Effectiveness of digital feedback on patient experience and 30-day complications after screening colonoscopy: a randomized health services study.

Background and study aims European guidelines (ESGE) recommend measuring patient experience and 30-day complication rate after colonoscopy. We compared digital and paper-based feedback on patients' experience and 30-day complications after screening colonoscopy. Patients and methods Screenees attending for primary screening colonoscopies in two centers from September 2015 to December 2016 were randomized (1:1) to an intervention arm (choice of feedback method) or control arm (routine paper-based feedback). Participants in the intervention arm could choose preferred feedback method (paper-based, automated telephone or online survey) and were contacted by automated telephone 30 days after colonoscopy to assess complications. Control group participants self-reported complications. Primary and secondary endpoints were response rates to feedback and complications questionnaire, respectively. Results There were 1,281 and 1,260 participants in the intervention and control arms, respectively. There was no significant difference in response rate between study groups (64.8 % vs 61.5 %; P  = 0.08). Free choice of feedback improved response for participants identified as poor responders: younger than 60 years (60.8 % vs 54.7 %; P  = 0.031), male (64.0 % vs 58.6 %; P  = 0.045) and in small non-public center (56.2 % vs 42.5 %; P  = 0.043). In the intervention arm, 1,168 participants (91.2 %) answered the phone call concerning complications. A total of 79 participants (6.2 %) reported complications, of which two (0.2 %) were verified by telephone as clinically relevant. No complications were self-reported in the control group. Conclusion The overall response rate was not significantly improved with digital feedback, yet the technology yielded significant improvement in participants defined as poor responders. Our study demonstrated feasibility and efficacy of digital patient feedback about complications after colonoscopy.

Beneficial dose-independent influence of Camellia sinensis supplementation on lipid profile, glycemia, and insulin resistance in an NaCl-induced hypertensive rat model.

Green tea extract exerts favorable influence on the lipid profile and insulin resistance in the high-sodium intake arterial hypertension. A high-sodium diet (HSD) was introduced to thirty Wistar rats to create a model of hypertension. Rats were randomized into three groups, 10 animals each. The SK group consumed HSD. The SH2 group consumed HSD with 2 g of green tea extract in kg of diet. The SH4 group was fed HSD with 4 g of green tea extract in kg of diet. After six-week trial blood samples were collected. The serum concentrations of glucose, insulin and lipids were estimated, and insulin sensitivity was calculated using homeostatic model assessment (HOMA). Neither the high-sodium diet nor supplementation with green tea extract had any significant influence on the body mass of the animals in either group. Total cholesterol (TCH) and low-density lipoproteins (LDL) cholesterol serum concentrations were significantly smaller in both supplemented groups than in the SK group. The insulin level in the SH2 rats and HOMA in SH2 and SH4 groups were found to be significantly smaller than in the SK group. There were no differences in glucose concentrations between groups. Within the whole population, statistically significant positive correlations between HOMA and LDL, TCH were found. We conclude that in NaCl-induced hypertensive Wistar rats, supplementation with green tea extract produced a dose-independent beneficial and parallel effect on the lipid profile and insulin resistance.

In Vitro Bioavailability of Calcium, Magnesium, Iron, Zinc, and Copper from Gluten-Free Breads Supplemented with Natural Additives.

The aim of this study was to measure the content of calcium, magnesium, iron, zinc, and copper and determine the bioavailability of these ingredients in gluten-free breads fortified with milk and selected seeds. Due to the increasing prevalence of celiac disease and mineral deficiencies, it has become necessary to produce food with higher nutritional values which maintains the appropriate product characteristics. This study was designed for gluten-free breads fortified with milk and seeds such as flax, poppy, sunflower seeds, pumpkin seeds or nuts, and flour with amaranth. Subsequently, digestion was performed in vitro and the potential bioavailability of the minerals was measured. In the case of calcium, magnesium, iron, and copper, higher bioavailability was observed in rice bread, and, in the case of copper and zinc, in buckwheat bread. This demonstrated a clear increase in bioavailability of all the minerals when the bread were enriched. However, satisfactory results are obtained only for the individual micronutrients.

Adenoma detection rate and risk of colorectal cancer.

GOALS: The aim of this paper was to discuss association between adenoma detection rate (ADR) and interval colorectal cancer risk. BACKGROUND: Adenoma detection rate is being used as a benchmark quality measure for colonoscopy. There are three studies showing inverse association between ADR and interval colorectal cancer risk. One recent study reports significant impact of increased ADR on decreasing interval colorectal cancer risk. STUDY: We discussed evidence for using ADR as a quality measures in colonoscopy and flexible sigmoidoscopy. We revised three studies (Kaminski et al., N Engl J Med 2010; Corley et al., N Engl J Med 2014 and Rogal et al., Clin Gastroenterol Hepatol, 2013) analyzing association between ADR and interval colorectal cancer. We collated strengths and weaknesses of these studies with the perspective of clinical impact of their results. RESULTS: Kaminski et al. and Corley et al. reported inverse association between ADR at colonoscopy and interval colorectal cancer. Kaminski et al. showed that patients examined by endoscopists with ADR of less than 20% had over 10 times greater risk of interval colorectal cancer during the follow-up time than those examined by endoscopists with ADR ≥20%. Additionally, Corley et al. showed that ADR ≥28% resulted in a significantly lower risk of colorectal cancer death than ADR of less than 19%. In parallel, Rogal et al. reported similar association for flexible sigmoidoscopy, with 2.4 higher odds of interval colorectal cancer diagnosis during follow-up time in patients examined by endoscopists with distal ADR <7.2% than those with distal ADR ≥7.2%. Apart from inevitable clinical importance of the studies, they are not without disadvantages. In Kaminski et al. study cohort and study endpoint are well defined, but there is lack of statistical power to provide more robust results. In Rogal et al. study cohort is well defined, but approximation of the study endpoint was used. Finally, Corley et al. study has both poorly defined study cohort and study endpoint, but has the highest statistical power of all three to detect the differences for both interval colorectal cancer and colorectal cancer death. CONCLUSION: Both, inverse relationship between ADR and ADR improvement and colorectal cancer risk and death reaffirm ADR as a crucial quality control parameter.

SPR-based assays enable the full functional analysis of bispecific molecules.

The increasing complexity of novel biotherapeutics such as bispecific antibodies or fusion proteins raises new challenges for functional characterization. When compared to standard antibodies, two individual interactions and the inter-dependency of binding events need to be considered for bispecific antibodies. We have previously described an SPR-based assay setup, which enables us to assess the binding activity of a bivalent-bispecific molecule to both targets simultaneously and - in addition to one individual target - in a single setup. However, there might be some pitfalls when applying the bridging assay, e.g. change of antigen activity upon immobilization. Therefore, we have developed an alternative SPR-based assay principle, which allows the individual assessment of both targets in solution. Comparison of data between the assays showed that simultaneous binding can be calculated based on both individual readouts, and revealed a good correlation. Hence, both SPR-based assay principles allow a "full" functional analysis of a bispecific CrossMab in only one assay. The assay principles can be qualified and enable an efficient drug development.

Clinical Muscle Testing Compared with Whole-Body Magnetic Resonance Imaging in Facio-scapulo-humeral Muscular Dystrophy.

OBJECTIVE: The objective of this study was to evaluate the clinical usefulness of whole-body magnetic resonance imaging (MRI) in facio-scapulo-humeral muscular dystrophy (FSHD). METHODS: In 20 patients with genetically proven FSHD1, we prospectively assessed muscular involvement and correlated the results of semi-quantitative manual muscle testing and other parameters such as disease duration, creatine kinase (CK) levels and repeat length of the D4Z4 locus with whole-body MRI. RESULTS: Clinical muscle testing revealed the trapezius, pectoralis and infraspinatus as the most severely affected muscles in the shoulder, and the knee flexors and gluteus medius in the hip girdle. MRI revealed the trapezius and serratus anterior muscles in the shoulder, and the hamstrings and adductor muscles in the hip girdle, as the most severely affected muscle groups. Overall, degrees of fatty degeneration on MRI scans correlated significantly with clinical weakness. Moreover, we could detect clear affection of the trunk muscles. Corresponding to earlier reports, asymmetric involvement was frequent in both clinical examination and MRI scoring. Moreover, MRI revealed inhomogeneous muscle degeneration in a considerable proportion of both, muscles and patients. Both clinical and MRI scores significantly correlated to disease duration, but not to fragment size or CK levels. CONCLUSION: Fatty degeneration in whole-body MRI correlates well to clinical muscle testing of the extremities but gives more information on deeper or trunk muscles. It shows structural changes in muscular disorders and may become an excellent tool for assessment of muscle involvement and follow-up studies.

Development and validation of a novel SPR-based assay principle for bispecific molecules.

Surface plasmon resonance (SPR) is increasingly applied in drug discovery, early development and production. However, there are remarkably few reports describing the application of SPR in a regulated environment. Here, we describe a novel SPR-based assay, which enables us to assess the binding activity of a bivalent-bispecific anti-Ang-2/anti-VEGF antibody to both targets in a single setup. Validation of the assay revealed a high level of precision, accuracy, linearity and specificity. Upon analysis of temperature stressed samples it could be shown that firstly, the assay is able to indicate function-loss and secondly, it allows the parallel analysis of an additional interaction. Therefore, the described assay is highly suitable for quality assessment of the Ang-2/VEGF CrossMab. Additionally, the use of SPR in the context of assay development and routine use in a GMP environment is discussed.

Cerebral vasospasm and delayed cerebral ischemia in intraventricular hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) with intraventricular extension (IVH) is a devastating disease with a particular high mortality. In some aspects, IVH may resemble subarachnoid hemorrhage. The incidence and role of cerebral vasospasm in ICH with IVH are poorly understood. Here, we aimed to analyze the incidence and relationship of cerebral vasospasm to clinical characteristics, in-hospital mortality, and functional outcome at 3 months in patients suffering ICH with IVH. METHODS: Patients with ICH and IVH treated on a neurological intensive care unit were prospectively enrolled in a single-center observational study. Vasospasm was defined using established ultrasound criteria. Delayed cerebral ischemia (DCI) was defined as a new hypodensity on follow-up cranial CT. Functional outcome at 3 months was assessed using the modified Rankin Scale. RESULTS: 129 patients with ICH and IVH were screened for the study. 62 patients entered the final analysis. The incidence of significant vasospasm was 37 %. A strong trend was found for the association between all cerebral vasospasm and DCI (P = 0.046). Early (up to 48 h) vasospasm was significantly associated with a DCI (P = 0.033). Overall mortality and outcome after 3 months did not differ between the groups. CONCLUSION: Cerebral vasospasm seems to be a frequent complication after ICH with IVH and might be associated with DCI. Larger studies are warranted to confirm this hypothesis.

The protective role of antiplatelet treatment against ulcer formation due to argon plasma coagulation in patients treated for chronic radiation proctitis.

AIM: Following treatment with argon plasma coagulation (APC), rectal ulceration is seen in approximately 50% of patients with haemorrhagic chronic radiation proctitis (CRP). This study aimed to assess the frequency of rectal ulcers (defined as a mucosal defect of 3 mm or more in diameter) in relation to the use of antiplatelet treatment for concomitant cardiovascular disease. METHOD: Sixty-two patients with CRP were included in this retrospective study. Patients underwent pelvic irradiation due to prostate cancer (n = 28), cervical cancer (n = 16), endometrial cancer (n = 17) or rectal cancer (n = 1). APC was performed in all patients. Control endoscopies were performed at 8 and 16 weeks after enrolment. RESULTS: Rectal ulcers were observed after APC in 35 (56%) patients. They were symptomatic in 5 and asymptomatic in 30. The 20 (32%) patients who were on antiplatelet therapy had a significantly lower risk of ulceration after APC (OR = 0.21; 95% CI 0.049-0.91; P = 0.019). The number of symptomatic ulcers (5% vs 10%; P = 1.0) and asymptomatic ulcers alone (30% vs 58%; P = 0.06) was also lower in patients respectively taking and not taking antiplatelet therapy, but these differences did not reach statistical significance. CONCLUSION: Argon plasma coagulation-related ulceration in patients treated for CRP is less common when concomitant antiplatelet treatment is administered. This preliminary finding suggests that antiplatelet therapy may benefit patients treated with APC for CRP.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial.

BACKGROUND: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Sucralfate or placebo following argon plasma coagulation for chronic radiation proctitis: a randomized double blind trial.

AIM: Chronic radiation proctitis is a long-term complication of radiation therapy for pelvic malignancy. The aim of this study was to compare the efficacy and safety of two treatment regimens, sucralfate or placebo, following argon plasma coagulation (APC) for chronic haemorrhagic radiation proctitis. METHOD: A single-centre, randomized, placebo-controlled, double-blind study was performed on patients with haemorrhagic chronic radiation proctitis after irradiation for prostate, uterine, cervical, rectal or vaginal cancer. All patients received APC, and were then randomized to oral sucralfate (6 g twice a day) or placebo treatment for 4 weeks. APC was repeated every 8 weeks if necessary after the first session. Patients were graded clinically and endoscopically according to the Chutkan and Gilinski scales before and at 8 and 16 weeks after initial APC treatment (1.5-2 l/min, 25-40 W) and after 52 weeks (clinical only). RESULTS: Of 122 patients, 117 completed the entire protocol, with 57/60 in the sucralfate group and 60/62 in the placebo group. At baseline there were no significant differences between the sucralfate and placebo groups. At 1 year, a significant improvement in the clinical scale in both groups occurred compared with baseline. After 16 weeks, the median overall clinical severity scores fell from 4 to 2 points and the median bleeding score from 2 to 0 in both groups. CONCLUSION: APC is safe and effective for the management of chronic radiation proctitis. Additional sucralfate treatment did not influence the clinical or endoscopic outcome.

ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making.

Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

The NordICC Study: rationale and design of a randomized trial on colonoscopy screening for colorectal cancer.

BACKGROUND AND STUDY AIM: While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial. STUDY DESIGN: Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. POWER ANALYSIS: We hypothesize a 50 % CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50 % compliance, yielding a 25 % mortality reduction among those invited to screening. For 90 % power and a two-sided alpha level of 0.05, using a 2:1 randomization, 45 600 individuals will be randomized to control, and 22 800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up. CONCLUSIONS: The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.

Persistence of recipient-type endothelium after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The possibility that allogeneic hematopoietic stem cell transplantation performed across the ABO blood group-barrier is associated with an increase of graft-versus-host disease, in particular endothelial damage, has not been elucidated so far. For this reason, we investigated the level of endothelial cell chimerism after allogeneic hematopoietic stem cell transplantation in order to delineate the role of hematopoietic stem cells in endothelial replacement. DESIGN AND METHODS: The frequency of donor-derived endothelial cells was analyzed in 52 hematopoietic stem cell transplant recipients, in 22 normal skin biopsies, in 12 skin samples affected by graft-versus-host disease, various tissues from five autopsies and four secondary solid tumors by ABH immunohistochemistry, XY fluorescence in situ hybridization and short tandem repeat analysis of laser captured endothelial cells. RESULTS: Skin biopsies from two patients transplanted with minor ABO-incompatible grafts (i.e. O in A) showed 3.3% and 0.9% H antigen-positive donor-derived endothelial cells by ABH immunohistochemistry. Tumor biopsies from two recipients showed 1.2% and 2.5% donor-derived endothelial cells by combined immunohistochemistry/ fluorescence in situ hybridization. All other skin samples, heart, liver, bone-marrow, and tumor tissues failed to reveal donor-type endothelial cells up to several years after ABO-incompatible hematopoietic stem cell transplantation. CONCLUSIONS: Endothelial cell replacement by bone marrow-derived donor cells after allogeneic hematopoietic stem cell transplantation is a rare event. It does not seem to represent a major mechanism of physiological in vivo blood vessel formation, tumor neoangiogenesis, vascular repair after graft-versus-host disease episodes or acceptance of ABO-incompatible grafts.

Spinocerebellar ataxia type 17 associated with an expansion of 42 glutamine residues in TATA-box binding protein gene.

BACKGROUND: Spinocerebellar ataxia type 17 (SCA17) is caused by abnormal expansions of CAG/CAA trinucleotides within the TATA-box binding protein gene (TBP). The currently accepted critical threshold of abnormal expansions is ≥43. OBJECTIVE: To investigate the minimal CAG/CAA expansion within the TBP in SCA17. RESULTS: 285 patients with autosomal-dominant ataxia were examined, and abnormal or borderline expansions of CAG/CAA within TBP in eight cases were found. Of those, four patients from three families had exactly 42 CAG/CAA trinucleotides, that is, one codon less than the currently accepted critical threshold of 43. The four patients presented with a relatively benign phenotype. All had dysdiadochokinesia and dysarthria. Mild gait ataxia was observed in three of the four patients. CONCLUSION: The reference definition of at least 43 CAG/CAA codons for pathological SCA17 alleles should be lowered to 42.

Diagnostic yield and safety of endoscopic ultrasound-guided trucut [corrected] biopsy in patients with gastric submucosal tumors: a prospective study.

BACKGROUND AND STUDY AIMS: Endoscopic-ultrasound-guided trucut needle biopsy (EUS-TCB) has not been adequately evaluated in patients with submucosal tumors (SMTs). PATIENTS AND METHODS: This prospective, uncontrolled study involving 49 consecutive patients with hypoechoic gastric SMTs (> or = 20 mm) evaluated diagnostic yield and 30-day morbidity of EUS-TCB, factors related to the success of EUS-TCB, and agreement between EUS-TCB and the surgical pathology diagnosis. Seventy-three percent of tumors were gastrointestinal stromal tumors (GIST). RESULTS: Tumor tissue adequate for diagnosis was obtained by EUS-TCB in 31 patients (63 %; 95 %CI 49 % to 75 %). In the remaining cases, EUS-TCB provided no tissue (n = 11) or an insufficient amount (n = 7). Logistic regression analysis showed that tumor location on the lesser curvature of the stomach was the only independent predictor of obtaining diagnostic material [odds ratio (OR) 7.4; 95 %CI 1.9 to 28; P = 0.004]. The experience of the endosonographer, the size of the tumor, and the location of the tumor relative to the long axis of the stomach were not related to the success of the biopsy. Agreement between EUS-TCB and surgical pathology specimens in respect of the diagnosis and CD117 status was high (0.9, standard error 0.31; and 0.95, standard error 0.16, respectively); however, there was no correlation between the mitotic index as determined on EUS-TCB and that determined on the surgical pathology specimen (correlation coefficient, 0.08). There were two severe septic complications in 52 procedures (3.9 %; 95 %CI 0.3 % to 14 %). CONCLUSIONS: The diagnostic yield of EUS-TCB in patients with gastric SMTs was moderate. Tissue samples were too small to reliably determine the mitotic index. Antibiotic prophylaxis should be considered because of possible septic complications.

Colorectal cancer screening by colonoscopy--current issues.

Of all colorectal cancer screening methods, colonoscopy used as a primary screening tool is both the most promising and the most discussed in the current literature. Several countries have introduced colonoscopic screening on a national scale, but many issues still require further research. The practicality of using colonoscopic screening can be questionable given the huge target population, which requires a great increase in endoscopic resources. Limiting the target population by shifting the use of colonoscopy from low-risk to high-risk groups is a valid option. The quality of colonoscopy related to the individual colonoscopist's skill has become a surprisingly considerable problem, and it is obvious that continuous quality improvement programs need to be established. The accuracy of detecting important colorectal lesions is also still influenced by the old problem of cleansing the large bowel, and further research would be welcome. Technological improvements in current endoscopic equipment will hopefully increase the diagnostic yield of colonoscopy and eventually strengthen its use in the setting of colorectal cancer screening.