Reproductive Markers in Alzheimer's Disease Progression: The Framingham Heart Study.

BACKGROUND: Reproductive status, such as the age of menarche or menopause, may be linked to cognitive abilities and risk for incident Alzheimer's disease (AD) but the evidence is conflicting. It is also not fully known if these factors interact with cortical beta-amyloid deposition. OBJECTIVES: To study the relationship between reproductive risks, sex hormone markers and risk for decline in specific cognitive domains in women. DESIGN, SETTING AND PARTICIPANTS: We analyzed the association of reproductive markers (age at menarche, number of births, age at menopause, sex hormone-binding globulin, estradiol, estrone, total testosterone, free testosterone) with incident AD and annualized cognitive decline in the community-based longitudinal Framingham Heart Study (FHS) Offspring women 60 years and older (n=772, mean age 68 years, mean follow-up 10.7 ± 3 years). We used the Cox proportional hazards regression model and linear regression model, adjusting for covariates. OUTCOME MEASURES: Incident AD dementia as well as the annualized change in memory, language, attention and executive functions. RESULTS: Older age at menopause was associated with a lower risk of incident AD dementia (p = 0.047, 6% lower risk per older year) after adjusting for baseline age, education, hormone therapy status, and MMSE score. Older age at menopause was significantly associated with a slower annualized decline in memory (beta = 0.085, p = 0.00059). The lower level of plasma Aß42 was also associated with a higher risk of incident AD (HR = 0.97, 95% CI = 0.95, 0.99; p = 0.0039) but there was no significant interaction effect with age at menarche, age at menopause or plasma sex hormone levels. CONCLUSION: Younger age at menopause is a risk factor for late-life memory decline and incident AD. This risk appears to be independent of Aß42 pathology. Further studies to understand the biological and social mechanisms underlying the differential effects of reproductive risks are warranted.

Functional assessment of military aircrew applicants in a hypobaric chamber.

BACKGROUND: Aircrew are exposed to environmental pressure changes. In the Republic of Singapore Air Force (RSAF), applicants assessed to be at intermediate risk of otic barotrauma undergo a hypobaric chamber assessment ["trial of chamber" (TOC)] to functionally evaluate their suitability for military aircrew vocations. AIMS: To identify factors associated with TOC failure among applicants with otorhinolaryngological conditions. METHODS: All applicants to RSAF aircrew vocations who were assessed to be at intermediate risk of otic barotrauma over a 3-yr period were identified using the RSAF Aeromedical Centre's electronic database. Their medical records, as well as the TOC assessment records of the subset of applicants who underwent TOC, were reviewed for demographic data, clinical findings, and TOC outcomes. RESULTS: Of the 483 identified applicants, 374 (77%) had abnormal otoscopic findings, 103 (21%) had rhinitis symptoms, and 6 (1%) had previous ENT surgery. 123 (25%) underwent TOC, of which 20 (16%) failed. Holding other predictor variables constant, the odds of TOC failure increased by 0.79 per unit decrease in BMI (95% CI 0.63-0.99), and the odds of TOC failure increased by 0.93 per kg decrease in body weight (95% CI 0.87-1.00). An abnormal tympanogram was not a statistically significant predictor of TOC failure (OR 1.96, 95% CI 0.59-6.42). Of the 47 applicants who passed TOC and were eventually recruited, none subsequently developed otic barotrauma (mean follow-up, 3.3 yr ± 1.5 yr). CONCLUSIONS: Applicants with lower weight and BMI are more likely to develop otic barotrauma with environmental pressure change. Tympanometry cannot be reliably used to identify applicants who would more likely pass TOC.

Cognitive Digital Biomarkers from Automated Transcription of Spoken Language.

BACKGROUND: Although patients with Alzheimer's disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. OBJECTIVE: To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing. DESIGN: Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. SETTING: Observational cohort study. PARTICIPANTS: 146 participants in the Framingham Heart Study. MEASUREMENTS: Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. RESULTS: Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. CONCLUSIONS: The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

Prophylactic vaccination targeting ERBB3 decreases polyp burden in a mouse model of human colorectal cancer.

Prophylactic vaccination is typically utilized for the prevention of communicable diseases such as measles and influenza but, with the exception of vaccines to prevent cervical cancer, is not widely used as a means of preventing or reducing the incidence of cancer. Here, we utilize a peptide-based immunotherapeutic approach targeting ERBB3, a pseudo-kinase member of the EGFR/ERBB family of receptor tyrosine kinases, as a means of preventing occurrence of colon polyps. Administration of the peptide resulted in a significant decrease in the development of intestinal polyps in C57BL/6J-ApcMin mice, a model of familial adenomatous polyposis (FAP). In addition, even though they were not vaccinated, ApcMin offspring born to vaccinated females developed significantly fewer polyps than offspring born to control females. Lastly, to validate ERBB as a valid target for vaccination, we found no overt toxicity, increases in apoptosis, or morphological changes in tissues where Erbb3 was ablated in adult mice. These results indicate that prophylactic vaccination targeting ERBB3 could prevent the development of colon polyps in an at-risk patient population.

Development of an E-learning System for the Endoscopic Diagnosis of Early Gastric Cancer: An International Multicenter Randomized Controlled Trial.

BACKGROUND: In many countries, gastric cancer is not diagnosed until an advanced stage. An Internet-based e-learning system to improve the ability of endoscopists to diagnose gastric cancer at an early stage was developed and was evaluated for its effectiveness. METHODS: The study was designed as a randomized controlled trial. After receiving a pre-test, participants were randomly allocated to either an e-learning or non-e-learning group. Only those in the e-learning group gained access to the e-learning system. Two months after the pre-test, both groups received a post-test. The primary endpoint was the difference between the two groups regarding the rate of improvement of their test results. FINDINGS: 515 endoscopists from 35 countries were assessed for eligibility, and 332 were enrolled in the study, with 166 allocated to each group. Of these, 151 participants in the e-learning group and 144 in the non-e-learning group were included in the analysis. The mean improvement rate (standard deviation) in the e-learning and non-e-learning groups was 1·24 (0·26) and 1·00 (0·16), respectively (P<0·001). INTERPRETATION: This global study clearly demonstrated the efficacy of an e-learning system to expand knowledge and provide invaluable experience regarding the endoscopic detection of early gastric cancer (R000012039).

Initial evaluation of a novel multibending backward-oblique viewing duodenoscope in endoscopic retrograde cholangiopancreatography.

A novel multibending backward-oblique viewing duodenoscope was developed to overcome the difficult technical aspect of deep cannulation into the bile duct during endoscopic retrograde cholangiopancreatography (ERCP). The aim of the present study was to evaluate the initial experience of a novel multibending backward-oblique viewing duodenoscope (M-D scope) for ERCP. This was a retrospective review of 23 patients with native papilla who received biliary ERCP with the M-D scope between April and December 2010. The procedures were performed by two well-experienced endoscopists. In all patients, biliary cannulation and therapeutic procedure were successfully completed. In two patients with Billroth I gastrectomy, ERCP were initially attempted with a conventional single-bending duodenoscope, but biliary cannulations were unsuccessful. However, with the use of the M-D scope, biliary cannulation and therapeutic procedures were successfully completed. A novel multibending backward-oblique viewing duodenoscope is safe and feasible for therapeutic and diagnostic ERCP.

Guideline on training and credentialing in endoscopic retrograde cholangiopancreatography.

The aim of the Endoscopic Retrograde Cholangiopancreatography (ERCP) Working Group was to examine the issues of training, credentialing and quality control in ERCP in Singapore. Published guidelines and clinical trials concerning issues of training, complications and quality control in ERCP have been reviewed. The Working Group recommended that a trainee reach a minimum threshold of 200 cases before the assessment of competency. The target for achievement of competency was set at an 85 percent successful cannulation rate for native papilla. To perform advanced ERCP, endoscopists should have undergone dedicated training either in a recognised training centre or in conjunction with and under the guidance of a more experienced colleague, until technical competency is achieved. Precut should only be performed by endoscopists with experience and expertise in performing Levels II and III ERCP, who have been formally proctored. An audit of ERCP should examine parameters such as appropriate indication, success rates of selective cannulation, technical success rate of commonly performed procedures and procedure-related complications. To maintain technical competency, an individual should be performing ERCP on a regular basis. In conclusion, the innate risks of ERCP necessitate that all ERCP practitioners should be appropriately trained, practise within their expertise level and maintain regular practice in order to minimise risks and improve patient outcome.

Diagnosis and endoscopic resection of early gastric cancer.

The overall prognosis of gastric cancer is generally poor due to late presentation and diagnosis. When detected early, the prognosis for gastric cancer is excellent, and curative endoscopic resection may be possible, without the need for surgery. Careful endoscopic examination is important so as to avoid missed lesions. Endoscopic resection, especially with the technique of endoscopic submucosal dissection, is a viable alternative to surgery for the curative treatment of early gastric cancer, with similar long term results, as long as strict inclusion criteria are adhered to.

A pilot study of EUS-guided hot saline injection for induction of pancreatic tissue necrosis.

BACKGROUND AND STUDY AIMS: Hot saline may be potentially useful for inducing necrosis of pancreatic tissue. However, the local and systemic effects are largely unknown. This pilot study aimed to evaluate the feasibility and safety of EUS-guided injection of hot saline into the pancreas in the porcine model. METHODS: Boiling hot saline was injected into the tail of normal porcine pancreas under EUS guidance in six pigs via a transgastric approach. Three pigs were killed 4 hours later to study the acute effect of the hot saline injection (acute study). The remaining three pigs were killed after 7 days of clinical observation (survival study). RESULT: Injection of 5 mL, 2 mL and 1 mL of hot saline produced localized necrosis (7 - 10 mm) of pancreatic tissue in the acute study. However, there was pooling of hot saline on the surface of the pancreas when 5mL was injected. On the basis of the results of the acute study, the volume of hot saline injected in the survival study was 1 mL. One milliliter of hot saline produced localized or sporadic necrosis of pancreatic tissue without any signs of pancreatitis in all three pigs in the survival study; hot saline was observed to pool on the pancreatic surface of one pig. There was no histological evidence of necrosis in the pancreatic tissue adjacent to the pooled hot saline in either the acute or the survival study. CONCLUSION: EUS-guided hot saline injection of pancreatic tissue in the porcine model was technically successful and led to localized necrosis of pancreatic tissue without any sign of pancreatitis.

Endoscopic ultrasound-guided drainage of abdominal abscesses and infected necrosis.

Traditionally abdominal abscesses have been treated with either surgical or radiologically guided percutaneous drainage. Surgical drainage procedures may be associated with considerable morbidity and mortality, and serious complications may also arise from percutaneous drainage. Endoscopic ultrasound (EUS)-guided drainage of well-demarcated abdominal abscesses, with adjunctive endoscopic debridement in the presence of solid necrotic debris, has been shown to be feasible and safe. This multicenter review summarizes the current status of the EUS-guided approach, describes the available and emerging techniques, and highlights the indications, limitations, and safety issues.

Total endoscopic resection of Barrett esophagus.

Barrett's esophagus with high grade intraepithelial neoplasia is associated with disease progression at rates of greater than 10% per year. Endoscopic resection is a lower risk alternative to surgery for the management of high grade intraepithelial neoplasia and intramucosal cancer. Two endoscopic approaches have been used, namely localized resection of the lesion and total endoscopic resection of all Barrett's mucosa. The latter strategy removes all at-risk mucosa. Currently it is performed mainly using piecemeal endoscopic mucosal resection techniques. In recent years endoscopic submucosal dissection has been attempted to obtain en bloc resection. This review will describe the techniques of total endoscopic resection, and summarize the key published data.

UNESCO Global Ethics Observatory: database on ethics related legislation and guidelines.

The Database on Ethics Related Legislation and Guidelines was launched in March 2007 as the fourth database of the UNESCO Global Ethics Observatory system of databases in ethics of science and technology. The database offers a collection of legal instruments searchable by region, country, bioethical themes, legal categories and applicability to specific articles of the UNESCO Universal Declaration on Bioethics and Human Rights and International Declaration on Human Genetic Data. This paper discusses the background and rationale for the database and its role as a consultative and comparative resource hub for the study of ethics related legal instruments across the world, with the purpose of informing and inspiring relevant stakeholders on the implementation of the principles contained within the UNESCO declarations on bioethics.

Magnetic resonance cholangiopancreatography in the diagnosis of primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: Magnetic resonance cholangiopancreatography (MRCP) is a less-invasive alternative to endoscopic retrograde cholangiopancreatography (ERCP) for the diagnosis of primary sclerosing cholangitis (PSC). This study evaluated the diagnostic accuracy of MRCP in PSC compared with ERCP, and assessed the diagnostic accuracy of different T2w sequences. PATIENTS AND METHODS: 95 patients (69 PSC, 26 controls) were evaluated using both ERCP and MRCP. Exclusion criteria included secondary sclerosing cholangitis and contraindications to MRCP. The diagnosis of PSC was confirmed in 69 patients based on ERCP as the reference gold standard. MRCP was performed using a 1.5 Tesla MR unit, using breath hold, coronal and transverse half-Fourier acquisition single-shot turbo spin-echo (HASTE), coronal-oblique, fat-suppressed half-Fourier rapid acquisition with relaxation enhancement (RARE), and coronal-oblique, fat-suppressed, multisection, thin-section HASTE (TS-HASTE) sequences. The MRCP morphological criteria of PSC were evaluated and compared with ERCP. RESULTS: The sensitivity, specificity, and diagnostic accuracy were 86%, 77%, and 83%, respectively, using the MRCP-RARE sequence, and increased further to 93%, 77%, and 88%, respectively, by the inclusion of follow-up MRCP in 52 patients, performed at 6-12-month intervals. HASTE and TS-HASTE sequences showed significantly lower diagnostic accuracy but provided additional morphologic information. CONCLUSIONS: MRCP can diagnose PSC but has difficulties in early PSC and in cirrhosis, and in the differentiation of cholangiocarcinoma, Caroli's disease, and secondary sclerosing cholangitis. A positive MRCP would negate some diagnostic ERCP studies but a negative MRCP would not obviate the need for ERCP.