Emerging treatment options for short bowel syndrome: potential role of teduglutide

INTRODUCTION: Current medical management of short bowel syndrome (SBS) involves the use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN dependence in patients with SBS. AREAS COVERED IN REVIEW: Advancing research of GLP-2 physiology has spurred the growing understanding of the diverse effects of GLP-2. The development of the degradation resistant GLP-2 analog, teduglutide (Gattex(TM), NPS Pharmaceuticals, Bedminster, NJ), has allowed its exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN requirements with good safety profiles. The reparative and immunomodulatory effects of teduglutide may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about possible carcinogenic properties during long-term use require ongoing evaluation. SUMMARY: GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for its use in other clinical settings like IBD has been shown in small pilot studies

Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior

Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (<5%) non-synonymous variants in CHRNB4 and investigated functional effects by co-expression with normal α3 or α4 subunits in human embryonic kidney cells. Voltage-clamp was used to obtain acetylcholine and nicotine concentration-response curves and qRT-PCR, western blots and cell-surface ELISAs were performed to assess expression levels. These results were used to functionally weight genetic variants in a gene-based association test. We find that there is a highly significant correlation between carrier status weighted by either acetylcholine EC50 (β = -0.67, r2 = 0.017, P = 2 × 10(-4)) or by response to low nicotine (β = -0.29, r2 = 0.02, P = 6 × 10(-5)) when variants are expressed with the α3 subunit. In contrast, there is no significant association when carrier status is unweighted (β = -0.04, r2 = 0.0009, P = 0.54). These results highlight the value of functional analysis of variants and the advantages to integrating such data into genetic studies. They also suggest that an increased sensitivity to low concentrations of nicotine is protective from the risk of developing nicotine dependence

The contribution of physician assistants/associates to secondary care : a systematic review

OBJECTIVE: To appraise and synthesise research on the impact of physician assistants/associates (PA) in secondary care, specifically acute internal medicine, care of the elderly, emergency medicine, trauma and orthopaedics, and mental health. DESIGN: Systematic review. SETTING: Electronic databases (Medline, Embase, ASSIA, CINAHL, SCOPUS, PsycINFO, Social Policy and Practice, EconLit and Cochrane), reference lists and related articles. INCLUDED ARTICLES: Peer-reviewed articles of any study design, published in English, 1995-2017. INTERVENTIONS: Blinded parallel processes were used to screen abstracts and full text, data extractions and quality assessments against published guidelines. A narrative synthesis was undertaken. OUTCOME MEASURES: Impact on: patients' experiences and outcomes, service organisation, working practices, other professional groups and costs. RESULTS: 5472 references were identified and 161 read in full; 16 were included-emergency medicine (7), trauma and orthopaedics (6), acute internal medicine (2), mental health (1) and care of the elderly (0). All studies were observational, with variable methodological quality. In emergency medicine and in trauma and orthopaedics, when PAs are added to teams, reduced waiting and process times, lower charges, equivalent readmission rate and good acceptability to staff and patients are reported. Analgesia prescribing, operative complications and mortality outcomes were variable. In internal medicine outcomes of care provided by PAs and doctors were equivalent. CONCLUSIONS: PAs have been deployed to increase the capacity of a team, enabling gains in waiting time, throughput, continuity and medical cover. When PAs were compared with medical staff, reassuringly there was little or no negative effect on health outcomes or cost. The difficulty of attributing cause and effect in complex systems where work is organised in teams is highlighted. Further rigorous evaluation is required to address the complexity of the PA role, reporting on more than one setting, and including comparison between PAs and roles for which they are substituting. PROSPERO REGISTRATION NUMBER: CRD42016032895

Physician associates working in secondary care teams in England: Interprofessional implications from a national survey

Physician associates (PAs) are a new type of healthcare professional to the United Kingdom; however, they are well established in the United States (where they are known as physician assistants). PAs are viewed as one potential solution to the current medical workforce doctor shortage. This study investigated the deployment of PAs within secondary care teams in England, through the use of a cross-sectional electronic, self-report survey. The findings from 14 questions are presented. Sixty-three PAs working in a range of specialties responded. A variety of work settings were reported, most frequently inpatient wards, with work generally taking place during weekdays. Both direct and non-direct patient care activities were reported, with the type of work undertaken varying at times, depending on the presence or absence of other healthcare professionals. PAs reported working within a variety of secondary care team staffing permutations, with the majority of these being interprofessional. Line management was largely provided by consultants; however day-to-day supervision varied, often relating to different work settings. A wide variation in ongoing supervision was also reported. Further research is required to understand the nature of PAs' contribution to collaborative care within secondary care teams in England

Long-Term Teduglutide for the Treatment of Patients With Intestinal Failure Associated With Short Bowel Syndrome

OBJECTIVES: In the pivotal 24-week, phase III, placebo-controlled trial, teduglutide significantly reduced parenteral support (PS) requirements in patients with short bowel syndrome (SBS). STEPS-2 was a 2-year, open-label extension of that study designed to evaluate long-term safety and efficacy of teduglutide. METHODS: Enrolled patients had completed 24 weeks of either teduglutide (TED/TED) or placebo (PBO/TED) in the initial placebo-controlled study or qualified for that study, but were not treated (NT/TED) because of full enrollment. Patients received subcutaneous teduglutide 0.05 mg/kg/day for up to 24 months (NT/TED and PBO/TED) or up to 30 months (TED/TED). Clinical response was defined as 20–100% reduction from baseline in weekly PS volume; baseline was considered the beginning of teduglutide treatment in the initial placebo-controlled study (TED/TED) or STEPS-2 (NT/TED and PBO/TED). Descriptive statistics summarized changes in efficacy and safety variables. RESULTS: Of 88 enrolled patients, 65 (74%) completed STEPS-2. The most common treatment-emergent adverse events were abdominal pain (34%), catheter sepsis (28%), and decreased weight (25%). Mean weight, body mass index, and serum albumin remained stable. In patients who completed the study, clinical response was achieved in 28/30 (93%) TED/TED, 16/29 (55%) PBO/TED, and 4/6 (67%) NT/TED patients. Mean PS volume reductions from baseline were 7.6 (66%), 3.1 (28%), and 4.0 (39%) l/week in the TED/TED, PBO/TED, and NT/TED groups, respectively. Thirteen patients achieved full enteral autonomy. CONCLUSIONS: In patients with SBS, long-term teduglutide treatment resulted in sustained, continued reductions in PS requirements. Overall health and nutritional status was maintained despite PS reductions

Physician associates and GPs in primary care: a comparison.

BACKGROUND: Physician associates [PAs] (also known as physician assistants) are new to the NHS and there is little evidence concerning their contribution in general practice. AIM: This study aimed to compare outcomes and costs of same-day requested consultations by PAs with those of GPs. DESIGN AND SETTING: An observational study of 2086 patient records presenting at same-day appointments in 12 general practices in England. METHOD: PA consultations were compared with those of GPs. Primary outcome was re-consultation within 14 days for the same or linked problem. Secondary outcomes were processes of care. RESULTS: There were no significant differences in the rates of re-consultation (rate ratio 1.24, 95% confidence interval [CI] = 0.86 to 1.79, P = 0.25). There were no differences in rates of diagnostic tests ordered (1.08, 95% CI = 0.89 to 1.30, P = 0.44), referrals (0.95, 95% CI = 0.63 to 1.43, P = 0.80), prescriptions issued (1.16, 95% CI = 0.87 to 1.53, P = 0.31), or patient satisfaction (1.00, 95% CI = 0.42 to 2.36, P = 0.99). Records of initial consultations of 79.2% (n = 145) of PAs and 48.3% (n = 99) of GPs were judged appropriate by independent GPs (P<0.001). The adjusted average PA consultation was 5.8 minutes longer than the GP consultation (95% CI = 2.46 to 7.1; P<0.001); cost per consultation was GBP £6.22, (US$ 10.15) lower (95% CI = -7.61 to -2.46, P<0.001). CONCLUSION: The processes and outcomes of PA and GP consultations for same-day appointment patients are similar at a lower consultation cost. PAs offer a potentially acceptable and efficient addition to the general practice workforce

The Grizzly, October 5, 2006

Family Day 2006 Hits Ursinus • Monumental Players in the Black Arts Movement Speak at Ursinus • MSA and Hillel Broke the Fast Together • Free Fitness Class Offered to Ursinus Students • Popping the Pill • Catching Up with Dane Cook • Spotlight on UC Professors: Dr. Bruce Rideout • Abstract Mastery: Exploring the Outdoor Sculpture Collection • Opinions: Forced Suffrage? • Bears Terrorize McDaniel, Ending Nine-Year Streak • Women Split, Men Earn First Conference Pointhttps://digitalcommons.ursinus.edu/grizzlynews/1720/thumbnail.jp

Therapeutic targeting of integrin αvβ6 in breast cancer

BACKGROUND: Integrin ?v?6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of ?v?6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (?6) was measured in breast cancers by immunohistochemistry (n &gt; 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ?6 in breast cell lines, the role of ?v?6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ? 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit ?6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ?6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P &lt; .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting ?v?6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.<br/