Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain.

The self-assembly of micellar structures from diblock polymers that contain hydrophilic and hydrophobic domains has been of great interest for the encapsulation of drugs and other hydrophobic molecules. While most commercially used surfactants are derived from hydrocarbon sources, there have been recent efforts to replace these with biodegradable, nontoxic, biologically synthesized alternatives. Previous examples have primarily examined naturally occurring self-assembling proteins, such as silk and elastin-like sequences. Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values in the low micromolar range, 3 orders of magnitude lower than the CMC of commonly used surfactant sodium dodecyl sulfate (SDS). The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications. Furthermore, the inherent flexibility in the design of these protein sequences enables the encoding of additional functionalities for many future applications. Overall, this work represents a new biomolecular alternative to traditional surfactants that are based on nonrenewable and poorly biodegradable hydrocarbon sources.

Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified. METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software. RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes. CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Almost Psychiatry: The Impact of Teaching Child and Adolescent Mental Health Studies to Undergraduate College Students.

OBJECTIVE: The Child and Adolescent Mental Health Studies (CAMS) program is housed in a Liberal Arts undergraduate college of a large research university. Psychiatrists, clinical psychologists, and social workers at the university's medical center teach the courses. The purpose of this study is to evaluate the extent to which CAMS encourages graduates of the program to pursue a career in child and adolescent mental health (CAMH). METHODS: In 2015-2016, graduates of the CAMS program were invited to participate in a mixed methods study. In addition to statistical analyses, qualitative thematic analyses were performed to interpret free-text responses. RESULTS: Forty-five percent (314/702) of invited graduates completed the online survey. Interviews were conducted with 11% (34/314) of participants by study staff over the phone. Quantitative results suggested that 81% (149/185) of participants enrolled in educational programs after graduation due to an interest in CAMH. A significantly higher proportion of the total sample (t = 3.661, p < .001) reported that they changed their career goals while undergraduate students compared to those who did so after graduation. Results of qualitative interviews with 34 participants uncovered five key themes unique to CAMS that may explain the program's influence on graduates' career choices and career development: practitioners-as-instructors, instructor mentorship, novel course content, experiential learning opportunities, and career training and skills. CONCLUSIONS: Quantitative and qualitative results indicated that teaching college undergraduate students about CAMH encourages them to set career goals within the field. These findings suggest the utility of implementing similar programs at other undergraduate colleges.

Reoperation risk following the first operation for internal herniation in patients with laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the most commonly used surgical procedure in the treatment of morbid obesity in Denmark. Internal herniation (IH) and intermittent internal herniation (IIH) are probably the most common late complications in patients with LRYGB. The aim of this study was to investigate a possible increased risk of subsequent operations after an initial IH or IIH event. METHODS: This long-term follow-up study of patients who had surgery for an initial IH or IIH event in 2006-2011, based on the Danish National Patient Registry (NPR), was performed to 2013. During this period, mesenteric defects were not closed routinely during LRYGB. RESULTS: Data were retrieved from 12 221 patients with LRYGB from the NPR. A total of 383 patients had surgery for an initial IH or IIH event. Some 102 patients (26·6 (95 per cent c.i. 22·5 to 31·3) per cent) had a second operation. Twenty-seven (26·5 (18·9 to 35·8) per cent) of these 102 patients had a third operation, and five (19 (8 to 37) per cent) of the 27 had a fourth operation. Of the 383 patients diagnosed with an initial IH or IIH event, 72 (18·8 per cent) had a second IH/IIH event, 14 (3·7 per cent) had a third event, and three (0·8 per cent) a fourth event requiring surgery. CONCLUSION: Patients who have surgery for IH or IIH have a substantial risk of needing further operations.

CDX2 downregulation is associated with poor differentiation and MMR deficiency in colon cancer.

BACKGROUND: Homeobox genes are often deregulated in cancer and can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. CDX2 has been implicated in differentiation, proliferation, cell adhesion, and migration. In this study, we investigated CDX2 mRNA and protein expression in relation to the clinicopathological characteristics of colon cancer, including mismatch repair status and recurrence risk. METHODS: Tumor samples were obtained from colon cancer patients. Biopsies from tumor tissue and normal adjacent tissue were fixed in liquid nitrogen for RNA extraction or in formalin and paraffin embedded (FFPE) for immunohistochemical staining. CDX2 mRNA expression was evaluated by RT-qPCR. FFPE sections were stained for MLH1, MSH2, MSH6, PMS2, and CDX2. RESULTS: A total of 191 patient samples were included in the study and analyzed by immunohistochemistry. Of these samples, 97 were further evaluated by RT-qPCR. There was no significant difference in CDX2 mRNA expression between tumor and normal tissues. CDX2 mRNA expression was significantly lower in right-sided tumors (p<0.05), poorly differentiated tumors (p<0.05), and MMR-deficient tumors (p<0.05). Similarly, CDX2 protein expression was more often low or absent in right-sided tumors (p<0.01), poorly differentiated tumors (p<0.001), and MMR-deficient tumors (p<0.001). Low CDX2 protein or mRNA expression was not associated with recurrence risk. CONCLUSION: We found that CDX2 downregulation is associated with MMR deficiency, right-sided tumors, and poor differentiation at both the mRNA and protein level. Whether CDX2 plays an active role in tumor progression in MSI/MMR-deficient tumors remains to be elucidated.

Psychiatry's Next Generation: Teaching College Students About Mental Health.

OBJECTIVE: The authors describe an integrated area of study for undergraduate college students that targets an increase in knowledge of mental health issues in children, adolescents, and emerging adults; encourages mental health service utilization on college campuses; and exposes young minds to the possibilities of working with children and adolescents in the mental health field. METHODS: An overview of the program is provided, including the resources required to oversee and manage the program, student requirements, a description of the role that clinicians and researchers play as the program faculty, and an explanation of the tuition model. RESULTS: The program currently includes 40 courses with an annual enrollment of over 3000 students, resulting in departmental revenues that currently exceed $11 million per year. Student evaluations of the courses are very positive, and in a program survey students reported that their participation in the program had a positive impact on their life (84.2%) and impacted their career choice (60.2%). CONCLUSIONS: The benefits of the program include a valuable outreach to college students regarding the importance of seeking help for mental health issues, a positive influence on early career decision-making, opportunities for clinical and research educators to develop their scholarly areas of interest, and a significant source of departmental discretionary revenues.

Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II).

BACKGROUND: This article reports on patient-reported sexual dysfunction and micturition symptoms following a randomized trial of laparoscopic and open surgery for rectal cancer. METHODS: Patients in the COLOR II randomized trial, comparing laparoscopic and open surgery for rectal cancer, completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR38 questionnaire before surgery, and after 4 weeks, 6, 12 and 24 months. Adjusted mean differences on a 100-point scale were calculated using changes from baseline value at the various time points in the domains of sexual functioning, sexual enjoyment, male and female sexual problems, and micturition symptoms. RESULTS: Of 617 randomized patients, 385 completed this phase of the trial. Their mean age was 67·1 years. Surgery caused an anticipated reduction in genitourinary function after 4 weeks, with no significant differences between laparoscopic and open approaches. An improvement in sexual dysfunction was seen in the first year, but some male sexual problems persisted. Before operation 64·5 per cent of men in the laparoscopic group and 55·6 per cent in the open group reported some degree of erectile dysfunction. This increased to 81·1 and 80·5 per cent respectively 4 weeks after surgery, and 76·3 versus 75·5 per cent at 12 months, with no significant differences between groups. Micturition symptoms were less affected than sexual function and gradually improved to preoperative levels by 6 months. Adjusting for confounders, including radiotherapy, did not change these results. CONCLUSION: Sexual dysfunction is common in patients with rectal cancer, and treatment (including surgery) increases the proportion of patients affected. A laparoscopic approach does not change this. REGISTRATION NUMBER: NCT00297791 (http://www.clinicaltrials.gov).

Tumour stage and preoperative chemoradiotherapy influence the lymph node yield in stages I-III rectal cancer: results from a prospective nationwide cohort study.

AIM: The study aimed to determine whether the lymph node yield (LNY) in rectal cancer is influenced by patient-related and histopathological factors and the use of preoperative chemoradiotherapy (CRT). METHOD: An analysis was carried out of the LNY in a nationwide Danish cohort of 7950 patients, treated by curative resection of Stage I-III rectal cancer during the period 2001-2011. The impact of year of diagnosis, age, gender, pathological stage of the tumour (pT-stage) and preoperative CRT on LNY was analysed. RESULTS: Twenty-nine per cent of the patients received preoperative CRT. The median LNY was 13 [interquartile range (IQR): 8-19]. A total of 43.4% of the patients had an LNY of < 12. The median LNY increased from 8 (IQR: 5-12) to 20 (IQR: 13-28) LNs over the years of the study period (P < 0.0001). Gender and body mass index (BMI) had no impact on the median LNY. Age had a minor impact, with a range of 12 (IQR: 8-18) to 13 (IQR: 9-20) (P < 0.0001). The LNY ranged from 9 (IQR: 6-14) to 16 (IQR: 10-26), according to pT-stage (pT0-pT4) (P < 0.0001). Median LNY, according to preoperative CRT or no preoperative CRT, was 10 (IQR: 6-16) and 14 (IQR: 8-18), respectively (P < 0.0001). The percentages of patients with an LNY of < 12, according to preoperative CRT or no preoperative CRT, were 58.7% and 37.1%, respectively (P < 0.0001). CONCLUSION: An increase in the LNY over the period of the study was observed, probably reflecting improved quality of surgery and histopathology. A minor significant reduction of LNY was found with increasing age of the patient. LNY was significantly related to pT-stage and to the use of preoperative chemoradiotherapy. For these reasons the minimum harvest of 12 LNs as a surrogate marker for the oncological quality of surgery should be questioned.

Health-related quality of life after surgery for advanced and recurrent rectal cancer: a nationwide prospective study.

AIM: Advances in the treatment of rectal cancer have made it possible to perform complex rectal cancer surgery (COMP-RCS) in patients with primary advanced rectal cancer penetrating beyond the total mesorectal excision planes and in patients with locally recurrent rectal cancer. The aim of this study was to examine health-related quality of life (HRQoL) before and during the first 2 years after COMP-RCS. METHOD: Between 2001 and 2008, 180 patients were treated with COMP-RCS at Aarhus University Hospital. HRQoL was assessed preoperatively and 3, 6, 12, 18 and 24 months after surgery using three questionnaires. The results were compared with those for patients treated with standard rectal cancer surgery (STAN-RCS) and with data from the general Danish population (NORM-data). RESULTS: One hundred and twenty-two (68%) patients responded to the questionnaires. Of these 80 (66%) with disease-free survival for 2 years after surgery were included in the main analysis. The lowest level of functioning and the highest degree of symptoms were reported preoperatively. The majority of the HRQoL scales improved or remained stable during the first postoperative year; a decrease was observed for body image only. One year after surgery, HRQoL in patients treated with COMP-RSC was comparable to that for patients treated with STAN-RCS. Lower levels were found for physical and emotional role functioning, compared with NORM-data. CONCLUSION: Patients treated with COMP-RCS experienced improvement in HRQoL in the first year after surgery. One year after surgery, HRQoL was similar to that of patients treated with STAN-RCS. Compared with NORM-data, lower levels were found for physical and emotional role functioning.

Pediatric Insomnia.

Insomnia is the most common sleep disorder among all ages; unfortunately, however, child and adolescent insomnia is infrequently addressed. Given the importance of adequate sleep for proper brain development, pediatric populations are particularly vulnerable to the negative effects of insomnia. Therefore, proper clinical assessment and treatment of pediatric insomnia is crucial. This article is the result of a comprehensive literature review and serves as a guide to the disorder and how it presents differently across child development.

Health-related quality of life after laparoscopic and open surgery for rectal cancer in a randomized trial.

BACKGROUND: Previous studies comparing laparoscopic and open surgical techniques have reported improved health-related quality of life (HRQL). This analysis compared HRQL 12 months after laparoscopic versus open surgery for rectal cancer in a subset of a randomized trial. METHODS: The setting was a multicentre randomized trial (COLOR II) comparing laparoscopic and open surgery for rectal cancer. Involvement in the HRQL study of COLOR II was optional. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR38, and EuroQol - 5D (EQ-5D™) before surgery, and 4 weeks, 6, 12 and 24 months after operation. Analysis was done according to the manual for each instrument. RESULTS: Of 617 patients in hospitals participating in the HRQL study of COLOR II, 385 were included. The HRQL deteriorated to moderate/severe degrees after surgery, gradually returning to preoperative values over time. Changes in EORTC QLQ-C30 and QLQ-CR38, and EQ-5D™ were not significantly different between the groups regarding global health score or any of the dimensions or symptoms at 4 weeks, 6 or 12 months after surgery. CONCLUSION: In contrast to previous studies in patients with colonic cancer, HRQL after rectal cancer surgery was not affected by surgical approach. REGISTRATION NUMBER: NCT00297791 (http://www.clinicaltrials.gov).

The relation between lymph node status and survival in Stage I-III colon cancer: results from a prospective nationwide cohort study.

AIM: This study involved a large nationwide Danish cohort to evaluate the hypothesis that a high lymph node harvest has a positive effect on survival in curative resected Stage I-III colon cancer and a low lymph node ratio has a positive effect on survival in Stage III colon cancer. METHOD: Analysis of overall survival was conducted using a nationwide Danish cohort of patients treated with curative resection of Stage I-III colon cancer. All 8901 patients in Denmark diagnosed with adenocarcinoma of the colon and treated with curative resection in the period 2003-2008 were identified from the Danish Colorectal Cancer Group (DCCG). The impact of lymph node count and lymph node ratio was analysed. RESULTS: Overall 5-year survival was 56.8 and 66.6%, (P < 0.0001) for lymph node counts of fewer than 12 and 12 or more, respectively. The percentages of lymph node positive patients in the two groups were 29.8 and 40.3% (P < 0.0001), respectively. When putting the Stage III patients into four subgroups according to the lymph node ratio (cut-off points 1/12, 1/4 and 1/2) we found an overall 5-year survival rate of 68.1, 57.2, 49.3 and 32.4% (P < 0.0001). Lymph node count and lymph node ratio were independent prognostic factors in multivariate analysis. CONCLUSION: High lymph node count was associated with improved overall survival in colon cancer. Lymph node ratio was superior to N-stage in differentiating overall survival in Stage III colon cancer. Stage migration was observed.

Video-teleconferencing with medical students to improve exposure to child and adolescent psychiatry.

OBJECTIVE: The chronic workforce shortage in child and adolescent psychiatry (CAP) remains a germane issue that has been difficult to deal with effectively. Collaboration between medical schools without sufficient CAP resources and those with enough to share may help improve interest in the field. METHOD: This lecture series piloted a collaborative effort between CAP residents from a Midwest academic center and student-led interest groups from two osteopathic medical schools. CAP residents led nine interactive lectures with medical students on relevant topics, using video-teleconferencing. Baseline and follow-up surveys were used to assess attitudes and responses to the lecture series. RESULTS A group of 175 students completed the baseline survey; 43 students completed the follow-up survey; 21 of 43 (48%) reported that the lectures would positively influence their career choice toward CAP. CONCLUSION: Interactive lectures via video teleconferencing demonstrated potential to improve medical students' exposure to CAP, and they were well received in this initial pilot study.

Validation of the Danish version of the disease specific instrument EORTC QLQ-CR38 to assess health-related quality of life in patients with colorectal cancer.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) quality of life colorectal questionnaire module (QLQ-CR38) was developed in 1999, and an update, the QLQ CR29 was published recently. To date the Danish version of the questionnaire has not been validated. The aim of this study was to examine the psychometric properties of the Danish version of EORTC QLQ-CR38. METHODS: EORTC QLQ-CR38 was administered to 190 patients with colorectal cancer in two Danish hospitals, one month after their operation. A psychometric evaluation of the questionnaire's structure, reliability, convergent, divergent and known-groups validity was performed. RESULTS: Data from 164 (86.3%) patients were available for analysis. The Danish version of EORTC QLQ-CR38 showed satisfactory psychometric properties for the scales: body image, sexual functioning, male sexual problems and defecations problems. Suboptimal psychometric performances were found for the scales: micturition problems, symptoms of the gastrointestinal tract and weight loss. Evaluation of the psychometric properties of the scale chemotherapy side effects was limited by the low number of patients receiving chemotherapy. It was not possible to assess the psychometric properties of the scale female sexual problems and the single item sexual enjoyment due to a high number of missing values. The homogeneity of the study population made the evaluation of known-group validity difficult. CONCLUSIONS: The results of this study suggest that the validity of the Danish version of EORTC QLQ-CR38 is acceptable. Furthermore, the results support the appropriateness of the updated version, the EORTC QLQ-CR29.

Health-related quality of life after surgery for primary advanced rectal cancer and recurrent rectal cancer: a review.

AIM: Health-related quality of life is an important outcome measure in treatment of cancer. A review of the literature was undertaken to provide an overview of health-related quality of life (HRQoL) after surgery for primary advanced or recurrent rectal cancer and to outline proposals for future HRQoL studies in this area. METHOD: A systematic literature search was undertaken. Only studies concerning surgery for primary advanced or recurrent rectal cancer and describing methods used for measuring HRQoL were considered. RESULTS: Seven studies were identified, including two prospective longitudinal studies, three cross-sectional studies and two based on qualitative data. Global quality of life, and physical, social, role and sexual function seemed to be impaired for a varying time after surgery. All the studies had methodical problems due to small sample size (12-44 patients) and different points of time for the assessment of HRQoL (12.3-47 months), which made it difficult to determine the period of time of impaired HRQoL and also if this is different after surgery for locally advanced or recurrent disease compared with after total mesorectal excision used for earlier tumours. CONCLUSION: Several aspects of HRQoL are impaired for a variable time after treatment for locally advanced or recurrence of rectal cancer. Larger prospective longitudinal studies are needed to provide further information regarding the effects of this extensive surgery on quality of life.

Use of a balloon catheter in management of the pelvic space following laparoscopic abdominoperineal excision.

AIM: Management of the pelvic space following laparoscopic abdominoperineal excision remains controversial. We describe a simple technique for obliteration of the pelvic space after laparoscopic abdominoperineal excision. METHOD: Pneumoperitoneum was re-established after completion of the operative procedure and a Foley catheter Ch. 24 was inserted through the right lower port under direct vision. The balloon of the catheter, placed in the presacral space, was filled with 50 ml of sterile saline and connected to passive drainage. The catheter was removed 10 days postoperatively. RESULTS: This technique was used in 15 patients with the median age of 74 years (range 63-86). Eleven patients were treated with preoperative chemoradiotherapy. The median length of hospital stay was 9 days (range 5-11). Two patients (13.3%) treated with chemoradiotherapy developed a superficial perineal wound infection and four patients (26.6%) had a deep pelvic abscess, which required surgical drainage. The median time of perineal wound healing was 3 months (range 2-8). The median follow-up time was 36 months (range 18-60). None of the patients developed perineal hernia or intestinal obstruction in the follow-up period. One patient underwent small bowel resection due to stenosis caused by radiation enteritis. There was no local recurrence, but two patients developed distant metastases after 12 months. CONCLUSION: Our results suggest that filling the pelvic cavity with a balloon catheter for 10 days results in the creation of a thin, fibrotic peritoneal layer which keeps the small intestine out of the pelvis and prevents loops of intestine adhering in the pelvic cavity.

Pediatric Insomnia.

Insomnia is the most common sleep disorder among all ages; unfortunately, however, child and adolescent insomnia is infrequently addressed. Given the importance of adequate sleep for proper brain development, pediatric populations are particularly vulnerable to the negative effects of insomnia. Therefore, proper clinical assessment and treatment of pediatric insomnia is crucial. This article is the result of a comprehensive literature review and serves as a guide to the disorder and how it presents differently across child development.