Efficacy and Findings of a Blinded Randomized Reintroduction Phase for the Low FODMAP Diet in Irritable Bowel Syndrome.

BACKGROUND & AIMS: The efficacy of a low fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in irritable bowel syndrome (IBS) is well established. After the elimination period, a reintroduction phase aims to identify triggers. We studied the impact of a blinded reintroduction using FODMAP powders to objectively identify triggers and evaluated the effect on symptoms, quality of life, and psychosocial comorbidities. METHODS: Responders to a 6-week low FODMAP diet, defined by a drop in IBS symptom severity score (IBS-SSS) compared with baseline, entered a 9-week blinded randomized reintroduction phase with 6 FODMAP powders (fructans, fructose, galacto-oligosaccharides, lactose, mannitol, sorbitol) or control (glucose). A rise in IBS-SSS (≥50 points) defined a FODMAP trigger. Patients completed daily symptom diaries and questionnaires for quality of life and psychosocial comorbidities. RESULTS: In 117 recruited patients with IBS, IBS-SSS improved significantly after the elimination period compared with baseline (150 ± 116 vs 301 ± 97, P < .0001, 80% responders). Symptom recurrence was triggered in 85% of the FODMAP powders, by an average of 2.5 ± 2 FODMAPs/patient. The most prevalent triggers were fructans (56%) and mannitol (54%), followed by galacto-oligosaccharides, lactose, fructose, sorbitol, and glucose (respectively 35%, 28%, 27%, 23%, and 26%) with a significant increase in abdominal pain at day 1 for sorbitol/mannitol, day 2 for fructans/galacto-oligosaccharides, and day 3 for lactose. CONCLUSION: We confirmed the significant benefit of the low FODMAP diet in tertiary-care IBS. A blinded reintroduction revealed a personalized pattern of symptom recurrence, with fructans and mannitol as the most prevalent, and allows the most objective identification of individual FODMAP triggers. Ethical commission University hospital of Leuven reference number: s63629; Clinicaltrials.gov number: NCT04373304.

Current prescribing for pyoderma gangrenosum in the UK and access to biologic medications: Results from a UK Dermatology Clinical Trials Network (UKDCTN) survey of UK Dermatologists.

Pyoderma gangrenosum (PG) is an ulcerative inflammatory disorder affecting the lower legs in 80% of cases. The use of biologic medications to treat PG is increasing although there is a limited evidence base to guide treatment choices. In some health systems, such as the UK NHS, limitations are placed on biologic prescribing for PG leading to wide variations in prescribing. A survey of mainly UK clinicians showed that prednisolone remains the first line treatment for PG (90%). Biologics have been used by 66% of clinicians as second line therapy but 19% have had prescribing requests declined. Further research is needed to determine optimal treatment strategies for PG.

Identification of citrus immune regulators involved in defence against Huanglongbing using a new functional screening system.

Huanglongbing (HLB) is the most devastating citrus disease in the world. Almost all commercial citrus varieties are susceptible to the causal bacterium, Candidatus Liberibacter asiaticus (CLas), which is transmitted by the Asian citrus psyllid (ACP). Currently, there are no effective management strategies to control HLB. HLB-tolerant traits have been reported in some citrus relatives and citrus hybrids, which offer a direct pathway for discovering natural defence regulators to combat HLB. Through comparative analysis of small RNA profiles and target gene expression between an HLB-tolerant citrus hybrid (Poncirus trifoliata × Citrus reticulata) and a susceptible citrus variety, we identified a panel of candidate defence regulators for HLB-tolerance. These regulators display similar expression patterns in another HLB-tolerant citrus relative, with a distinct genetic and geographic background, the Sydney hybrid (Microcitrus virgata). Because the functional validation of candidate regulators in tree crops is always challenging, we developed a novel rapid functional screening method, using a C. Liberibacter solanacearum (CLso)/potato psyllid/Nicotiana benthamiana interaction system to mimic the natural transmission and infection circuit of the HLB complex. When combined with efficient virus-induced gene silencing in N. benthamiana, this innovative and cost-effective screening method allows for rapid identification and functional characterization of regulators involved in plant immune responses against HLB, such as the positive regulator BRCA1-Associated Protein, and the negative regulator Vascular Associated Death Protein.

Small Intestinal Bacterial Overgrowth in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Case-Control Studies.

INTRODUCTION: We conducted a systematic review and meta-analysis to compare the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) and controls. METHODS: Electronic databases were searched up to December 2018 for studies reporting SIBO prevalence in patients with IBS. Prevalence rates, odds ratios (ORs), and 95% confidence intervals (CIs) of SIBO in patients with IBS and controls were calculated. RESULTS: We included 25 studies with 3,192 patients with IBS and 3,320 controls. SIBO prevalence in patients with IBS was significantly increased compared with controls (OR = 3.7, 95% CI 2.3-6.0). In studies using only healthy controls, the OR for SIBO in patients with IBS was 4.9 (95% CI 2.8-8.6). With breath testing, SIBO prevalence in patients with IBS was 35.5% (95% CI 33.6-37.4) vs 29.7% (95% CI 27.6-31.8) in controls. Culture-based studies yielded a SIBO prevalence of 13.9% (95% CI 11.5-16.4) in patients with IBS and 5.0% (95% CI 3.9-6.2) in controls with a cutoff value of 10 colony-forming units per milliliter vs 33.5% (95% CI 30.1-36.9) in patients with IBS and 8.2% (95% CI 6.8-9.6) in controls with a cutoff value of 10 colony-forming unit per milliliter, respectively. SIBO prevalence diagnosed by lactulose breath test is much greater in both patients with IBS (3.6-fold) and controls (7.6-fold) compared with glucose breath test. Similar difference is seen when lactulose breath test is compared with culture methods. OR for SIBO in patients with IBS-diarrhea compared with IBS-constipation was 1.86 (95% CI 1.83-2.8). Methane-positive breath tests were significantly more prevalent in IBS-constipation compared with IBS-diarrhea (OR = 2.3, 95% CI 1.2-4.2). In patients with IBS, proton pump inhibitor was not associated with SIBO (OR = 0.8, 95% CI 0.5-1.5, P = 0.55). DISCUSSION: This systematic review and meta-analysis suggests a link between IBS and SIBO. However, the overall quality of the evidence is low. This is mainly due to substantial "clinical heterogeneity" due to lack of uniform selection criteria for cases and controls and limited sensitivity and specificity of the available diagnostic tests.

Fatigue and sleepiness responses to experimental inflammation and exploratory analysis of the effect of baseline inflammation in healthy humans.

Inflammation is believed to be a central mechanism in the pathophysiology of fatigue. While it is likely that dynamic of the fatigue response after an immune challenge relates to the corresponding cytokine release, this lacks evidence. Although both fatigue and sleepiness are strong signals to rest, they constitute distinct symptoms which are not necessarily associated, and sleepiness in relation to inflammation has been rarely investigated. Here, we have assessed the effect of an experimental immune challenge (administration of lipopolysaccharide, LPS) on the development of both fatigue and sleepiness, and the associations between increases in cytokine concentrations, fatigue and sleepiness, in healthy volunteers. In addition, because chronic-low grade inflammation may represent a risk factor for fatigue, we tested whether higher baseline levels of inflammation result in a more pronounced development of cytokine-induced fatigue and sleepiness. Data from four experimental studies was combined, giving a total of 120 subjects (LPS N = 79, 18 (23%) women; Placebo N = 69, 12 (17%) women). Administration of LPS resulted in a stronger increase in fatigue and sleepiness compared to the placebo condition, and the development of both fatigue and sleepiness closely paralleled the cytokine responses. Individuals with stronger increases in cytokine concentrations after LPS administration also suffered more from fatigue and sleepiness (N = 75), independent of gender. However, there was no support for the hypothesis that higher baseline inflammatory markers moderated the responses in fatigue or sleepiness after an inflammatory challenge. The results demonstrate a tight connection between the acute inflammatory response and development of both fatigue and sleepiness, and motivates further investigation of the involvement of inflammation in the pathophysiology of central fatigue.

Induction of Meal-related Symptoms as a Novel Mechanism of Action of the Duodenal-Jejunal Bypass Sleeve.

BACKGROUND: Treatment with a duodenal-jejunal bypass sleeve (DJBS) induces clinically significant weight loss, but little is known about the mechanisms of action of this device. AIM: The aim of this study was to characterize the mechanisms of action of the DJBS and determine the durability of weight loss and metabolic improvements. MATERIALS AND METHODS: We studied a cohort of 19 subjects with severe obesity and type 2 diabetes (baseline body mass index: 43.7±5.3 kg/m). Anthropometry, body composition, blood pressure, biochemical measures, and dietary intake were monitored for 48 weeks after DJBS implantation, and then for 1 year after device removal. Gastric emptying and triglyceride absorption were measured at baseline, 8 weeks after implant, and within 3 weeks of device explant. Visceral sensory function was assessed at baseline, 4 weeks after implant, and within 3 weeks after explant. RESULTS: Significant weight loss (P<0.01) occurred following DJBS placement, with a mean weight reduction of 17.0±6.5% at 48 weeks. The symptom burden following a standardized nutrient challenge was increased after DJBS implantation (P<0.05), returning to baseline after DJBS removal. Neither gastric emptying nor triglyceride absorption changed with the device in situ. A significant reduction in energy intake was observed [baseline: 7703±2978 kJ (1841±712 kcal), 24 weeks: 4824±2259 kJ (1153±540 kcal), and 48 weeks: 4474±1468 kJ (1069±351 kcal)]. After 1 year, anthropometry remained significantly improved, but there was no durable impact on metabolic outcomes. CONCLUSIONS: DJBS treatment resulted in substantial weight loss. Weight loss is related to reduced caloric intake, which seems linked to an augmented upper gastrointestinal symptom response, but not altered fat absorption.

Duodenal eosinophils as predictors of symptoms in coeliac disease: a comparison of coeliac disease and non-coeliac dyspeptic patients with controls.

Introduction: Duodenal eosinophilia is a key feature of functional dyspepsia, particularly in those with early satiety. Duodenal eosinophilia is also recognised in coeliac disease, although its relevance to symptoms is not understood. We aimed to determine if duodenal eosinophilia is present in patients with coeliac disease presenting with dyspepsia, and whether other histological characteristics were associated with clinical features on presentation.Methods: The coeliac study population comprised 61 patients with a new presentation of coeliac disease to a single centre from 2003 to 2013. A standard symptom assessment was documented for all patients. The control population (55 adults) presenting for endoscopy without coeliac disease was drawn from the same centre with similar demographics for age and gender. Duodenal biopsies from both groups were assessed for eosinophil counts and histological features.Results: Dyspepsia was present in 18.0% of coeliac patients and early satiety in 24.6%. The eosinophil counts were significantly higher in the stomach (12.1/mm2 vs. 4.0/mm2, p < .001) and duodenum (60.4/mm2 vs. 18.0/mm2, p < .001) of coeliac patients compared with controls. There was no significant difference in the mean duodenal eosinophil count in coeliac disease with and without early satiety (55.4/mm2 vs. 66.9/mm2, p = .51). Duodenal eosinophilia was not associated with the severity of coeliac enteropathy. The degree of villous atrophy was associated with iron deficiency at presentation (p = .01), but not symptoms.Conclusions: Although duodenal eosinophil counts are higher in coeliac disease than controls, we were not able to demonstrate an association with presenting symptoms or markers of disease severity.

Link Between Celiac Disease and Inflammatory Bowel Disease.

GOAL: The aim of this analysis was to assess in patients with inflammatory bowel disease (IBD) the risk of celiac disease and in celiac disease patients the risk of IBD. BACKGROUND: Previous studies report a possible association between IBD and celiac disease; however, this link is controversial. STUDY: Using the search terms "inflammatory bowel disease" and "celiac disease," we identified initially 1525 publications. In total 27 studies met inclusion criteria. Proportions and 95% confidence intervals (CIs) for the prevalence of IBD in celiac disease and vice versa were compared with published prevalence rates for the respective geographic regions. RESULTS: We included 41,482 adult IBD patients (20,357 with Crohn's disease; 19,791 with ulcerative colitis; and 459 patients with celiac disease). Overall, in IBD patients the prevalence of celiac disease was 1110/100,000 (95% CI, 1010-1210/100,000) as compared with a prevalence of 620/100,000 (95% CI, 610-630/100,000) in the respective populations (odds ratio, 2.23; 95% CI, 1.99-2.50). In contrast, in patients with celiac disease, 2130/100,000 had IBD (95% CI, 1590-2670/100,000) as compared with 260/100,000 (95% CI, 250/100,000-270/100,000) in the respective populations (odds ratio, 11.10; 95% CI, 8.55-14.40). This effect was not different for ulcerative colitis and Crohn's disease. Although there was no evidence for publication bias for celiac disease in IBD, the funnel plot suggested that the association between IBD in celiac disease might be influenced by publication bias. CONCLUSIONS: The data are consistent with the notion that celiac disease is a risk factor for IBD and to lesser degree patients with IBD have an increased risk of celiac disease.

Duodenal Pathology in Patients with Rumination Syndrome: Duodenal Eosinophilia and Increased Intraepithelial Lymphocytes.

BACKGROUND: Rumination syndrome is a functional gastrointestinal disorder characterized by effortless, postprandial regurgitation. Duodenal eosinophilia has been described in patients with functional dyspepsia. Because of the significant symptomatic overlap between functional dyspepsia and rumination syndrome, we hypothesized that histological changes might exist among patients with rumination syndrome. METHODS: We included patients with rumination syndrome in whom we had obtained duodenal biopsies and compared these with controls. Digital images of biopsy specimens were analyzed for routine pathology and eosinophil counts by a pathologist blinded to the case-control status. RESULTS: The 22 patients with rumination syndrome had a mean age of 39.2 years (range 21-71) and 77% were female. The 10 controls had a mean age of 34.3 (range 27-69) and 80% were female. There was a significant increase in the mean eosinophil count among the patients with rumination syndrome compared to controls, 26 per mm2 (range 16-42) versus 18 per mm2 (range 10-28), p = 0.006. Intraepithelial lymphocyte counts were significantly higher in rumination patients (mean 15/100 enterocytes, range 8-29) versus controls (mean 11/100 enterocytes, range 11-18), p = 0.02. CONCLUSION: Patients with rumination syndrome have subtle duodenal pathology with eosinophilia and increased intraepithelial lymphocyte counts compared to controls.

Overlap of Irritable Bowel Syndrome and Functional Dyspepsia in the Clinical Setting: Prevalence and Risk Factors.

BACKGROUND: According to Rome IV criteria, functional dyspepsia (FD) and irritable bowel syndrome (IBS) are distinct functional gastrointestinal disorders (FGID); however, overlap of these conditions is common in population-based studies, but clinical data are lacking. AIMS: To determine the overlap of FD and IBS in the clinical setting and define risk factors for the overlap of FD/IBS. METHODS: A total of 1127 consecutive gastroenterology outpatients of a tertiary center were recruited and symptoms assessed with a standardized validated questionnaire. Patients without evidence for structural or biochemical abnormalities as a cause of symptoms were then categorized based upon the symptom pattern as having FD, IBS or FD/IBS overlap. Additionally, this categorization was compared with the clinical diagnosis documented in the integrated electronic medical records system. RESULTS: A total of 120 patients had a clinical diagnosis of a FGID. Based upon standardized assessment with a questionnaire, 64% of patients had FD/IBS overlap as compared to 23% based upon the routine clinical documentation. In patients with severe IBS or FD symptoms (defined as symptoms affecting quality of life), the likelihood of FD/IBS overlap was substantially increased (OR = 3.1; 95%CI 1.9-5.0) and (OR = 9.0; 95%CI 3.5-22.7), respectively. Thus, symptom severity for IBS- or FD symptoms were significantly higher for patients with FD/IBS overlap as compared to patients with FD or IBS alone (p all < 0.01). Age, gender and IBS-subtype were not associated with overlap. CONCLUSION: In the clinical setting, overlap of FD and IBS is the norm rather than the exception. FD/IBS overlap is associated with a more severe manifestation of a FGID.

Factors Associated With Response to Placebo in Patients With Irritable Bowel Syndrome and Constipation.

BACKGROUND & AIMS: A high proportion of patients with irritable bowel syndrome (IBS) respond to placebo in clinical trials (estimated at about 40%). We aimed to identify factors that contribute to the high placebo response rate using data from a placebo-controlled trial of patients with IBS. METHODS: We performed a retrospective analysis of 599 women with IBS with constipation who were in the placebo group of a 12-week, randomized, double-blind, phase 3 trial of the experimental medication renzapride. Primary analyses evaluated frequency of abdominal pain in patients who received placebo, defined as ≥30% pain improvement from baseline for ≥6 of the 12 study weeks. We performed backward elimination regression with bootstrapping to identify factors associated with response to placebo. RESULTS: In the placebo group, 29.0% of the patients had an abdominal pain response. Factors associated with a response to placebo were baseline variation in abdominal pain (odds ratio [OR], 1.71), maximum baseline pain severity (OR, 1.34), and placebo response in study week 2 (OR, 2.23) or week 3 (OR, 3.69). Factors associated with lack of response to placebo were number of baseline complete spontaneous bowel movements (OR, 0.73; P = .019) and final baseline pain ratings (OR, 0.73; P < .001). CONCLUSIONS: We identified factors associated with a response in abdominal pain to placebo using original data from an IBS clinical trial. Baseline factors associated with the placebo response in women with IBS and constipation included variation in baseline pain symptoms, severity of baseline symptoms, and early improvement of abdominal pain. These findings have significant implications for clinical trial design.

Systematic Review and Meta-Analysis: Prevalence of Small Intestinal Bacterial Overgrowth in Chronic Liver Disease.

The authors conducted a meta-analysis of the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with chronic liver disease (CLD) and controls. Using the search terms "small intestinal bacterial overgrowth (SIBO)" and "chronic liver disease (CLD)" or "cirrhosis," 19 case-control studies were identified. Utilizing breath tests, the prevalence of SIBO in CLD was 35.80% (95% CI, 32.60-39.10) compared with 8.0% (95% CI, 5.70-11.00) in controls. Using culture techniques, the prevalence was 68.31% (95% CI, 59.62-76.00) in CLD patients as compared with 7.94% (95% CI, 3.44-12.73) in controls. No difference between cirrhotic and noncirrhotic patients was found. SIBO is significantly more frequent in CLD patients as compared with controls. The association of SIBO and CLD was not confined to patients with advanced CLD, suggesting that SIBO is not a consequence of advanced liver disease but may play a role in the progression of CLD.

Is There a Link Between H. Pylori and the Epidemiology of Crohn's Disease?

INTRODUCTION: Case control studies suggest an inverse association between Helicobacter pylori (H. pylori) and Crohn's disease (CD). It is possible this could be accounted for by confounders such as antibiotic therapy. Analyzing the geographic distribution of H. pylori and the links with the incidence and prevalence of CD would be an alternative approach to circumvent these confounders. METHODS: The literature was searched for studies published between 1990 and 2016 that reported incidence or prevalence data for CD in random population samples in developed countries (GDP per capita >20,000 USD/year). Corresponding prevalence studies for H. pylori in these same regions were then sought matched to the same time period (±6 years). The association between the incidence and prevalence of CD and H. pylori prevalence rates were assessed before and after adjusting for GDP and life expectancy. RESULTS: A total of 19 CD prevalence and 22 CD incidence studies from 10 European countries, Japan, USA, and Australia with date-matched H. pylori prevalence data were identified. The mean H. pylori prevalence rate was 43.4% (range 15.5-85%), and the mean rates for incidence and prevalence for CD were 6.9 and 91.0/100,000 respectively. The incidence (r = -0.469, p < 0.03) and prevalence (r = -0.527, p = 0.02) of CD was inversely and significantly associated with prevalence of H. pylori infection. CONCLUSIONS: Our data demonstrate a significant inverse association between geographic distribution of H. pylori and CD. Thus, it is highly unlikely that the findings of previous case control studies were simply due to confounding factors such as concomitant antibiotic use in CD patients.

Equitable resourcing of primary health care in remote communities in Australia's Northern Territory: a pilot study.

BACKGROUND: Improved Primary Health Care (PHC) utilisation is central to reducing the unacceptable morbidity and mortality rates characterising populations living in remote communities. Despite poorer health, significant inequity characterises the funding of PHC services in Australia's most remote areas. This pilot study sought to ascertain what funding is required to ensure equitable access to sustainable, high quality primary health care irrespective of geographical remoteness of communities. METHODS: High performing remote Primary Health Care (PHC) services were selected using improvement measures from the Australian Primary Care Collaboratives Program and validated by health experts. Eleven PHC services provided data relating to the types of services provided, level of service utilisation, human resources, operating and capital expenses. A further four services that provide visiting PHC to remote communities provided information on the level and cost of these services. Demographic data for service catchment areas (including estimated resident population, age, Indigenous status, English spoken at home and workforce participation) were obtained from the Australian Bureau of Statistics 2011 census. Formal statistical inference (p-values) were derived in the linear regression via the nonparametric bootstrap. RESULTS: A direct linear relationship was observed between the total cost of resident PHC services and population, while cost per capita decreased with increasing population. Services in smaller communities had a higher number of nursing staff per 1000 residents and provided more consultations per capita than those in larger communities. The number of days of visiting services received by a community each year also increased with population. A linear regression with bootstrapped statistical inference predicted a significant regression equation where the cost of resident services per annum is equal to $1,251,893.92 + ($1698.83 x population) and the cost of resident and visiting services is equal to $1,378,870.85 + ($2600.00 x population). CONCLUSIONS: The research findings provide empirical evidence based on real costs to guide funding for remote PHC services that takes into account the safety and equity requirements for a minimum viable service. This method can be used as a transparent, coordinated approach to ensure the equitable delivery of sustainable, high quality PHC in remote communities. This will in turn contribute to improved health outcomes.

A Nonresponse Bias Analysis of the Health Information National Trends Survey (HINTS).

We conducted a nonresponse bias analysis of the Health Information National Trends Survey (HINTS) 4, Cycles 1 and 3, collected in 2011 and 2013, respectively, using three analysis methods: comparison of response rates for subgroups, comparison of estimates with weighting adjustments and external benchmarks, and level-of-effort analysis. Areas with higher concentrations of low socioeconomic status, higher concentrations of young households, and higher concentrations of minority and Hispanic populations had lower response rates. Estimates of health information seeking behavior were higher in HINTS compared to the National Health Interview Survey (NHIS). The HINTS estimate of doctors always explaining things in a way that the patient understands was not significantly different from the same estimate from the Medical Expenditure Panel Survey (MEPS); however, the HINTS estimate of health professionals always spending enough time with the patient was significantly lower than the same estimate from MEPS. A level-of-effort analysis found that those who respond later in the survey field period were less likely to have looked for information about health in the past 12 months, but found only small differences between early and late respondents for the majority of estimates examined. There is some evidence that estimates from HINTS could be biased toward finding higher levels of health information seeking.

How a diverse research ecosystem has generated new rehabilitation technologies: Review of NIDILRR's Rehabilitation Engineering Research Centers.

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a "total approach to rehabilitation", combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970's, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program.

Characteristics of immunosuppressive regulatory T cells in cutaneous squamous cell carcinomas and role in metastasis.

BACKGROUND: Non-melanoma skin cancer is the most common cancer worldwide, and cutaneous squamous cell carcinomas (SCCs) account for substantial morbidity and mortality because of their potential for metastasis. SCCs are surrounded by an immune cell infiltrate containing regulatory T cells (Tregs). The aim of this study was to characterise Tregs in SCCs and investigate whether increased Treg numbers in primary skin SCCs are associated with subsequent metastasis. METHODS: Lymphocytes were extracted from freshly excised skin SCC tumours and corresponding peripheral blood and normal skin. Flow cytometry was used for T-cell analysis and cell sorting. Tritiated thymidine based lymphocyte proliferation assays and interferon γ (IFNγ) ELISPOT assays were used to assess peritumoral lymphocyte function in vitro. Immunohistochemistry was performed on primary cutaneous SCC sections from tumours that subsequently metastasised and from those that did not after 5-year follow-up. FINDINGS: Increased frequencies of CD3+CD4+CD25hiCD127loFOXP3+ Tregs were found in SCCs (21·5% of CD4+ immune infiltrate, n=60 tumours) compared with corresponding peripheral blood (5·4%) and normal skin (7·6%). SCC Tregs expressed significantly higher levels of the co-stimulatory molecules OX40 (37·2% of FOXP3+ cell population, n=10 tumours) and 4-1BB (12·6%, n=9) than peritumoral non-regulatory T cells and Tregs from peripheral blood and normal skin (p=0·0005). The inhibitory receptor CTLA4 and the transcription factor Helios were expressed at high levels in peritumoral Tregs. SCC Tregs significantly suppressed phytohaemagglutinin-stimulated peritumoral CD4+ T-cell proliferation (p=0·005, n=10), peritumoral CD8+ T-cell proliferation (p=0·015, n=9), and IFNγ secretion by CD4+ effector T cells (p=0·026, n=10). Increased in-vitro proliferation of phytohaemagglutinin-stimulated peritumoral CD4+ T cells was shown after the addition of anti-OX40 antibodies (p=0·0078, n=9 tumours) and anti-4-1BB antibodies (p=0·0039, n=9). Immunohistochemistry showed fewer CD8+ T cells in SCCs that metastasised (n=29) than in non-metastatic SCCs (n=26) (28·5% of immune infiltrate vs 44·6%%, p<0·0001) and more FOX3+ Tregs (28·5% of immune infiltrate vs 49·3%, p<0·0001). INTERPRETATION: Our study shows that immunosuppressive Tregs are present in the immune infiltrate of cutaneous SCCs, and contribute to ineffective anti-tumour immune responses, thereby permitting SCC development and promoting metastasis. FUNDING: Wellcome Trust, National Institute for Health Research.

Fecal Impaction in the Emergency Department: An Analysis of Frequency and Associated Charges in 2011.

GOALS: The aim of this study was to analyze the incidence and associated charges of fecal impaction for trends in hospital and patient demographics in emergency departments (ED) across the United States. BACKGROUND: In 2010, an ICD-9-CM code (560.32) for fecal impaction was introduced, allowing for assessment of fecal impaction incidence. STUDY: Data were obtained from the National Emergency Department Sample records in which fecal impaction (ICD-9-CM code 560.32) was first listed as a diagnosis in 2011. RESULTS: In 2011, there were 42,481 [95% confidence interval (CI), 39,908-45,054] fecal impaction ED visits, with an overall rate of 32 fecal impaction visits per 100,000 ED visits. Adjusted for inflation in 2014 dollars, the associated mean charge of a fecal impaction ED visit was $3060.47 (95% CI, $2943.02-$3177.92), with an aggregate national charge in the US of $130,010,772 (95% CI, $120,688,659-$139,332,885). All charges were adjusted for inflation and reported in 2014 dollars. Late elders (85+ y) had the highest rate of fecal impaction ED visits, followed by early elders (65 to 84 y). Medicare was the primary payer for the greatest number of fecal impaction ED visits accounting for nearly two thirds of visit payments. CONCLUSION: This study reports previously unexplored statistics on the number, frequency, and associated charges of ED visits with a primary diagnosis of fecal impaction, a condition found most commonly among elders.

Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer's Disease.

Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase (BuChE). The hybrid compounds were non-toxic to the murine hippocampal cell line HT-22 and lipoate esters were neuroprotective at 10 and 25 µM when the cells were challenged with glutamate (5 mM) in a similar manner to the positive control quercetin. The benzyl carbamate 7a was a potent inhibitor of BuChE (IC50 150 nM) and it was effective in reducing glutamate toxicity to neuronal cells at >5 µM. Representative compounds exhibited an antioxidant effect in the oxygen radical absorbance capacity assay as the lipoate 7d was not active, whereas the ferulate 8a showed a weak, but significant, activity with 0.635 ± 0.020 Trolox Equivalent.

The quality of cardiovascular disease prevention in rural primary care.

OBJECTIVE: To measure the differences in the recording of risk factors and lifestyle advice between those at high risk of cardiovascular disease and those diagnosed with cardiovascular disease, and to identify the practice characteristics associated with such recording in rural primary care. DESIGN: A cross-sectional observation study of 14 general practices. Medical records were audited to measure recording of risk factors and lifestyle advice for those at high risk of and those diagnosed with cardiovascular disease. Practice characteristics were collected, with logistic regression used to test for an association with the recording of risk factors. SETTING: General practices in rural Australia. PARTICIPANTS: Each practice was asked to identify 20 patients; 10 at high risk and 10 diagnosed with cardiovascular disease. MAIN OUTCOME MEASURES: The recording of risk factors and lifestyle advice in patient records and practice characteristics. RESULTS: 282 records were audited with 142 being high risk and 140 diagnosed with cardiovascular disease.Measures recorded significantly less in the high-risk group were: blood pressure (94% versus 99%; P = 0.019); physical activity (24% versus 56%; P = 0.000); dietary advice (32% versus 51%; P = 0.001); and physical activity advice (34% versus 56%; P = 0.000). Recording of risk factors was positively associated with practice involvement in quality improvement (P < 0.001), continuing education (P < 0.001), and greater percentage of general practitioners (P < 0.05) and practice nurses (P < 0.001). CONCLUSIONS: There is substantial room for enhanced cardiovascular disease prevention through rural primary care in Australia, particularly for high-risk patients. This study has demonstrated an association between practice factors (including targeted education, quality improvement activities and appropriate workforce) and improved preventive activities.