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BACKGROUND: Approximately one third of the colorectal cancer survivors (CRCS) experience high levels of psychological distress. Common concerns experienced by CRCS include distress related to physical problems, anxiety, fear of cancer recurrence (FCR) and depressive symptoms. However, psychological interventions for distressed CRCS are scarce. Therefore, a blended therapy was developed, combining face-to-face cognitive behavioral therapy (CBT) with online self-management activities and telephone consultations. The aim of the study is to evaluate the efficacy and cost-effectiveness of this blended therapy in reducing psychological distress in CRCS. METHODS/DESIGN: The CORRECT study is a two-arm multicenter randomized controlled trial (RCT). A sample of 160 highly distressed CRCS (a score on the Distress Thermometer of 5 or higher) will be recruited from several hospitals in the Netherlands. CRCS will be randomized to either the intervention condition (blended CBT) or the control condition (care as usual). The blended therapy covers approximately 14 weeks and combines five face-to-face sessions and three telephone consultations with a psychologist, with access to an interactive self-management website. It includes three modules which are individually-tailored to patient concerns and aimed at decreasing: 1) distress caused by physical consequences of CRC, 2) anxiety and FCR, 3) depressive symptoms. Patients can choose between the optional modules. The primary outcome is general distress (Brief Symptom Inventory-18). Secondary outcomes are quality of life and general psychological wellbeing. Assessments will take place at baseline prior to randomization, after 4 and 7 months. DISCUSSION: Blended CBT is an innovative and promising approach for providing tailored supportive care to reduce high distress in CRCS. If the intervention proves to be effective, an evidence-based intervention will become available for implementation in clinical practice. TRIAL REGISTRATION: This trial is registered in the Netherlands Trial Register ( NTR6025 ) on August 3, 2016.

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PURPOSE: To estimate the diagnostic accuracy of multiparametric MRI (mpMRI) for the detection of locally advanced prostate cancer (T-stage 3-4) prior to radical prostatectomy, in a multicenter cohort representing daily clinical practice. In addition, the radiologic learning curve for the detection of locally advanced disease is evaluated. METHODS: Preoperative mpMRI findings of 430 patients (2012-2016) were compared to pathology results following radical prostatectomy. The diagnostic accuracy (sensitivity, specificity, PPV, and NPV) for the detection of locally advanced disease was calculated and compared for all years separately, to evaluate the presence of a radiological learning curve. RESULTS: Of all 137 patients with locally advanced disease, 62 patients were preoperatively detected with mpMRI [sensitivity 45.3% (95% CI 36.9-53.6%), specificity 75.8% (CI 70.9-80.7%), PPV 46.6% (CI 38.1-55.1%), and NPV 74.7% (CI 69.8-79.7%)]. The diagnostic accuracy did not improve significantly over time (sensitivity p = 0.12; specificity p = 0.57). CONCLUSIONS: In daily clinical practice, the diagnostic accuracy of mpMRI for the detection of locally advanced prostate cancer remains limited. It, therefore, seems questionable whether mpMRI is adequate to guide preoperative decision-making. No significant radiologic learning curve for the detection of locally advance disease was observed.

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BACKGROUND: Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied. METHODS: To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent. RESULTS: TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules. CONCLUSION: We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.

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BACKGROUND: Cognitive behavioural therapy (CBT) effectively reduces fatigue directly following treatment in patients with Multiple Sclerosis (MS), but little is known about the process of change during and after CBT. DESIGN: Additional analysis of a randomized clinical trial. OBJECTIVE: To investigate which psychological factors mediate change in fatigue during and after CBT. METHODS: TREFAMS-CBT studied the effectiveness of a 16-week CBT treatment for MS-related fatigue. Ninety-one patients were randomized (44 to CBT, 47 to the MS-nurse consultations). Mediation during CBT treatment was studied using assessments at baseline, 8 and 16weeks. Mediation of the change in fatigue from post-treatment to follow-up was studied separately using assessments at 16, 26 and 52weeks. Proposed mediators were: changes in illness cognitions, general self-efficacy, coping styles, daytime sleepiness, concentration and physical activity, fear of disease progression, fatigue perceptions, depression and physical functioning. Mediators were separately analysed according to the product-of-coefficients approach. Confidence intervals were calculated with a bootstrap procedure. RESULTS: During treatment the decrease in fatigue brought on by CBT was mediated by improved fatigue perceptions, increased physical activity, less sleepiness, less helplessness, and improved physical functioning. Post-treatment increases in fatigue levels were mediated by reduced physical activity, reduced concentration, and increased sleepiness. CONCLUSION: These results suggests that focusing on improving fatigue perceptions, perceived physical activity, daytime sleepiness, helplessness, and physical functioning may further improve the effectiveness of CBT for fatigue in patients with MS. Maintenance of treatment effects may be obtained by focusing on improving physical activity, concentration and sleepiness.

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Drug-induced injury (DILI) is a frequent cause of abnormal liver tests and a leading cause of liver failure in the United States. Colchicine has long been used as a systemic anti-inflammatory agent for treatment of gout by inhibiting mitotic activity and neutrophil function. We present the first case of colchicine-induced hepatoxicity, supported by histopathologic findings characteristic of colchicine-induced injury and resolution of liver enzyme abnormalities after its discontinuation. Colchicine-associated DILI has implications for the evaluation of patients with abnormal liver tests and gout, especially for patients with alcoholism and non-alcoholic fatty liver disease, in whom there is an increased incidence of gout.

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OBJECTIVE: Encapsulated non-invasive follicular variant papillary thyroid cancer (ENIFVPTC) has recently been retermed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This designation specifically omits the word "cancer" to encourage conservative treatment since patients with NIFTP tumors have been shown to derive no benefit from completion thyroidectomy or adjuvant radio-active iodine (RAI) therapy. METHODS: This was a retrospective study of consecutive cases of tumors from 2007 to 2015 that met pathologic criteria for NIFTP. The conservative management (CM) group included patients managed with lobectomy alone or appropriately indicated total thyroidectomy. Those included in the aggressive management (AM) group received either completion thyroidectomy or RAI or both. RESULTS: From 100 consecutive cases of ENIFVPTC reviewed, 40 NIFTP were included for the final analysis. Of these, 10 (27%) patients treated with initial lobectomy received completion thyroidectomy and 6 of 40 (16%) also received postsurgical adjuvant RAI. The mean per-patient cost of care in the AM group was $17,629 ± 2,865, nearly twice the $8,637 ± 309 costs in the CM group, and was largely driven by the cost of completion thyroidectomy and RAI. CONCLUSION: The term NIFTP has been recently promulgated to identify a type of thyroid neoplasm, formerly identified as a low-grade cancer, for which initial surgery represents adequate treatment. We believe that since the new NIFTP nomenclature intentionally omits the word "cancer," the clinical indolence of these tumors will be better appreciated, and cost savings will result from more conservative and appropriate clinical management. ABBREVIATIONS: AM = aggressive management CM = conservative management ENIFVPTC = encapsulated noninvasive form of FVPTC FVPTC = follicular variant of papillary thyroid carcinoma NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features PTC = papillary thyroid carcinoma PTMC = papillary thyroid microcarcinoma RAI = radio-active iodine US = ultrasound.

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Over 50 million people have been displaced, some as a result of conflict, which exposure can lead to psychiatric sequelae. The aims of this study were to provide estimates of pre-emigration trauma, post-migration stress, and psychological sequelae of immigrants and refugees from predominantly Sub-Saharan Africa who immigrated to Sweden. We also examined the predictors of the psychiatric sequelae as well as acculturation within the host country. A total of 420 refugees and immigrants were enrolled using stratified quota sampling. A battery of questionnaires including the Harvard Trauma Questionnaire, Post-Migration Living Difficulties Scale, the Cultural Lifestyle Questionnaire; and the Hopkins Checklist were administered. Descriptive statistics, Chi square analyses, Pearson correlations, analysis of variance, and logistic and linear regression were performed to test the aims of the study. Eighty-nine percent of participants reported at least one traumatic experience prior to emigration. Forty-seven percent of refugees reported clinically significant PTSD and 20 % reported clinically significant depressive symptoms. Males reported a significantly greater number of traumatic events [F(1, 198) = 14.5, p < 0.001] and post-migration stress than females [F(1, 414) = 5.3, p = 0.02], particularly on the financial, discrimination, and healthcare subscales. Females reported a higher prevalence of depressive symptoms when compared to males [F(1, 419) = 3.9, p = 0.05]. Those with a shorter duration in Sweden reported higher rates of PTSD [F(63, 419) = 1.7, p < 0.001]. The greater number of traumatic events was found to be significantly associated with the severity of PTSD symptoms [F(34, 419) = 9.6, p < 0.001]. Using regression analysis, 82 and 83 % of the variances associated with anxiety and depression, respectively, was explained by gender, education, religion, PTSD and post-migration stress. Sixty-nine percent of the variance associated with PTSD included education, number of traumatic events, depressive symptoms and post-migration stress. Forty-seven percent of the variance for acculturation was accounted for by a model that included age, education, duration in Sweden, anxiety, depression, and post-migration stress. These predictors were also significant for employment status with the exception of depressive symptoms. Multidimensional interventions that provide treatments to improve psychiatric symptoms in combination with advocacy and support to reduce stress (e.g., financial, access to health care) are recommended. The focus of the intervention may also be modified based on the gender of the participants.

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Ureaplasma is a significant cause of nongonococcal urethritis. This is a case of rectal Ureaplasma found on culture in a young man who has sex with men not previously reported in the literature. Nucleic acid amplification tests are now standard of care for sexually transmitted infection testing, but they do not test for Ureaplasma and, therefore, may be missing important infections. Ureaplasma could have important implications in urethritis and rectal HIV transmission among men who have sex with men engaging in condomless anal intercourse. Further study of Ureaplasma's role as a rectal pathogen may be warranted.

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BACKGROUND: Cystic Fibrosis (CF) lung disease is characterised by an inexorable decline in lung function, punctuated by periods of symptomatic worsening known as pulmonary exacerbations (referred to here as CFPE). Despite their clinical significance, the cause of CFPE remains undetermined. It has been suggested that an increase in bacterial density may be a trigger, although this has not been shown empirically. METHODS: Here, a previously validated quantitative PCR-based approach was used to assess numbers of Pseudomonas aeruginosa and of total bacteria in respiratory secretions from patients during the period leading up to CFPE. Sputum samples collected from 12 adult CF patients were selected retrospectively to fall approximately 21, 14, 7 and 0 days prior to CFPE diagnosis. In addition, the relationships between clinical parameters (FEV(1), temperature and patient reported outcome measures) and microbiological data were investigated. RESULTS: No significant changes either in total bacterial or P. aeruginosa numbers were identified prior to CFPE. Of all the correlations tested, only temperature showed a significant correlation with total bacterial numbers in the period leading to CFPE. CONCLUSIONS: These findings strongly suggest that CFPE do not generally result from increased bacterial density within the airways. Instead, data presented here are consistent with alternative models of pulmonary exacerbation.

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Office hysteroscopy may be performed without anaesthesia. Endometrial biopsy can be performed during hysteroscopy. Antalgics or other treatment to reduce discomfort are not indicated. Prophylactic antibiotics are not indicated. Diagnostic value of hysteroscopy for endometrial pathology is interesting. Pipelle is the most appropriate instrument for endometrial biopsy.

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Vaginoscopic hysteroscopy permits to avoid several painful gestures of classical office hysteroscopy. The aim of this article is to describe the advantages such vaginoscopic approach. Six studies were thus selected, dealing with vaginoscopic hysteroscopy. The diameter of the hysteroscope, always a rigid one, was between 3.5 and 5 mm, and CO(2) or saline infusions were indifferently used. Failure rate is inferior to 5%. One study, comparing pain induced by vaginoscopic versus classical hysteroscopy, concluded that vaginoscopic approach was less painful.

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OBJECTIVE: To determine the value of health-related quality of life (HRQoL) to predict change in disability status in patients with multiple sclerosis (MS). METHODS: Over a 5-year period, data were collected on HRQoL (Medical Outcomes Study Short Form-36 Health Survey) and disability status (Expanded Disability Status Scale) from a heterogeneous group of 81 Dutch-speaking patients with MS. RESULTS: Multivariate logistic regression analysis showed that HRQoL in the domains of Physical Functioning and Role-Physical Functioning is a significant predictor of change in disability status. CONCLUSIONS: A patient's subjectively perceived health-related quality of life may not be only a clinically and psychosocially meaningful outcome per se but may also be a predictor of objective outcomes such as change in disability status over a substantial period of time.

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The characteristics of intestinal calcium transport in chronic cholestasis remain largely unknown. Using an experimental model of biliary cirrhosis in the rat, we aimed to investigate changes in calcium transport at the jejunal and ileal levels. Two methods were used: 1) uptake of 45Ca in brush border membrane vesicles and 2) measurements of transepithelial fluxes of calcium in Ussing chambers. Thirty days postsurgery, cholestatic rats presented biliary cirrhosis, with normal growth, normal daily energy, and calcium intakes, but had depressed circulating levels of 25-(OH)-vitamin D2 and 1,25-(OH)-vitamin D3. Compared with sham-operated controls, 45Ca uptake ([Ca2+] = 0.03 mmol) measured in vesicles from cholestatic rats was decreased by 3-fold in the duodenojejunum, in concordance with a lower content in brush border membrane calmodulin. Other changes in brush border membrane composition included decreases in structural proteins, microvillous enzymes, and in triglyceride content. Transepithelial fluxes of calcium measured in the ileum ([Ca2+] = 1.2 mmol) revealed in controls a net basal secretion flux (Jnet = -30.4 +/- 8.1 mmol.h-1.cm-2) that was reduced by 3-fold (p < 0.05) in vitamin D-deficient rats (Jnet = -10.4 +/- 4.8 mmol.h-1.cm-2). In response to 25-(OH)-vitamin D2 treatment, calcium uptake rates increased by 40% in the jejunum, whereas in the ileum, the secretion flux returned to basal control levels. Oral administration of taurocholate or tauroursodeoxycholate (50 mmol) depressed almost completely calcium uptake capacity in the duodenojejunum. By complexing free calcium, tauroconjugated bile acids inhibited in vitro calcium uptake proportionally to their concentration in the medium (0-40 mmol). Our data indicate that, in rat biliary cirrhosis, transport capacity of calcium in the duodenojejunum is markedly reduced in association with vitamin D deficiency and alterations in brush border membrane composition.

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Malnutrition and growth retardation remain a major complication in infants with extrahepatic biliary atresia associated cholestasis. The purpose of this study was to investigate whether oral supplementation with branched chain amino acids (BCAA) can correct malnutrition in a rat model of biliary atresia. Four groups of 15 rats, 30 d old, were used. Group A were shamoperated animals, given a normal laboratory diet (17.5% of caloric intake as proteins). Group B were cholestatic rats (biliary atresia) fed a diet enriched in BCAA (supplement of 8.5%, valine/leucine/isoleucine ratio 1:1:1). Group C were cholestatic mice fed a diet enriched in casein (supplement of 8.5%). Group D were cholestatic mice fed a normal diet. Thirty-two days after surgery, groups were compared for body weight, serum amino acid content, nitrogen balance, muscle mass, and carcass composition. The results showed that the weight of group B, C, and D animals was 85, 81, and 64% of group A (controls). Serum BCAA levels were markedly increased in group B animals. Nitrogen retention was similar in groups B and A, but reduced to 63 and 44% in groups C and D, respectively. Dry weights were similar in group A (39.1% of body weight) and B (37.7%), but reduced to 28.1 and 28.6% of body weight in groups C and D. Body proteins were higher in groups A (13.9%) and B (14.2%) than in group D (9.7%) rats. Mineral content of group B animals was 84% of those of group A, 50% in group C, and 23% in group D rats. It was concluded that an oral supplement of BCAA can correct growth, nitrogen retention, and body composition in experimental biliary atresia. Administration of BCAA supplements to cholestatic infants should be considered.

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Using a sensitive high-performance liquid chromatography method, we quantified the concentration of polyamines (putrescine, spermidine, and spermine) in human milk as well as in a representative group of commonly used artificial infant formulas. Variations in polyamine levels were also analyzed in human milk during the immediate postnatal period. During the first week postpartum, putrescine levels in human milk remained very low and varied little, while spermidine and spermine concentrations rose markedly during the first 3 days, reaching plateau levels that were 12 and eight times higher, respectively, than the values measured on day 0. The mean total polyamine concentration was 557 +/- 18 nmol/dl with the following profile: spermine, 313 +/- 16; spermidine, 220 +/- 20; and putrescine, 24 +/- 3.5. In artificial powdered formulas, the polyamine concentration was approximately 10 times lower than in human milk, with no difference in putrescine and spermine contents between first-age and second-age formulas. By contrast, semi-elemental diets prepared by hydrolytic procedures using crude extracts of pancreatic enzymes were shown to be major sources of polyamines with a profile similar to that of human milk. Compared with first-age formulas, mean concentrations in spermine and spermidine were 39 and six times higher, respectively, in these semi-elemental diets, whereas putrescine levels remained almost equivalent in all types of milk tested. These data indicate that human milk and some semi-elemental diets provide substantial amounts of spermine and spermidine to neonates and infants that could potentially modulate intestinal maturation.

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To determine the zonal distribution of alcohol dehydrogenase in normal and cirrhotic human livers, we measured activities of this enzyme by quantitative cytochemical analysis along the liver cell plate in liver specimens from 10 normal organ donors and from 7 children with extrahepatic biliary atresia cirrhosis. In normal human liver samples, a continuous increase in alcohol dehydrogenase activity was observed along the sinusoid from the periportal to the perivenular hepatocytes (mean extinction units from 16.2 +/- 10.0 to 58.0 +/- 14.8). A similar observation was made in cirrhotic nodules, with activity increasing continuously from nodule periphery to center (7.6 +/- 4.1 to 44.9 +/- 13.3). This study demonstrates a heterogeneous pattern of alcohol dehydrogenase distribution along the sinusoid in normal human liver specimens. In addition, demonstration of this heterogeneity in human cirrhosis suggests that the cirrhotic liver is able to maintain a parenchymal functional organization, with persistence of metabolic zonation.

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To evaluate whether liver metabolic zonation persists in human biliary cirrhosis, we used quantitative cytochemistry to measure activities of glucose 6 phosphatase (G6P) and NADPH dehydrogenase (ND) in hepatocytes situated in different zones of liver cirrhotic nodules. Liver specimens were obtained from 13 children with extrahepatic biliary atresia with compensated cirrhosis. Activity and distribution were compared with zonal activities measured in 17 control human liver specimens obtained during reduction hepatectomies for orthotopic liver transplantation. In normal human liver, G6P was 1.86 times more active in the periportal than in the perivenular zone. On the contrary, ND activity was lower in the periportal zone (63% of perivenular activity). A metabolic zonation persisted in extra-hepatic biliary atresia with compensated cirrhosis. G6P activity was 1.56 times greater at the nodule periphery than at the nodule center, whereas ND activity was lower at the periphery (75% of nodule center activity). This metabolic zonation is the opposite of that observed in animal toxic (CCl4) cirrhosis, in which greater G6P activity is observed at the nodule center and greater ND activity at its periphery. This confirms our previous hypothesis that the type of cirrhotic metabolic zonation may depend on the site of initial liver damage.

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