechanism of amivantamab and highlight trogocytosis as an important mechanism of action to exploit in designing new antibody-based cancer therapies.

A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia.

CD33 is expressed in 90% of patients with acute myeloid leukemia (AML), and its extracellular portion consists of a V domain and a C2 domain. A recent study showed that a single nucleotide polymorphism (SNP), rs12459419 (C > T), results in the reduced expression of V domain-containing CD33 and limited efficacy of V domain-binding anti-CD33 antibodies. We developed JNJ-67571244, a novel human bispecific antibody capable of binding to the C2 domain of CD33 and to CD3, to induce T-cell recruitment and CD33+ tumor cell cytotoxicity independently of their SNP genotype status. JNJ-67571244 specifically binds to CD33-expressing target cells and induces cytotoxicity of CD33+ AML cell lines in vitro along with T-cell activation and cytokine release. JNJ-67571244 also exhibited statistically significant antitumor activity in vivo in established disseminated and subcutaneous mouse models of human AML. Furthermore, this antibody depletes CD33+ blasts in AML patient blood samples with concurrent T-cell activation. JNJ-67571244 also cross-reacts with cynomolgus monkey CD33 and CD3, and dosing of JNJ-67571244 in cynomolgus monkeys resulted in T-cell activation, transient cytokine release, and sustained reduction in CD33+ leukocyte populations. JNJ-67571244 was well tolerated in cynomolgus monkeys up to 30 mg/kg. Lastly, JNJ-67571244 mediated efficient cytotoxicity of cell lines and primary samples regardless of their SNP genotype status, suggesting a potential therapeutic benefit over other V-binding antibodies. JNJ-67571244 is currently in phase 1 clinical trials in patients with relapsed/refractory AML and high-risk myelodysplastic syndrome.

Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab.

PURPOSE: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. EXPERIMENTAL DESIGN: We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. RESULTS: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. CONCLUSIONS: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.

Comparisons of Serum Infliximab and Antibodies-to-Infliximab Tests Used in Inflammatory Bowel Disease Clinical Trials of Remicade®.

Monitoring infliximab (IFX) concentrations and antibodies-to-IFX (ATI) titers during inflammatory bowel disease treatment may allow more informed decisions in assessing exposure/response and determining appropriate dosing. To aid in interpreting results from different commercial tests in the context of Janssen's published Remicade® results, the reliability of Janssen's IFX and ATI assays was compared with commercial assays from KU Leuven, Sanquin, Dynacare, and LabCorp. Test results were independently reported to Janssen. All assays were tested for specificity, selectivity, and precision. ATI assays were evaluated for sensitivity, drug interference, and potential interference of tumor necrosis factor-alpha (TNF-α). IFX assays were specific, accurate, and reproducible. Intra-class correlation of Janssen IFX assay results with those from KU Leuven, Sanquin, Dynacare, and LabCorp were 0.960, 0.895, 0.931, and 0.971, respectively. ATI titers >10 interfered with IFX assessment in all IFX assays, whereas TNF-α (≤50 ng/mL) did not interfere with IFX detection in any assay. ATI assays specifically and reproducibly detected ATI. Janssen, Sanquin, and LabCorp ATI methods were more resistant to IFX interference than Dynacare and KU Leuven, which were affected by IFX concentrations at ≥2 µg/mL. TNF-α (<5 ng/mL) did not interfere with ATI detection. Strong agreement was observed between Janssen's IFX and ATI assays and the diagnostic service provider assays. Our study results indicate that all four commercially available assays are suitable for therapeutic drug monitoring of IFX. The substantial agreement reported here between the comparator assays and the Janssen drug-tolerant assay provides support to clinicians in their use of these commercial assays, and for understanding their patients' IFX and ATI results relative to published data from clinical studies of Remicade.

A functional genomics predictive network model identifies regulators of inflammatory bowel disease.

A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.

Clinical-pathological features and treatment modalities associated with recurrence in DCIS and micro-invasive carcinoma: Who to treat more and who to treat less.

The primary aim in the management of DCIS is the prevention of recurrence and contralateral tumor. Risk factors for DCIS recurrence and appropriate treatments are still widely debated. Adjuvant therapies after surgical resection reduce recurrences and contralateral disease, but these treatments have significant financial costs, side effects and there is a group of low-risk patients who would not gain additional benefit. The aim of our analysis was to identify clinical-pathological features and treatment modalities associated with recurrence in DCIS and microinvasive carcinoma. In the Thomas Jefferson University Cancer Registry of Philadelphia, we identified 865 patients with DCIS or micro-invasive carcinoma treated between 2003 and 2013. Associations between recurrence and demographic factors (age at diagnosis, ethnicity), biological features (ER, PR and HER2) and treatment modalities (surgery, radiotherapy and endocrine treatment) were assessed. Our single institution register-based study showed that distribution of age at diagnosis and biological features did not significantly differ among ethnic groups. Younger women and micro-invasive carcinoma patients were more likely to undergo mastectomy, while African Americans were more likely to take endocrine therapy and undergo radiotherapy. In our sample only ER/PR negative DCIS were associated with significantly higher recurrence rate. Moreover, we reported a high rate of HER2 positive recurrences, suggesting that expression of this oncogene may represent a potential biomarker for DCIS at high risk of recurrence. To better define the molecular profile of the subgroup at worse prognosis might help to identify biomarkers predictive of recurrence or second tumors, identifying patients candidates for more appropriate treatments.

A pharmacist-led medication assessment used to determine a more precise estimation of the prevalence of complementary and alternative medication (CAM) use among ambulatory senior adults with cancer.

OBJECTIVES: The prevalence of complementary and alternative medication (CAM) use in senior adult oncology (SAO) patients is widely variable and little is known about whether polypharmacy (PP) and potentially inappropriate medication (PIM) use influences CAM use given the increased number of comorbidities and polypharmacy. One approach to optimize medication management is through utilization of pharmacists as part of a team-based, healthcare model. MATERIALS AND METHODS: Prevalence of CAM and factors influencing CAM use was examined in a secondary analysis of 248 patients who received an initial comprehensive geriatric oncology assessment between January 2011 and June 2013. Data was collected from electronic medical records. CAM was defined as herbal medications, minerals, or other dietary supplements, excluding vitamins. Patient characteristics influencing CAM use (e.g. comorbidities, PP and PIM use) were analyzed. RESULTS: Only 234 patients (evaluated by pharmacists) were included in the final analysis. Mean age was 79.9 years [range 61-98]; 64% women, 74% Caucasian, 87% with a solid tumor, mean comorbidities, 7.69. CAM prevalence was 26.5% (n=62) and median CAM use was 0 (range 0-10). The proportion of CAM use (1, 2, and 3) was 19.2%, 6.4%, and 0.4%, respectively. Associations with CAM use (versus no-CAM) were polypharmacy (P=0.045), vision impairment (P=0.048) and urologic comorbidities (P=0.021). CONCLUSIONS: A pharmacist-led comprehensive medication assessment demonstrated a more precise estimation of CAM prevalence in the ambulatory SAO population. CAM use was associated with polypharmacy, ophthalmic and urologic medical conditions. Integrating pharmacists into team-based (geriatric and oncology) care models is an underutilized yet viable solution to optimize medication use.

Autonomic dysregulation during sensory stimulation in children with autism spectrum disorder.

Autonomic nervous system (ANS) activity during sensory stimulation was measured in 59 children with autism spectrum disorder (ASD) ages 6-9 in comparison to 30 typically developing controls. Multivariate comparisons revealed significant differences between groups in the respiratory sinus arrhythmia (parasympathetic measure) vector of means across sensory stimuli (p = 0.02) and in change from domain to domain (p = 0.01). Sympathetic activity, measured by pre-ejection period, did not differ significantly between groups, although it was higher in ASD participants. Findings suggest that participants with ASD demonstrated a different pattern of parasympathetic activity during sensory stimulation. Findings are discussed in relation to the biological mechanisms of sensory processing in autism, insight into the autism phenotype, and the utility of ANS activity as an outcomes marker.

Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy and potentially inappropriate medication use among ambulatory senior adults with cancer.

PURPOSE: The use of multiple and/or inappropriate medications in seniors is a significant public health problem, and cancer treatment escalates its prevalence and complexity. Existing studies are limited by patient self-report and medical record extraction compared with a pharmacist-led comprehensive medication assessment. PATIENTS AND METHODS: We retrospectively examined medication use in ambulatory senior adults with cancer to determine the prevalence of polypharmacy (PP) and potentially inappropriate medication (PIM) use and associated factors. PP was defined as concurrent use of five or more and less than 10 medications, and excessive polypharmacy (EPP) was defined as 10 or more medications. PIMs were categorized by 2012 Beers Criteria, Screening Tool of Older Person's Prescriptions (STOPP), and the Healthcare Effectiveness Data and Information Set (HEDIS). RESULTS: A total of 248 patients received a geriatric oncology assessment between January 2011 and June 2013 (mean age was 79.9 years, 64% were women, 74% were white, and 87% had solid tumors). Only 234 patients (evaluated by pharmacists) were included in the final analysis. Mean number of medications used was 9.23. The prevalence of PP, EPP, and PIM use was 41% (n = 96), 43% (n = 101), and 51% (n = 119), respectively. 2012 Beers, STOPP, and HEDIS criteria classified 173 occurrences of PIMs, which were present in 40%, 38%, and 21% of patients, respectively. Associations with PIM use were PP (P < .001) and increased comorbidities (P = .005). CONCLUSION: A pharmacist-led comprehensive medication assessment demonstrated a high prevalence of PP, EPP, and PIM use. Medication assessments that integrate both 2012 Beers and STOPP criteria and consider cancer diagnosis, prognosis, and cancer-related therapy are needed to optimize medication use in this population.