This article urges educators of the gifted and talented to become knowledgeable about educational reform efforts at the local, state, and national levels. Specific initiatives pertinent to gifted ...education include ungraded primary schools; performance-based assessment of student progress; use of student portfolios; and rigorous, revamped curricula. (DB)
Background & Aims Crohn’s disease (CD) usually recurs after intestinal resection; postoperative endoscopic monitoring and tailored treatment can reduce the chance of recurrence. We investigated ...whether monitoring levels of fecal calprotectin (FC) can substitute for endoscopic analysis of the mucosa. Methods We analyzed data collected from 135 participants in a prospective, randomized, controlled trial, performed at 17 hospitals in Australia and 1 hospital in New Zealand, that assessed the ability of endoscopic evaluations and step-up treatment to prevent CD recurrence after surgery. Levels of FC, serum levels of C-reactive protein (CRP), and Crohn’s disease activity index (CDAI) scores were measured before surgery and then at 6, 12, and 18 months after resection of all macroscopic Crohn’s disease. Ileocolonoscopies were performed at 6 months after surgery in 90 patients and at 18 months after surgery in all patients. Results Levels of FC were measured in 319 samples from 135 patients. The median FC level decreased from 1347 μg/g before surgery to 166 μg/g at 6 months after surgery, but was higher in patients with disease recurrence (based on endoscopic analysis; Rutgeerts score, ≥i2) than in patients in remission (275 vs 72 μg/g, respectively; P < .001). Combined 6- and 18-month levels of FC correlated with the presence (r = 0.42; P < .001) and severity (r = 0.44; P < .001) of CD recurrence, but the CRP level and CDAI score did not. Levels of FC greater than 100 μg/g indicated endoscopic recurrence with 89% sensitivity and 58% specificity, and a negative predictive value (NPV) of 91%; this means that colonoscopy could have been avoided in 47% of patients. Six months after surgery, FC levels less than 51 μg/g in patients in endoscopic remission predicted maintenance of remission (NPV, 79%). In patients with endoscopic recurrence at 6 months who stepped-up treatment, FC levels decreased from 324 μg/g at 6 months to 180 μg/g at 12 months and 109 μg/g at 18 months. Conclusions In this analysis of data from a prospective clinical trial, FC measurement has sufficient sensitivity and NPV values to monitor for CD recurrence after intestinal resection. Its predictive value might be used to identify patients most likely to relapse. After treatment for recurrence, the FC level can be used to monitor response to treatment. It predicts which patients will have disease recurrence with greater accuracy than CRP level or CDAI score.
Summary Background Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to ...identify the optimal strategy to prevent postoperative disease recurrence. Methods In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT00989560. Findings Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0·03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0·03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio OR 2·4, 95% CI 1·2–4·8, p=0·02) and the presence of two or more clinical risk factors including smoking (OR 2·8, 95% CI 1·01–7·7, p=0·05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 82% of 122 vs 45 87% of 52; p=0·51) and (33 27% of 122 vs 18 35% of 52; p=0·36), respectively. Interpretation Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. Funding AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.
•Immune checkpoints correlate with higher grade tumours and poor treatment response.•First-line chemotherapies stimulate anti-tumour T cell immunity.•Dual nivolumab-ipilimumab enhances ...lymphocyte-mediated killing of tumour cells.•Lymphocyte-mediated killing of tumour cells is enhanced by FLOT chemotherapy.
Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting ‘cold’ tumours into ‘hot’ tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.
Study schematic - (A) Immune checkpoint (IC) expression profiles of T cells in tumour biopsies and whole blood from OAC patients was assessed by flow cytometry and correlated with clinical demographics. (B) The effect of first-line chemotherapy regimens on anti-tumour T cell phenotypes was next assessed using flow cytometry. PBMCs were isolated from age-matched healthy donor and OAC donor blood and expanded ex vivo for 72 h using anti-CD3/28 + IL-2 T cell activation protocol followed by an additional 48 h treatment with vehicle, FLOT or CROSS chemotherapy (CT) regimens in the absence and presence of immune checkpoint blockade (ICB). (C) The ability of ICB to boost the cytolytic effector function of OAC donor lymphocytes was next assessed in the absence and presence of post-vehicle/FLOT/CROSS CT tumour cell secretome to determine if the chemotherapy altered tumour microenvironment enhanced lymphocyte-mediated killing of tumour cells. Collection of post-chemotherapy tumour cell secretome: OE33 cells were treated for 48 h with vehicle/FLOT/CROSS CT and washed twice with PBS. Tumour cell secretome was then harvested an additional 48 h later. Key Findings – (D) ICs were upregulated on tumour-infiltrating T cells. CTLA-4, TIM-3 and ICOS were decreased 6 weeks post-FLOT or CROSS chemoradiotherapy treatment on tumour-infiltrating T cells. (E) IC expression correlated with more advanced staged tumours, nodal metastasis and poor response to treatment. (F) The direct 48 h effects of FLOT and CROSS CT treatment revealed that these regimens upregulated a range of ICs and downregulated TIM-3 and LAG-3 on T cells ex vivo. Co-stimulatory markers were differentially affected, ICOS and CD69 were upregulated however CD27 was downregulated on T cells. Anti-tumour T cell cytokine profiles were also enhanced. (G) ICB attenuated the chemotherapy-mediated downregulation of CD27. Dual nivolumab and ipilimumab treatment increased lymphocyte-mediated killing of tumour cells which was further enhanced in the presence of post-FLOT tumour cell secretome suggesting the potential of immunostimulatory synergism between first-line OAC chemotherapy regimens and ICB. Display omitted
Extreme weather alerting systems are one of the central tools utilised in adapting to changing weather patterns resulting from climate change. This paper evaluates the effectiveness of the current ...alerting systems for hot and cold weather used in England to notify the health and social care sector of upcoming extreme weather events. We consider the views of stakeholders on the current system and explore their perspectives on the proposal to move towards an impact-based system. The paper concludes that while the current system is an effective tool, stakeholders feel they need to draw on additional material to assist with the development of an appropriate response. We also highlight that many stakeholders are concerned about the potential for creating alert fatigue due to a lack of clarity of the geographical area impact of some of the alerts. Consequently, there was a high level of support from stakeholders for the move towards an impact-focused system.
•Extreme weather alerting systems are an important tool for protecting public health.•Impact-focused alerting systems can help planners and front-line staff deliver a more effective response to extreme weather.•It is important alerts are not sent out unnecessarily to protect the credibility of the system and avoid alert fatigue.
Introduction:
Patients with Crohn’s disease have poorer health-related quality of life HRQoL than healthy individuals, even when in remission. Although HRQoL improves in patients who achieve ...drug-induced or surgically induced remission, the effects of surgery overall have not been well characterised.
Methods:
In a randomised trial, patients undergoing intestinal resection of all macroscopically diseased bowel were treated with postoperative drug therapy to prevent disease recurrence. All patients were followed prospectively for 18 months. C-reactive protein CRP, Crohn’s Disease Activity Index CDAI, and faecal calprotectin FC were measured preoperatively and at 6, 12, and 18 months. HRQoL was assessed with a general SF36 and disease-specific IBDQ questionnaires at the same time points.
Results:
A total of 174 patients were included. HRQoL was poor preoperatively but improved significantly p < 0.001 at 6 months postoperatively. This improvement was sustained at 18 months. Females and smokers had a poorer HRQoL when compared with males and non-smokers, respectively. Persistent endoscopic remission, intensification of drug treatment at 6 months, and anti-tumour necrosis factor therapy were not associated with HRQoL outcomes different from those when these factors were not present. There was a significant inverse correlation between CDAI, but not endoscopic recurrence, CRP, or FC on HRQoL.
Conclusion:
Intestinal resection of all macroscopic Crohn’s disease in patients treated with postoperative prophylactic drug therapy is associated with significant and sustained improvement in HRQoL irrespective of type of drug treatment or endoscopic recurrence. HRQoL is lower in female patients and smokers. A higher CDAI, but not direct measures of active disease or type of drug therapy, is associated with a lower HRQoL.
Introduction: The occurrence of severe sepsis may be associated with deficient pro-inflammatory cytokine production. Transforming growth factor β-1 (TGFβ-1) predominantly inhibits inflammation and ...may simultaneously promote IL-17 production. Interleukin-17 (IL-17) is a recently described pro-inflammatory cytokine, which may be important in auto-immunity and infection. We investigated the hypothesis that the onset of sepsis is related to differential TGFβ-1 and IL-17 gene expression.
Methods: A prospective observational study in a mixed intensive care unit (ICU) and hospital wards in a university hospital. Patients (59) with severe sepsis; 15 patients with gram-negative bacteraemia but without critical illness and 10 healthy controls were assayed for TGFβ-1, IL-17a, IL-17f, IL-6 and IL-1β mRNA in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR and serum protein levels by ELISA.
Results: TGFβ-1 mRNA levels are reduced in patients with bacteraemia and sepsis compared with controls (
p
=
0.02). IL-6 mRNA levels were reduced in bacteraemic patients compared with septic patients and controls (
p
=
0.008). IL-1β mRNA levels were similar in all groups, IL-17a and IL-17f mRNA levels are not detectable in peripheral blood mononuclear cells. IL-6 protein levels were greater in patients with sepsis than bacteraemic and control patients (
p
<
0.0001). Activated TGFβ-1 and IL-17 protein levels were similar in all groups. IL-1β protein was not detectable in the majority of patients.
Conclusions: Down regulation of TGFβ-1 gene transcription was related to the occurrence of infection but not the onset of sepsis. Interleukin-17 production in PBMC may not be significant in the human host response to infection.
Myocarditis is a precursor of dilated cardiomyopathy.
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3
Aberrant cellular and humoral immune responses have been proposed as possible mechanisms in postviral myocarditis,
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7
and ...immunosuppressive therapy has appeared to improve the course of the disease.
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11
The efficacy of immunosuppression, however, has not been clearly established.
The Myocarditis Treatment Trial
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14
was designed to evaluate the efficacy of immunosuppression in patients with myocarditis and to identify immunologic markers of the severity of the disease and the response to therapy. In this report we describe the results of the clinical trial and explore the relation between the outcomes and the . . .
Introduction: The occurrence of severe sepsis may be associated with deficient pro-inflammatory cytokine production. Transforming growth factor b-1 (TGFb-1) predominantly inhibits inflammation and ...may simultaneously promote IL-17 production. Interleukin-17 (IL-17) is a recently described pro-inflammatory cytokine, which may be important in auto-immunity and infection. We investigated the hypothesis that the onset of sepsis is related to differential TGFb-1 and IL-17 gene expression. Methods: A prospective observational study in a mixed intensive care unit (ICU) and hospital wards in a university hospital. Patients (59) with severe sepsis; 15 patients with gram-negative bacteraemia but without critical illness and 10 healthy controls were assayed for TGFb-1, IL-17a, IL-17f, IL-6 and IL-1b mRNA in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR and serum protein levels by ELISA. Results: TGFb-1 mRNA levels are reduced in patients with bacteraemia and sepsis compared with controls (p = 0.02). IL-6 mRNA levels were reduced in bacteraemic patients compared with septic patients and controls (p = 0.008). IL-1b mRNA levels were similar in all groups, IL-17a and IL-17f mRNA levels are not detectable in peripheral blood mononuclear cells. IL-6 protein levels were greater in patients with sepsis than bacteraemic and control patients (p < 0.0001). Activated TGFb-1 and IL-17 protein levels were similar in all groups. IL-1b protein was not detectable in the majority of patients. Conclusions: Down regulation of TGFb-1 gene transcription was related to the occurrence of infection but not the onset of sepsis. Interleukin-17 production in PBMC may not be significant in the human host response to infection.
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