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Full-length RNA-sequencing methods using long-read technologies can capture complete transcript isoforms, but their throughput is limited. We introduce multiplexed arrays isoform sequencing (MAS-ISO-seq), a technique for programmably concatenating complementary DNAs (cDNAs) into molecules optimal for long-read sequencing, increasing the throughput >15-fold to nearly 40 million cDNA reads per run on the Sequel IIe sequencer. When applied to single-cell RNA sequencing of tumor-infiltrating T cells, MAS-ISO-seq demonstrated a 12- to 32-fold increase in the discovery of differentially spliced genes. Programmable concatenation of cDNA molecules increases the throughput of PacBio sequencing about 15-fold. [ABSTRACT FROM AUTHOR]

Purpose: The assumption that patient–provider communication may mediate patients' sense of control over cancer to affect health outcomes has limited evidence. This study examines whether patient-perceived cancer care communication quality (PPCQ) mediates stress appraisal and coping behavior, affecting physical functioning across different racial groups. Methods: Two hundred and twenty Chinese American and 216 non-Hispanic White (NHW) women (ages 28–80) with stage 0–III breast cancer, 1–5 years post-diagnosis, and without recurrence, enrolled and completed a cross-sectional telephone survey. Physical functioning was measured by the NIH-PROMIS short form. Validated measures of PPCQ, patients' evaluation of their socioeconomic well-being, stress appraisal (perceived severity and control), use of coping strategies, treatment-related symptoms, and comorbidities were also assessed. Path analyses were used to examine the mediation for each racial group. Results: Regardless of race, treatment-related symptoms, comorbidities, and socioeconomic well-being were all directly related to physical functioning (p < 0.05). The impact of PPCQ on physical functioning was mediated by perceived control in the Chinese American group (p < 0.05), but not in the NHW group. Perceived severity and coping were not mediators of physical functioning in either group. Conclusions: The mediational pathway from PPCQ to perceived control to physical functioning in Chinese American survivors may be partially explained by their lower socioeconomic well-being and culturally valued conformity to physicians as a medical authority. These sociocultural dynamics reinforce the importance of cancer care communication. For NHW survivors, the impact of treatment-related symptoms and socioeconomic well-being on physical functioning outweighed their PPCQ and perceived control. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have transformed the management of cancer, producing durable responses in a subset of treated patients across multiple malignancies. Immune-mediated diarrhea and colitis (imDC) occurs in up to 20% of ICI-treated patients. The risk of ICI imDC is dependent upon the agent and is commoner with anti-CTLA-4 compared to anti-PD-1 ICIs. Generally, imDC is treated with steroids and agents targeting TNFα or α4β7 integrin. However, the management of steroids and/or biologic refractory imDC is unclear. We present a case of imDC in a 68-year-old female who failed to respond clinically, biochemically and immunohistochemically to corticosteroids, infliximab and vedolizumab. A trial of tofacitinib, a pan-JAK inhibitor, led to rapid clinical, biochemical and immunohistochemical control of imDC. ICIs result in a striking accumulation of cytotoxic and proliferative CD8 + T cells within tumor. However, the cellular and molecular mechanisms underlying imDC remain unclear. Herein, we observed significant T cell enrichment; and the successful treatment with tofacitinib highlights the potential of multiple convergent inflammatory pathways in imDC and inflammatory colitis. [ABSTRACT FROM AUTHOR]

Purpose: High-volume hospitals are associated with improved surgical outcomes for acoustic neuromas (ANs). Due to the benign and slow-growing nature of ANs, many patients travel to geographically distant cities, states, or countries for their treatment. However, the impact of travel burden to high-volume centers, as well as its relative benefit are poorly understood. We compared post-operative outcomes between AN patients that underwent treatment at local, low-volume hospitals with those that traveled long distances to high-volume hospitals. Methods: The National Cancer Database was used to analyze AN patients that underwent surgery (2004–2015). Patients in the lowest quartile of travel distance and volume (Short-travel/Low-Volume: STLV) were compared to patients in the highest quartile of travel distance and volume (Long-travel/High-Volume: LTHV). Only STLV and LTHV cases were included for analysis. Results: Of 13,370 cases, 2,408 met inclusion criteria. STLV patients (n = 1,305) traveled a median of 6 miles (Interquartile range [IQR] 3–9) to low-volume centers (median 2, IQR 1–3 annual cases) and LTHV patients (n = 1,103) traveled a median of 143 miles [IQR 103–230, maximum 4,797] to high-volume centers (median 34, IQR 28–42 annual cases). LTHV patients had lower Charlson/Deyo scores (p = 0.001), mostly received care at academic centers (81.7% vs. 39.4%, p < 0.001), and were less likely to be minorities (7.0% vs. 24.2%, p < 0.001) or underinsured (4.2% vs. 13.8%, p < 0.001). There was no difference in average tumor size. On multivariable analysis, LTHV predicted increased likelihood of gross total resection (odds ratio [OR] 5.6, 95% confidence interval [CI] 3.8–8.4, p < 0.001), longer duration between diagnosis and surgery (OR 1.3, 95% CI 1.0-1.6, p = 0.040), decreased length of hospital stay (OR 0.5, 95% CI 0.4–0.7, p < 0.001), and greater overall survival (Hazard Ratio [HR] 0.6, 95% CI 0.4–0.95, p = 0.029). There was no significant difference in 30-day readmission on adjusted analysis. Conclusion: Although traveling farther to high-volume centers was associated with greater time between diagnosis and treatment for AN patients, they experienced superior postoperative outcomes compared to patients who received treatment locally at low-volume centers. Enabling access and travel to high-volume centers may improve AN patient outcomes. [ABSTRACT FROM AUTHOR]

Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling. STING is an intracellular sensor of pathogen- or host-derived DNA. In this study, the authors identify an ESCRT complex that regulates STING degradation, thus acting as a homeostatic regulator of STING signalling and type-I interferon responses. [ABSTRACT FROM AUTHOR]

The purpose of this study is to evaluate the direct and indirect effects of a web-based, Protection Motivation Theory (PMT)–informed breast cancer education and decision support tool on intentions for risk-reducing medication and breast MRI among high-risk women. Women with ≥ 1.67% 5-year breast cancer risk (N = 995) were randomized to (1) control or (2) the PMT-informed intervention. Six weeks post-intervention, 924 (93% retention) self-reported PMT constructs and behavioral intentions. Bootstrapped mediations evaluated the direct effect of the intervention on behavioral intentions and the mediating role of PMT constructs. There was no direct intervention effect on intentions for risk-reducing medication or MRI (p's ≥ 0.12). There were significant indirect effects on risk-reducing medication intentions via perceived risk, self-efficacy, and response efficacy, and on MRI intentions via perceived risk and response efficacy (p's ≤ 0.04). The PMT-informed intervention effected behavioral intentions via perceived breast cancer risk, self-efficacy, and response efficacy. Future research should extend these findings from intentions to behavior. ClinicalTrials.gov Identifier: NCT03029286 (date of registration: January 24, 2017). [ABSTRACT FROM AUTHOR]

Pathogenic variants in the BRCA1 and BRCA2 (BRCA1/2) genes are associated with elevated cancer risks in men and women. Due to a founder effect, Ashkenazi Jewish individuals are at higher risk for carrying three specific BRCA1/2 pathogenic variants. There have been recent calls for population screening in this population because many carriers do not have family histories suggestive of hereditary cancer. One approach could be to integrate optional BRCA1/2 testing into routinely offered reproductive carrier screening for recessive and X-linked disorders. However, the differing goals of these types of testing (i.e., personal health risks versus family planning) raise questions about the implications for patient education and informed consent. To this end, we aimed to determine interest, attitudes, and preferences regarding integrating such testing by electronically surveying 331 Ashkenazi Jewish participants in JScreen — a national, not-for-profit, at-home carrier screening program focused on genetic risks in Jewish communities. We found that while 41% of participants had plans to pursue BRCA1/2 testing, 93% would have opted for such testing if offered as an add-on to reproductive carrier screening. This was particularly true of those with higher perceived cancer risk and more positive attitudes toward genetic testing. With respect to preferences about delivery of this service, more than 85% of participants preferred remote (telephone, print, or web-based) genetic education rather than traditional genetic counseling. These results suggest that offering optional BRCA1/2 testing within the context of reproductive carrier screening might provide opportunities for cancer prevention without overburdening scarce genetic counseling resources. [ABSTRACT FROM AUTHOR]

Health and safety concerns during the COVID-19 pandemic required many face-to-face United States schools to suddenly shut their doors, moving classes to virtual learning environments. Amidst concerns of technology overuse, adolescents across the country saw dramatic increases in both personal screen time use and social isolation as they learned to navigate online schooling. Understanding the impact of the pandemic-related shutdowns upon adolescent well-being, learning, and social life is critical for designing effective online learning experiences, but research provides few insights from the adolescent perspective. This mixed methods study works to fill this gap by investigating adolescent needs and perceptions during the pandemic. The main questions asked are: To what extent does adolescent well-being during the pandemic differ from pre-pandemic well-being? What factors do adolescents view as influences upon their learning during the imposed shift to online schooling? What social changes and concerns do adolescents report during the pandemic? Twenty-one adolescents completed Likert scale surveys and participated in semi-structured one-to-one interviews. Results showed a significant decrease in positive affect and a significant increase in negative affect during the pandemic, suggesting a decline in well-being. The majority of participants reported high distractibility and noted the lure of entertaining technology, but also described their smartphones as "connecting" and "necessary". Social interactions were a priority for all participants, but participants agreed that opportunities for social connectedness in online education were limited. The challenges of online learning, the importance of identifying and responding to student needs, and suggested strategies for online education are discussed. [ABSTRACT FROM AUTHOR]

Cascade testing for hereditary breast/ovarian cancer is an important public health priority. Increasing attention has been paid to the relevance of testing for men within BRCA1/2-positive families given that such testing may provide important information about their cancer risks, particularly for prostate cancer, and risks to their offspring. However, men are much less likely to seek genetic counseling and testing than their at-risk female relatives. To facilitate access to pre-test information and testing, we developed a web-based intervention (WI) for men that we are evaluating in a pilot randomized controlled trial (RCT). This paper describes three phases of research in the development of the WI: (1) formative (qualitative) research among men from BRCA1/2 families to assess needs and preferences for education; (2) a detailed description of the organization, format, and content of the WI; and (3) usability testing. We discuss the aims and hypotheses of the pilot RCT in which the WI is being compared with an enhanced usual care condition among at-risk men. We expect that the WI described here will foster informed decisions and lead to increased use of BRCA1/2 counseling and testing, potentially yielding improved cancer control outcomes for this understudied group, and for their at-risk relatives. [ABSTRACT FROM AUTHOR]

Purpose: Recent trends indicate increased use of contralateral prophylactic mastectomy (CPM) among newly diagnosed breast cancer patients, particularly those who test positive for a pathogenic variant in the BRCA1/2 genes. However, the rate of CPM among patients who test negative or choose not to be tested is surprisingly high. We aimed to identify patient predictors of CPM following breast cancer diagnosis among such patients. Methods: As part of a randomized controlled trial of rapid genetic counseling and testing vs. usual care, breast cancer patients completed a baseline survey within 6 weeks of diagnosis and before definitive surgery. Analyses focused on patients who opted against testing (n = 136) or who received negative BRCA1/2 test results (n = 149). We used multivariable logistic regression to assess the associations between sociodemographic, clinical- and patient-reported factors with use of CPM. Results: Among patients who were untested or who received negative test results, having discussed CPM with one's surgeon at the time of diagnosis predicted subsequent CPM. Patients who were not candidates for breast-conserving surgery and those with higher levels of cancer-specific intrusive thoughts were also more likely to obtain a CPM. Conclusion: The strongest predictors of CPM in this population were objective clinical factors and discussion with providers. However, baseline psychosocial factors were also independently related to the receipt of CPM. Thus, although CPM decisions are largely guided by relevant clinical factors, it is important to attend to psychosocial factors when counseling newly diagnosed breast cancer patients about treatment options. [ABSTRACT FROM AUTHOR]

Disparities for genetic cancer risk assessment (GCRA) for hereditary breast and ovarian cancer (HBOC) persist between Latina and non-Hispanic Whites. There are few tested culturally targeted interventions. We developed a culturally targeted video to enhance GCRA uptake in at-risk Latinas. Interviews with healthcare providers (n = 20) and at-risk Latinas (n = 20) were conducted as formative research to inform the development of the video. Findings from the formative research, health behavior conceptual models, and evidence-based risk communication strategies informed the messages for the script. Then, we conducted a focus group with at-risk Latinas (n = 7) to obtain feedback for final refinement of the script. The final video was piloted for acceptability and potential dissemination in a sample of Latino community health workers (CHWs) (n = 31). Providers and at-risk Latinas suggested using simple language and visual aids to facilitate comprehension. Participants in the focus group identified areas for further clarification (e.g., cost). The result was an 18-min video that illustrates "Rosa's" story. Rosa learns about HBOC risk factors and overcomes barriers to attend genetic counseling. CHWs reported high overall satisfaction with the video (M = 9.61, SD =.88, range 1–10). A culturally targeted video has the potential to reach underserved populations with low literacy and English proficiency. [ABSTRACT FROM AUTHOR]

Background: Dermatologic manifestations of inflammatory bowel disease (IBD) are common, and certain IBD medications increase the risk of skin cancer.Aims: To define the rates of care and factors associated with dermatologic utilization with a focus on skin cancer screening.Methods: We utilized a prospective, natural history IBD research registry to evaluate all outpatient healthcare encounters from 2010 to 2016. Gastrointestinal, dermatologic and primary care visits per individual were identified. We calculated the proportion of patients obtaining care, categorized primary indications for dermatologic visits, determined the incidence of melanoma and non-melanoma skin cancers, and used logistic regression to determine factors associated with dermatology utilization.Results: Of the 2127 IBD patients included, 452 (21.3%) utilized dermatology over the study period, and 55 (2.6%) had a total body skin examination at least once. The 452 patients incurred 1633 dermatology clinic visits, 278 dermatologic procedures, and 1108 dermatology telephone encounters. The most frequent indication was contact dermatitis or dermatitis. Factors associated with dermatology use were family history of skin cancer, employment, systemic steroids, longer disease duration, emergency room use, and the number of IBD-related clinic visits. Between 8.3 and 11% of IBD patients recommended for skin cancer screening visited dermatology each year, and the resulting incidence of non-melanoma skin cancer was 35.4/10,000 [95% CI 23.3-51.5] and melanoma was 6.56/10,000 [95% CI 2.1-15.3].Conclusions: Less than one in ten IBD patients obtain dermatologic care. Given the increased risk of skin cancers among IBD patients, an emphasis on education, prevention, and screening merits attention. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer patients who carry BRCA1/BRCA2 gene mutations may consider bilateral mastectomy. Having bilateral mastectomy at the time of diagnosis not only reduces risk of a contralateral breast cancer, but can eliminate the need for radiation therapy and yield improved reconstruction options. However, most patients do not receive genetic counseling or testing at the time of their diagnosis. In this trial, we tested proactive rapid genetic counseling and testing (RGCT) in newly diagnosed breast cancer patients in order to facilitate pre-surgical genetic counseling and testing.Methods: We recruited newly diagnosed breast cancer patients at increased risk for carrying a BRCA1/2 mutation. Of 379 eligible patients who completed a baseline survey, 330 agreed to randomization in a 2:1 ratio to RGCT (n = 220) versus UC (n = 108). Primary outcomes were genetic counseling and testing uptake and breast cancer surgical decisions.Results: RGCT led to higher overall (83.8% vs. 54.6%; p < 0.0001) and pre-surgical (57.8% vs. 38.7%; p = 0.001) genetic counseling uptake compared to UC. Despite higher rates of genetic counseling, RGCT did not differ from UC in overall (54.1% vs. 49.1%, p > 0.10) or pre-surgical (30.6% vs. 27.4%, p > 0.10) receipt of genetic test results nor did they differ in uptake of bilateral mastectomy (26.6% vs. 21.8%, p > 0.10).Conclusions: Although RGCT yielded increased genetic counseling participation, this did not result in increased rates of pre-surgical genetic testing or impact surgical decisions. These data suggest that those patients most likely to opt for genetic testing at the time of diagnosis are being effectively identified by their surgeons. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is a heterogeneous collection of chronic inflammatory disorders of the digestive tract. Clinical, genetic, and pathological heterogeneity makes it increasingly difficult to translate efficacy studies into real-world practice. Our objective was to develop a comprehensive natural history registry derived from multi-year observational data to facilitate effectiveness and clinical phenotypic research in IBD.Methods: A longitudinal, consented registry with prospectively collected data was developed at UPMC. All adult IBD patients receiving care at the tertiary care center of UPMC are eligible for enrollment. Detailed data in the electronic health record are accessible for registry research purposes. Data are exported directly from the electronic health record and temporally organized for research.Results: To date, there are over 2565 patients participating in the IBD research registry. All patients have demographic data, clinical disease characteristics, and disease course data including healthcare utilization, laboratory values, health-related questionnaires quantifying disease activity and quality of life, and analytical information on treatment, temporally organized for 6 years (2009-2015). The data have resulted in a detailed definition of clinical phenotypes suitable for association studies with parameters of disease outcomes and treatment response. We have established the infrastructure required to examine the effectiveness of treatment and disease course in the real-world setting of IBD.Conclusions: The IBD research registry offers a unique opportunity to investigate clinical research questions regarding the natural course of the disease, phenotype association studies, effectiveness of treatment, and quality of care research. [ABSTRACT FROM AUTHOR]

Telephone genetic counseling (TC) for high-risk women interested in BRCA1/2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5-item genetic counselor process questionnaire (GCQ) assessing key elements of pre-test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision-making) with the 479 female participants (TC, N = 236; UC, N = 243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11, p = 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (β = 0.172, p < 0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21, p = 0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non-Hispanic Whites). We discuss other potential clinical and research implications of our findings. [ABSTRACT FROM AUTHOR]

Objective: To describe breast cancer risk perceptions, determine risk comprehension, and evaluate mammography adherence among Latinas.Methods: Latina women age >or=35, primarily from Central and South America, were recruited from community-based clinics to complete in-person interviews (n = 450). Risk comprehension was calculated as the difference between numeric perceived risk and Gail risk score. Based on recommended guidelines from the year data were collected (2002), mammography adherence was defined as having a mammogram every one to two years for women >or=40 years of age.Results: Breast cancer risk comprehension was low, as 81% of women overestimated their risk and only 6.9% of women were high risk based on Gail risk scores. Greater cancer worry and younger age were significantly associated with greater perceived risk and risk overestimation. Of women age eligible for mammography (n = 328), 29.0% were non-adherent to screening guidelines. Adherence was associated with older age, (OR = 2.99, 95% CI = 1.76-5.09), having insurance (OR = 1.81, 95% CI = 1.03-3.17), greater acculturation (OR = 1.18, 95% CI = 1.02-1.36), and higher breast cancer knowledge (OR = 2.03, 95% CI = 1.21-3.40).Conclusions: While most Latinas over-estimated their breast cancer risk, older age, having insurance, being more acculturated, and having greater knowledge were associated with greater screening adherence in this Latino population. Perceived risk, risk comprehension, and cancer worry were not associated with adherence. In Latinas, screening interventions should emphasize knowledge and target education efforts at younger, uninsured, and less acculturated mammography-eligible women. [ABSTRACT FROM AUTHOR]

Practice guidelines incorporate genomic tumor profiling, using results such as the Oncotype DX Recurrence Score (RS), to refine recurrence risk estimates for the large proportion of breast cancer patients with early-stage, estrogen receptor-positive disease. We sought to understand the impact of receiving genomic recurrence risk estimates on breast cancer patients' well-being and the impact of these patient-reported outcomes on receipt of adjuvant chemotherapy. Participants were 193 women (mean age 57) newly diagnosed with early-stage breast cancer. Women were interviewed before and 2-3 weeks after receiving the RS result between 2011 and 2015. We assessed subsequent receipt of chemotherapy from chart review. After receiving their RS, perceived pros ( t = 4.27, P < .001) and cons ( t = 8.54, P < .001) of chemotherapy increased from pre-test to post-test, while perceived risk of breast cancer recurrence decreased ( t = 2.90, P = .004). Women with high RS tumors were more likely to receive chemotherapy than women with low RS tumors (88 vs. 5 %, OR 0.01, 0.00-0.02, P < .001). Higher distress (OR 2.19, 95 % CI 1.05-4.57, P < .05) and lower perceived cons of chemotherapy (OR 0.50, 95 % CI 0.26-0.97, P < .05) also predicted receipt of chemotherapy. Distressed patients who saw few downsides of chemotherapy received this treatment. Clinicians should consider these factors when discussing chemotherapy with breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) has been linked to an increased risk of coronary heart disease and stroke. Dyslipidemia is a well-established risk factor for cardiovascular disease. The aim of this study was to investigate the long-term lipid profiles in a large cohort of IBD patients.Methods: Data of patients from an IBD registry who had more than one measurement of total cholesterol and triglyceride levels during the follow-up period were analyzed. The lipid profiles of IBD patients were compared to those of the general population according to National Health and Nutrition Examination Survey (2009-2012). Quartiles of cholesterol or triglyceride levels in relation to surrogate markers of disease severity were analyzed.Results: Seven hundred and one IBD patients [54% Crohn's disease (CD), 46% ulcerative colitis (UC)] were included. IBD patients had less frequent high total cholesterol and high LDL cholesterol (6 vs. 13 and 5 vs. 10%) and more frequent low HDL and high triglycerides (24 vs. 17 and 33 vs. 25%) compared to the general population (all p < 0.001). Median total cholesterol levels were lower and median triglycerides higher in CD compared to UC (171 vs. 184; 123 vs. 100 mg/dL; both p < 0.001). In the multiple regression analysis, lipid profile was independently associated with hospitalizations (low cholesterol) and IBD surgeries (low cholesterol and high triglycerides).Conclusions: Low total cholesterol and high triglyceride levels are more frequent in IBD patients (in particular CD) compared to healthy controls and are independently associated with more severe disease. [ABSTRACT FROM AUTHOR]

Prescription opioid use for chronic non-cancer pain has reached epidemic levels in the USA. With this increased use is the recognition of serious opioid-related gastrointestinal complications such as narcotic bowel syndrome (NBS) and opioid-induced constipation (OIC). NBS consists of a paradoxical worsening of abdominal pain with escalating doses of opioids and is likely mediated by the central nervous system. Therapy requires an intensive multidisciplinary approach to detoxification. OIC is the most common gastrointestinal side effect of opioids. Several novel therapeutics are available to treat OIC that fails to respond to laxative therapy. This review will summarize recent findings on the pathophysiology and treatment approaches to NBS and OIC with a focus on controversies about diagnosis and intervention. [ABSTRACT FROM AUTHOR]

To compare profiles of subjects with and without cervical dystonia (CD)-associated pain, to evaluate the contribution of pain and the motor component of CD on quality of life, and to compare the initial botulinum toxin treatment paradigm between pain groups, baseline data were used from the CD Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE), a multicenter, prospective, observational registry designed to capture real-world practices and outcomes for onabotulinumtoxinA CD treatment. Subjects were divided into no/mild pain [Pain Numeric Rating Scale (PNRS) score 0-3] and moderate/severe pain groups (PNRS score 4-10). Descriptive and differential statistics were utilized to compare groups. 1,037 subjects completed the first treatment session, reported baseline botulinum toxin status, and completed baseline PNRS. Those with no/mild pain were significantly older at baseline. Those subjects with moderate/severe pain had higher Toronto Western Spasmodic Torticollis Rating Scale Severity (17.7 ± 5.1 vs. 16.2 ± 5.6, p < 0.0001) and Disability (12.7 ± 6.1 vs. 7.5 ± 5.6, p < 0.0001). CD subjects with moderate/severe pain received a higher mean dose (177.3 ± 82.9 vs. 158.0 ± 67.1 U, p = 0.0001) of onabotulinumtoxinA and were injected in more muscles (4.1 ± 1.4 vs. 3.7 ± 1.2, p < 0.0001) at initial treatment. CD PROBE clearly demonstrates the frequency of pain in CD and substantiates its importance when determining an optimal treatment paradigm. Future analyses of CD PROBE will further our understanding of the treatment patterns and outcomes related to onabotulinumtoxinA therapy for this disabling condition. [ABSTRACT FROM AUTHOR]

Background and Aims: The U.S. population is aging and the burden of geriatric inflammatory bowel disease (IBD) patients has increased. Systematic data describing phenotypic presentation, treatment regimens, outcomes and comorbidities in elderly IBD patients is limited. We performed a retrospective observational study of IBD patients age ≥65 followed in a 20-hospital system to determine patterns of phenotypic presentation, treatment, polypharmacy, nutritional status and comorbidity. Methods: Data were extracted from electronic medical record based on ICD-9 coding/indexed terms on Crohn's disease (CD) and ulcerative colitis (UC) patients. Results: A total of 393 geriatric IBD patients were identified (49.1% males; 50.9% females; 61.8% UC; 38.2% CD; 73.4 ± 6.6 years old). Younger age at diagnosis of CD (≤64) was associated with greater prevalence of small bowel surgeries (63.6%) compared with those diagnosed after age ≥65 (20.9%) ( p < 0.005). Fistulizing/penetrating disease was frequent in patients diagnosed with CD at a younger age (43.6% compared to 7%) ( p < 0.005). IBD maintenance treatment included: 44% 5-ASA agents; 31.6% maintenance prednisone (defined as ≥6 months treatment duration); 4.8% steroid suppositories; 5.6% 6MP/azathioprine; 1.3% methotrexate; 1.3% adalimumab; 1.3% infliximab; 9.4% loperamide/diphenoxylate/atropine; 0.5% had no IBD medications. Longer duration of CD disease correlated with vitamin B12, vitamin D and iron deficiency. Conclusion: Geriatric patients diagnosed with CD earlier in life had greater small bowel involvement compared with new onset geriatric CD. There is low utilization of immunomodulator and biologic agents in geriatric IBD patients. Duration of CD correlates with nutrient deficiency. Prospective studies are warranted in this respect. [ABSTRACT FROM AUTHOR]

Unlike other immune cells, B cells express both an antigen-specific B cell receptor (BCR) and Toll-like receptors (TLRs). Dual BCR and TLR engagement can fine-tune functional B cell responses, directly linking cell-intrinsic innate and adaptive immune programmes. Although most data regarding B cell-specific functions of the TLR signalling pathway have been obtained in mice, the discovery of patients with a deficiency in this pathway has recently provided an insight into human B cell responses. Here, we highlight the importance of the integration of signalling pathways downstream of BCRs and TLRs in modulating B cell function, focusing when possible on B cell-intrinsic roles. [ABSTRACT FROM AUTHOR]

Background: Infliximab is effective treatment for Crohn's disease and has been associated with rare, but serious infectious complications. Emerging data suggest a benefit of infliximab in preventing postoperative Crohn's disease recurrence. It is not known whether administration of infliximab shortly after resective surgery for Crohn's disease increases postoperative complications.Aims: To evaluate the risk of developing postoperative complications among Crohn's disease patients receiving infliximab within 4 weeks of intestinal resection.Methods: As part of a randomized placebo-controlled infliximab postoperative prevention study, adverse events were prospectively monitored. Crohn's disease patients undergoing intestinal resection were randomized to placebo or infliximab 2-4 weeks after surgery. Study infusions were administered at 0, 2, and 6 weeks then every 8 weeks for 1 year. To evaluate whether infliximab increased postoperative complications, we analyzed all adverse events for 1 year after surgery.Results: Twenty-four patients were randomized to infliximab or placebo after intestinal resection for Crohn's disease. Mean time to first postoperative infusion was 20 days (range 14-25 days). Over the course of 1 year, there were 22 total adverse events, but no difference between infliximab and placebo patients (12 versus 10, respectively, P = 1.0). In the immediate postoperative period, within 8 weeks of surgery, the number of adverse events was also similar between the two groups (3 infliximab and 5 placebo patients, P = 0.68). There were no serious adverse events and no complications related to wound healing or infection.Conclusions: Initiation of infliximab within 4 weeks of intestinal resection was not associated with postoperative complications. [ABSTRACT FROM AUTHOR]

Few studies have quantitatively evaluated the uptake and outcomes of BRCA1/2 genetic counseling and testing in men. We conducted a prospective longitudinal study to describe and compare uptake of and psychosocial outcomes following BRCA1/2 testing in a sample of men and women at high-risk for carrying a BRCA1/2 mutation. Men ( n = 98) and women ( n = 243) unaffected with cancer completed baseline assessments prior to genetic counseling and testing and then 6- and 12-months post-testing. Most men ( n = 94; 95.9%) opted to have genetic testing, of whom 44 received positive BRCA1/2 genetic test results and 50 received true negative results. Among women, 93.4% had genetic testing, of whom 79 received positive results and 148 received negative results. In multivariate models, male BRCA1/2 carriers reported significantly higher genetic testing distress (6-months: Z = 4.48, P < 0.0001; 12-months: Z = 2.78, P < 0.01) than male non-carriers. After controlling for baseline levels of distress, no statistically significant differences emerged between male and female BRCA1/2 carriers in psychological distress at 12-months post-testing, although absolute differences were evident over time. Predictors of distress related to genetic testing among male carriers at 12-months included higher baseline cancer-specific distress ( Z = 4.73, P < 0.0001) and being unmarried ( Z = 2.18, P < 0.05). Similarly, baseline cancer-specific distress was independently associated with cancer-specific distress at 6- ( Z = 3.66, P < 0.001) and 12-months ( Z = 4.44, P < 0.0001) post-testing among male carriers. Clinically, our results suggest that pre-test assessment of distress and creation of educational materials specifically tailored to the needs and concerns of male carriers may be appropriate in this important but understudied high-risk group. [ABSTRACT FROM AUTHOR]

In this article, we present a methodological framework that meets novel requirements emerging from upcoming types of accelerated and highly configurable neuromorphic hardware systems. We describe in detail a device with 45 million programmable and dynamic synapses that is currently under development, and we sketch the conceptual challenges that arise from taking this platform into operation. More specifically, we aim at the establishment of this neuromorphic system as a flexible and neuroscientifically valuable modeling tool that can be used by non-hardware experts. We consider various functional aspects to be crucial for this purpose, and we introduce a consistent workflow with detailed descriptions of all involved modules that implement the suggested steps: The integration of the hardware interface into the simulator-independent model description language PyNN; a fully automated translation between the PyNN domain and appropriate hardware configurations; an executable specification of the future neuromorphic system that can be seamlessly integrated into this biology-to-hardware mapping process as a test bench for all software layers and possible hardware design modifications; an evaluation scheme that deploys models from a dedicated benchmark library, compares the results generated by virtual or prototype hardware devices with reference software simulations and analyzes the differences. The integration of these components into one hardware-software workflow provides an ecosystem for ongoing preparative studies that support the hardware design process and represents the basis for the maturity of the model-to-hardware mapping software. The functionality and flexibility of the latter is proven with a variety of experimental results. [ABSTRACT FROM AUTHOR]

Women who receive positive or uninformative BRCA1/2 test results face a number of decisions about how to manage their cancer risk. The purpose of this study was to prospectively examine the effect of receiving a positive versus uninformative BRCA1/2 genetic test result on the perceived pros and cons of risk-reducing mastectomy (RRM) and risk-reducing oophorectomy (RRO) and breast cancer screening. We further examined how perceived pros and cons of surgery predict intention for and uptake of surgery. 308 women (146 positive, 162 uninformative) were included in RRM and breast cancer screening analyses. 276 women were included in RRO analyses. Participants completed questionnaires at pre-disclosure baseline and 1-, 6-, and 12-months post-disclosure. We used linear multiple regression to assess whether test result contributed to change in pros and cons and logistic regression to predict intentions and surgery uptake. Receipt of a positive BRCA1/2 test result predicted stronger pros for RRM and RRO ( P < 0.001), but not perceived cons of RRM and RRO. Pros of surgery predicted RRM and RRO intentions in carriers and RRO intentions in uninformatives. Cons predicted RRM intentions in carriers. Pros and cons predicted carriers' RRO uptake in the year after testing ( P < 0.001). Receipt of BRCA1/2 mutation test results impacts how carriers see the positive aspects of RRO and RRM and their surgical intentions. Both the positive and negative aspects predict uptake of surgery. [ABSTRACT FROM AUTHOR]

Poorly controlled Crohn's disease (CD) often requires surgery for such complications as strictures, fistulas, and abscesses. The goal of postoperative treatment is to suppress or prevent inflammation and maintain mucosal healing. Probiotics, antibiotics, 5-aminosalicylates, immunomodulators, and antibodies to tumor necrosis factor are all used to prevent postoperative recurrence. In this article, recent studies are reviewed. Azathioprine/6-mercaptopurine are moderately effective at preventing and treating postoperative CD, whereas infliximab/adalimumab are highly effective and probiotics and 5-aminosalicylates minimally effective. We base the choice of postoperative medical therapy on the patient's risk profile for postoperative recurrence. Whatever postoperative therapy is used, the mucosa should be assessed within 12 months to determine if the approach is effective. If active inflammation is found, then treatment should be intensified. By treating CD aggressively after a first surgery, future surgeries can be delayed or averted. [ABSTRACT FROM AUTHOR]

Recently, conventional therapies for inflammatory bowel disease (IBD) have not received the same amount of attention as biologic therapies, yet they remain the backbone of therapy for IBD because of their efficacy, safety, and relatively low cost. Advances in efficacy and safety continue because of modifications in drug dosing and monitoring. Higher doses of mesalamine per pill, together with once-daily dosing, may help to optimize drug delivery and patient compliance. Budesonide, an effective agent for both induction and short-term remission maintenance in Crohn’s disease, is devoid of many of the toxicities common to corticosteroids. Assessments of thiopurine methyltransferase and metabolite levels are helping to fine-tune dose optimization for the thiopurines azathioprine and 6-mercaptopurine. The oral calcineurin inhibitors tacrolimus and cyclosporine have been shown to have expanded roles in IBD, and methotrexate may be useful in some patients with refractory ulcerative colitis. Probiotics are showing promise for maintenance of remission in Crohn’s disease, ulcerative colitis, and pouchitis. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Many disease activity indices are used to measure ulcerative colitis. Invasive indices incorporate an endoscopic score, while noninvasive indices do not require endoscopy. In clinical practice, many patients are treated based on their symptoms without endoscopic evaluation. However, invasive indices are commonly used in clinical research. Our objective was to determine whether endoscopy is necessary for the assessment of disease activity in patients with ulcerative colitis.METHODS: Sixty-six consecutive ulcerative colitis patients were evaluated with invasive indices: the St. Mark's index and the Ulcerative Colitis Disease Activity Index (UCDAI); and noninvasive indices: the Simple Clinical Colitis Activity Index (SCCAI) and the Seo index. The correlations between the indices were measured. The contribution of the endoscopic items was measured with linear regression modeling. The overlap of endoscopy with other items in the standard indices was determined through factor analysis.RESULTS: The two noninvasive indices correlated well with the invasive St. Mark's Index (SCCAI 0.86, Seo 0.70). After adjusting for the three noninvasive UCDAI items, the UCDAI endoscopy item predicted only 0.04% of the variance in the St. Mark's index. Factor analysis demonstrated that this is because the endoscopy items in the invasive indices correlate with stool frequency and stool blood items.CONCLUSIONS: Endoscopy items contribute little additional information to indices of disease activity in ulcerative colitis. The clinical practice of treating patients based on reported symptoms is appropriate. The use of noninvasive indices in clinical trials could lower study costs and may increase subjects' willingness to participate.(Am J Gastroenterol 2005;100:355–361) [ABSTRACT FROM AUTHOR]

The objectives of this study were (1) to describe perceptions of stress and confidence following genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and (2) to identify predictors of these processes. Participants were 130 high-risk women affected with cancer who received BRCA1/2 test results. Individual difference characteristics and interpersonal factors were measured by self-report before genetic counseling and perceptions of stress and confidence were evaluated by self-report 1 month following disclosure of test results. BRCA1/2 test results had a significant effect only on perceptions of stress (β = 0.38, p = 0.0001), while trait anxiety had a significant effect on both perceptions of stress (β = 0.44, p = 0.0001) and confidence (β = -0.41, p = 0.001). These results suggest that interventions designed to address perceptions of stress related to medical decision-making and familial concerns may need to be targeted to BRCA1/2 mutation carriers and individuals who are highly anxious. [ABSTRACT FROM AUTHOR]

In this study we sought to evaluate the prospective association between psychological distress and mammography utilization among women with a family history of breast cancer. We evaluated the association of cancer worry, cancer-specific distress, and general distress with mammography utilization after controlling for potential confounders. The results revealed that 74% of our sample had obtained a mammogram within 12 months of the baseline assessment. Logistic regression models revealed that after controlling for potential confounding variables, cancer worry and general distress were independent predictors of mammography utilization. Specifically, women who reported higher levels of worry and/or distress at baseline were less likely to report having received a mammogram in the 12 months following the baseline assessment. These results are in contrast to the only other prospective study in this population. Additional research is needed to determine the prospective association between distress and adherence and to identify potential mechanisms for such an association. [ABSTRACT FROM AUTHOR]

Studies in women with a family history of cancer demonstrate a wide variability in the uptake of cancer screening measures. Little data exist regarding the breast and ovarian cancer screening practices of women who are members of hereditary breast cancer families. In order to address this issue, we examined the screening behaviors and the determinants of screening in a clinic based group of 216 women with a strong family history of breast or ovarian cancer who were participating in a free genetic counseling and testing research program. At baseline, prior to obtaining genetic counseling or testing, 50% of women ages 30–39, 83% of those age 40–49, 69% of those 50–64, and 53% of those ≥65 reported having a mammogram in the prior year. Adherence to mammography recommendations was correlated with age, number of relatives with breast cancer, and income. Twenty percent of participants had at least one CA-125 performed and 31% had ever obtained a screening ultrasound. Having at least one relative with ovarian cancer was very strongly associated with ovarian cancer screening [OR = 12.3, 95% CI = 4.6–33 for CA-125; OR = 4.9, 95% CI = 2.4,10.1 for ultrasound]. No association between cancer worries/distress and either breast or ovarian cancer screening was found. In conclusion, the breast and ovarian screening uptake in healthy women from hereditary breast cancer families is suboptimal, even for women over age 50, for whom annual mammography is clearly indicated. These findings indicate a need for better education about screening guidelines for high-risk women. [ABSTRACT FROM AUTHOR]

This study sought to evaluate physical activity in women at moderate risk for breast cancer, the correlates of engaging in regular physical activity, and whether physical activity relates to psychological well-being. The results revealed that 55% of women were regularly active. Logistic regression models indicated that positive affect was associated with increased and negative affect was associated with decreased overall and leisure activity. Older, married, and employed women were more likely to engage in household/occupational activity, whereas women who perceived their risk for breast cancer as high were less likely. More educated women and those with higher perceived risk were more likely to engage in leisure activity, and married women were less likely. These results suggest a need to increase activity levels in women at moderate risk for breast cancer, provide variables upon which interventions can be tailored to promote activity, and point to psychological benefits of activity in this population. [ABSTRACT FROM AUTHOR]

Halogen phenyl-substituted methyl 2-cyano-3-phenyl-2-propenoates, RC6H4CH=C(CN)CO2CH3 (R= 2-fluoro, 3-fluoro, 2-bromo, and 3-bromo), were prepared by the piperidine catalyzed Knoevenagel condensation of corresponding substituted benzaldehydes and methyl cyanoacetate. Novel copolymers of the propenoates and styrene were prepared at equimolar monomer feed by solution copolymerization in the presence of a radical initiator. The order of relative reactivity (1/ r1) was 3Br (3.02) > 2Br (2.63) > 3F (1.84) > 2F (1.66). High glass transition temperatures of the copolymers compared that of polystyrene indicates a substantial decrease in chain mobility of the copolymers due to the high dipolar character of the trisubstituted ethylene monomer unit. [ABSTRACT FROM AUTHOR]

Sialic acid is the most abundant terminal monosaccharide on mammalian cell surface glycoconjugates. The crystal structures of a mammalian sialyltransferase, that of porcine ST3Gal-I, in the apo form and bound to analogues of the donor and acceptor substrate are now described, providing insights into the catalytic mechanism and for inhibitor design. [ABSTRACT FROM AUTHOR]