Using the NANA toolkit at home to predict older adults' future depression.

BACKGROUND: Depression is currently underdiagnosed among older adults. As part of the Novel Assessment of Nutrition and Aging (NANA) validation study, 40 older adults self-reported their mood using a touchscreen computer over three, one-week periods. Here, we demonstrate the potential of these data to predict future depression status. METHODS: We analysed data from the NANA validation study using a machine learning approach. We applied the least absolute shrinkage and selection operator with a logistic model to averages of six measures of mood, with depression status according to the Geriatric Depression Scale 10 weeks later as the outcome variable. We tested multiple values of the selection parameter in order to produce a model with low deviance. We used a cross-validation framework to avoid overspecialisation, and receiver operating characteristic (ROC) curve analysis to determine the quality of the fitted model. RESULTS: The model we report contained coefficients for two variables: sadness and tiredness, as well as a constant. The cross-validated area under the ROC curve for this model was 0.88 (CI: 0.69-0.97). LIMITATIONS: While results are based on a small sample, the methodology for the selection of variables appears suitable for the problem at hand, suggesting promise for a wider study and ultimate deployment with older adults at increased risk of depression. CONCLUSIONS: We have identified self-reported scales of sadness and tiredness as sensitive measures which have the potential to predict future depression status in older adults, partially addressing the problem of underdiagnosis.

Assisted reproductive technology treatment outcomes.

Information on the outcomes of ART treatments in Ireland is not readily available to Irish practitioners. The data for hospital affiliated clinics has been made available for many years and is included in the hospital reports. We present a 10-year analysis of the Irish ART results voluntarily reported by six out of seven IVF clinics. The data was collected from published ESHRE reports and from results (2007-8) not yet published. Data collected included: number of clinics and ART cycles, female age, clinical and multiple pregnancy rates and treatment complications. The clinical pregnancy rate per embryo transfer was 31.7% for IVF and 29.8% for ICSI. The proportion of singleton, twin and triplet deliveries for IVF and ICSI combined was 75%, 23.35% and 1.64%. The rate of ovarian hyperstimulation was 0.8%. ART practice in Ireland is safe, effective and responsible. Financial and societal savings could result from the introduction of state funded IVF with compulsory eSET where recommended.

Frozen-thawed transfer cycles: are they comparable with fresh?

Cryopreservation of zygotes and subsequent thaw and transfer is an established ART treatment. We assessed if success rates frozen-thawed (day 2) zygotes are comparable with the outcome in fresh cycles of treatment. We performed a prospective follow-up and analysis of all frozen (FZT) and fresh cycles of treatment during a 12 months period. One hundred and nineteen patients in the frozen-thawed and 652 in the fresh group had a transfer. The overall thaw-survival rate was 71.7%. Clinical pregnancy rates per thaw and transfer were respectively 15.1% and 21% in the frozen and 29.1% (per transfer) in the fresh group. Implantation rates in fresh and frozen cycles were 16% and 12.3% respectively. The pregnancy loss rate was higher in the FZT group (29% vs. 18.3%). Cryopreservation of good quality zygotes, after fresh transfer offers optimal success rates in subsequent frozen treatment. It also encourages consideration of elective single zygote transfers.

Pregnancy and perinatal outcomes after assisted reproduction: a comparative study.

BACKGROUND: Increasing use of fertility therapy has elicited concerns regarding adverse effects for expectant mothers and the health of children thus conceived. AIMS: To study the risk of adverse perinatal outcomes, birth defects and pregnancy complications following assisted reproductive technology (ART). METHODS: Questionnaire-based study involving 1,524 children and 1,182 pregnancies conceived following in vitro fertilisation (IVF) in two units. Outcomes were compared with the general population. RESULTS: In the study group versus the general population; multi-foetal gestations, 26 versus 2%; singleton preterm delivery and low birth weight, 8.7 and 6.4 versus 4.3 and 4%, respectively; non-lethal congenital malformation rate, 2.6 versus 2.1%; placenta praevia, 2.8 versus 0.5%. CONCLUSIONS: Multi-foetal gestations remain the principal cause of adverse perinatal outcomes after ART. Singleton ART pregnancies have an increased risk of preterm delivery and low birth weight at term. Non-lethal congenital malformation rates are not increased following ART. Placenta praevia is increased following ART.

Cadherin switching dictates the biology of transitional cell carcinoma of the bladder: ex vivo and in vitro studies.

Bladder cancer is the fifth most common malignancy in the UK. Clinically, the most important process in determining prognosis is the development of invasion, initially of the lamina propria and then beyond as these transitional cell carcinomas (TCCs) progress from stage pT1 to stages T2+. Cadherins and catenins are the main mediators of cell-cell interactions in epithelial tissues, and loss of membranous E-cadherin immunoreactivity is strongly correlated with high grade, advanced stage and poor prognosis in bladder cancer and other malignancies. However, the role of P-cadherin is yet to be fully elucidated in bladder TCC. The objectives of this study were to establish how the expression of cadherins and catenins determines clinical and in vitro behaviour in bladder TCC. Utilizing immunohistochemistry, immunofluorescence and western blotting, we demonstrated a significant reduction in the expression of E-cadherin and beta-catenin as grade and stage of bladder TCC progress, accompanied by a significant increase in P-cadherin expression (all p < 0.05, Pearson's chi2 test). Increased P-cadherin expression was also associated with a significantly worse bladder cancer-specific survival (log rank p = 0.008), with Cox regression showing P-cadherin to be an independent prognostic factor. Utilizing a variety of tissue culture models in a range of functional studies, we demonstrated that P-cadherin mediates defective cell-cell adhesion and enhances anchorage-independent growth. The results provide evidence that increased P-cadherin expression promotes a more malignant and invasive phenotype of bladder cancer, and appears to have a novel role late in the disease.

Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels.

CONTEXT: TSH is known to have a circadian rhythm, but the relationship between this and any rhythm in T(4) and T(3) has not been clearly demonstrated. OBJECTIVE: With a view to optimizing thyroid hormone replacement therapy, we have used modern assays for free T(4) (FT4) and free T(3) (FT3) to investigate circadian rhythmicity. SETTING: The study was performed at a university hospital. DESIGN AND SUBJECTS: This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis. RESULTS: Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH. CONCLUSIONS: FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.

Ownership and uses of human tissue: what are the opinions of surgical in-patients?

AIMS: To investigate whether patient opinion about the uses of tissue removed at therapeutic operations has changed since the adverse publicity surrounding the Alder Hey and Bristol Royal Infirmary Inquiries, and to see whether it aligns with the Human Tissue Act 2004. METHODS: A questionnaire was given to 220 postoperative patients in a teaching hospital during an 11 week period. Aggregated responses to each question were ranked in frequency order. Unweighted centroid linkage hierarchical clustering analysis was performed with dendrogram display for the main data on tissue usage. RESULTS: 203 completed questionnaires were collected (compliance rate 92.3%). 96.3% of patients indicated that they would not object to their tissue being used in research, significantly higher than in the 1996 study (89.1%) with no overlap of the 95% CIs. 29.1% of patients believed that the hospital had ownership of tissue once it has been removed during surgery, 23.2% believed they had ownership, 19.7% believed that the pathology laboratory had ownership, and 15.3% believed that nobody had ownership rights in the case of tissue samples. CONCLUSIONS: This new survey indicates that despite a turbulent decade for those involved in human tissue retention in the UK, public support for a wide range of human tissue based activities, especially biomedical research, has not diminished and that patient opinion aligns well with the Human Tissue Act 2004.

Maternal folate status and neural tube defects in Ireland: the need for a national food fortification program.

To determine the present risk of a Neural Tube Defect [NTD] pregnancy in the caucasian primigravid population in Dublin by comparing the serum folate and red cell folate status of primigravid patients attending the first prenatal booking clinic with data from the late 80's. This Cross-sectional population study looking at blood folate status of over 400 sequential primigravid caucasian women with a singleton pregnancy, booking at less than or equal to 20 weeks gestation. All patients were attending a prenatal booking clinic at the Rotunda Hospital in Dublin during 2003-2004. Comparing serum and red cell folate values in 454 primigravid patients in 2003-4 to values to in a large case-control study based on over 56,000 women attending maternity hospitals in Dublin from 1986 to 1990. Just 13.9% of our patients took periconceptual folate, 33.5% of patients took folate in the first 20 weeks of pregnancy and 58.8% of mothers were taking no folate supplement. Overall, 30% of mothers had RCF levels below 400 ug/L--a level recommended as the minimum value required for protection. NTD risk occurred most frequently amongst patients with RCF levels between 300 and 400 ng/mL.

Cholecystobronchial fistula secondary to adenomyomatosis of the gallbladder.

A case of cholecystobronchial fistula secondary to adenomyomatosis of the gallbladder is described. A cholecystobronchial fistula is a very unusual cause of fistulation between the bronchial and biliary tree. This is only the fifth reported case in the English language literature.

From egg to offspring. Survival rates in in-vitro fertilisation: where does it go wrong?

This retrospective study examines the attrition that occurs from all eggs inseminated and fertilised through to babies taken home in an IVF fresh/frozen programme undertaken between 2001-4. Poor survival rates are to be found, particularly during the recognised in-vitro developmental stages, Present practice which promotes quantity from the start, increases problem potential, is wasteful and against the concept of one embryo one baby. This suggests the need to develop better criteria for egg selection for insemination thus enabling a rethink to the approach to ovarian stimulation of one of quality rather than quantity.

The hidden costs of IVF.

Whether the payment is personal or funded via a third party, IVF is expensive. Clinical and drug costs are known and if necessary can be budgeted for. But, indirect expenses involved in participation also need to be considered. In order to find out what these latter might be, women attending Human Assisted Reproduction Ireland at the Rotunda Hospital Dublin completed prospectively a detailed questionnaire on all likely areas of extra expense during a single IVF cycle from down-regulation to zygote transfer. Four groups participated, divided according to their distance from the clinic. Group A were within Dublin and Group B within a 50 mile radius. Group C were between a 50-130 mile radius and Group D a 130-200 mile radius. Mean levels of costs increased with distance:- Group A 104 euros. to Group D 703 euros. Food, meals and accommodation were the main contributors. Travel time and time-off work also increased with distance. These were respectively, Group A to Group D 15hrs to 139hrs: 35hrs to 75hrs. The study demonstrates that significant extra expense in time and money can be spent in an IVF cycle over and above medical and drug costs. This must be advised prior to commencement. All other issues being equal, geographical location should be part of the decision as to which clinic to attend.

Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables.

BACKGROUND: Receptor activator of nuclear factor kappabeta ligand (RANKL) has an important role in bone remodelling, and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) can induce apoptosis in cancer cells. Their functions are linked by their interactions with osteoprotegerin (OPG). OBJECTIVE: To investigate the expression of RANKL and TRAIL in a large series of unselected breast cancers and to analyse the relations between these expressions and the expression of OPG, oestrogen receptor, and clinicopathological variables. METHODS: 395 breast cancers were sampled into tissue microarrays and immunohistochemistry undertaken for RANKL and TRAIL. RESULTS: There was strong expression of RANKL in 14% of the cancers and strong expression of TRAIL in 30%. Expression of RANKL had a negative association with expression of oestrogen receptor (p = 0.036). Expression of TRAIL had a negative association with the Nottingham Prognostic Index (p = 0.021). There was a significant negative relation between expression of RANKL and TRAIL (p<0.005). Unsupervised cluster analysis produced a dendrogram that showed a clear division into two groups, and the expression of oestrogen receptor was significantly higher in one of those groups (p = 0.012). CONCLUSIONS: There is apparent loss of expression of RANKL in 86% of breast cancers; those tumours that retain expression tend to be oestrogen receptor negative and of a high histological grade. There is strong expression of TRAIL in 30% of breast cancers and these tend to be of better prognostic type. These results may be important in the processes of metastasis to bone and the apoptotic cell death pathway in cancer.

Identification of patients with evolving coronary syndromes by using statistical models with data from the time of presentation.

OBJECTIVE: To derive statistical models for the diagnosis of acute coronary syndromes by using clinical and ECG information at presentation and to assess performance, portability, and calibration of these models, as well as how they may be used with cardiac marker proteins. DESIGN AND METHODS: Data from 3462 patients in four UK teaching hospitals were used. Inputs for 8, 14, 25, and 43 factor logistic regression models were selected by using log10 likelihood ratios (log10 LRs). Performance was analysed by receiver operating characteristic curves. RESULTS: A 25 factor model derived from 1253 patients from one centre was selected for further study. On training data, 98.2% of ST elevation myocardial infarctions (STEMIs) and 96.2% of non-ST elevation myocardial infarctions (non-STEMIs) were correctly classified, whereas only 2.1% of non-cardiac cases were incorrectly classified. On data from three other centres, 97.3% of STEMIs and 91.9% of non-STEMIs were correctly classified. Differences in log10 LRs for individual inputs from different centres accounted for the decline in performance when models were applied to unseen data. Classification was improved when output was combined with either clinical opinion or marker proteins. CONCLUSIONS: Logistic regression models based on data available at presentation can classify patients with chest pain with a high degree of accuracy, particularly when combined with clinical opinion or marker proteins.

Preservation of fertility in women affected by cancer. An audit of the cryopreservation services provided for women at Human Assisted Reproduction Ireland.

There has been a remarkable improvement in survival rates for adult and childhood cancers, due to progress in cancer treatments. However multiagent chemotherapy and radiotherapy are associated with gonadal failure. Whereas sperm banking is commonly performed, female gametes are not so amenable to cryopreservation. Options available to women for fertility preservation include, embryo and oocyte cryopreservation. Our unit established an oocyte/embryo cryopreservation service for women affected by cancer in October 2003. Ninteen women have been referred and five (26%) women have had oocytes cryopreserved. The mean age of women in the group cryopreserved was 34 years (range 21-41). Their mean day 3 FSH was 6.2 IU (range 5.5-6.8). The mean dose of rFSH used was 1870 units (range 1500-2600). The mean number of oocytes cryopreserved was 8 (range 3-16). Preservation of fertility is of major concern to women affected by cancer. This service offers them hope for their future fertility.

The metabolic marker tumour pyruvate kinase type M2 (tumour M2-PK) shows increased expression along the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's oesophagus.

BACKGROUND: Proliferating and tumour cells express the glycolytic isoenzyme, pyruvate kinase type M2 (M2-PK). In tumours cells, M2-PK usually exists in dimeric form (tumour M2-PK), causing the accumulation of glycolytic phosphometabolites, which allows cells to invade areas with low oxygen and glucose concentrations. AIMS: To investigate the expression of tumour M2-PK during the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus, and to assess the prognostic usefulness of tumour M2-PK in oesophageal cancer. MATERIALS/METHODS: One hundred and ninety cases selected from the histopathology archives as follows: 17 reflux oesophagitis, 37 Barrett's oesophagus, 21 high grade dysplasia, 112 adenocarcinomas, and three control tumours. Sections were stained immunohistochemically with antibody to tumour M2-PK. RESULTS: Tumour M2-PK was expressed in all cases, and increased cytoplasmic expression was seen with progression along the metaplasia-dysplasia-adenocarcinoma sequence. All cases of adenocarcinoma showed 100% staining so that tumour M2-PK was not a useful prognostic marker. CONCLUSIONS: Tumour M2-PK is not a specific marker of Barrett's adenocarcinoma, but may be important as a marker of transformed and highly proliferating clones during progression along the metaplasia-dysplasia-adenocarcinoma sequence.

Early pregnancy loss: how do men feel?

One in five pregnancies (20%) end in miscarriage. A specialized early pregnancy loss clinic to provide dedicated medical advice and support was established at the Rotunda Hospital in July 2002. A qualitative pilot study was conducted in July 2002 to assess the emotional response of male partners and also to establish if sufficient support services are provided for them. Ten consecutive couples attending the clinic 6-8 weeks following early pregnancy loss were included in the study. The partners were asked to complete a questionnaire with open and closed questions and return in the envelope provided. Nine questionnaires were returned. The average age of men attended was 28.6 years (range 20-39). The feelings described by men were typical of the grief and bereavement process. All wanted more time for discussion with doctors. They felt marginalized and although they felt support services for their partner were adequate, they felt that more support services for male partners should be provided. Based on these research findings, the specialized early pregnancy loss clinic is being developed to partner's needs and expectations. The appointment letter sent to the women now specifically states that the partner is welcome to attend. Partners are now included in the consultation.

The role of beta-catenin signaling in the malignant potential of cystitis glandularis.

PURPOSE: Chronic inflammation is a risk factor for malignant transformation in the bladder. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFalpha) is a mediator of such inflammation that induces nuclear localization of the adherens junction component beta-catenin. This mechanism has a key role in the initiation and progression of the premalignant lesion Barrett's metaplasia of the esophagus. Cystitis glandularis is a metaplastic lesion of the bladder urothelium occurring in the presence of chronic inflammation and in up to 13% of asymptomatic bladders. Two subtypes are described (typical and intestinal/colonic) with uncertain malignant potential. Etiologically and histologically cystitis glandularis mimics Barrett's metaplasia. We investigated the roles of beta-catenin and TNFalpha in cystitis glandularis. MATERIALS AND METHODS: Immunohistochemistry and immunofluorescence were used to demonstrate the expression and localization of E-cadherin, beta-catenin and TNFalpha in 9 sections of typical cystitis glandularis and 4 of intestinal/colonic cystitis glandularis. Appropriate controls were used for all experiments. RESULTS: Immunohistochemistry demonstrated normal membranous expression of E-cadherin and beta-catenin in all cystitis glandularis sections with increased TNFalpha expression. Immunofluorescence showed nuclear localization of beta-catenin in the intestinal/colonic subtype only, which was not observed in typical cystitis glandularis. CONCLUSIONS: The presence of nuclear beta-catenin suggests that intestinal/colonic cystitis glandularis shares the same signaling pathway with the premalignant lesion Barrett's metaplasia of the esophagus and the intestinal/colonic subtype of cystitis glandularis may have the potential to progress to malignancy. This finding has important implications for the management of this lesion.

A survey of Irish consultants regarding awareness of sperm freezing and assisted reproduction.

Chemotherapy and radiotherapy decrease male fertility. Pretreatment semen cryopreservation offers a chance for future fatherhood. However many eligible patients are not referred. One potential reason for the reduced uptake is lack of awareness by referring consultants. We sent a questionnaire to all 41 consultant oncologists, haematologists and urologists listed in the Irish Medical Directory. The questionnaire surveyed the current knowledge, opinions and clinical practices of this key group regarding semen cryopreservation for male cancer patients. 63% responded. 73% routinely discuss semen freezing with their male cancer patients (mostly testicular carcinomas and lymphomas). 100% believe semen cryopreservation helps the patient psychologically. 12% do not know where facilities exist. 92% will only refer men aged between 20 and 40 years. 92% are unaware that semen freezing does not delay cancer treatment. 54% have heard of intracytoplasmic sperm injection (ICSI) but 88% are unaware of its benefits for patients with low sperm counts. Consultants dealing with male cancer patients do not prioritise future fertility. Most of the consultants surveyed were unaware of the advances in reproductive technology and this may be contributing to underutilization of sperm cryopreservation by male cancer patients. Units offering this service need to increase awareness of its potential benefits.

Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C.

BACKGROUND AND AIM: Cirrhosis with liver failure due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT). Reinfection of the transplanted liver by HCV is inevitable, and aggressive hepatitis with accelerated progression to graft cirrhosis may be observed. Of concern, recent reports suggest that the outcome of LT for HCV may have deteriorated in recent years. Determinants of rate of progression to cirrhosis in the immunocompetent non-transplant patient are well defined, and the most powerful determinant is patient age at the time of infection. Following LT for HCV, recipient age does not affect outcome of HCV reinfection. However, the impact of donor age on graft fibrosis progression rate following LT has not been examined. METHODS: We have examined post-transplant biopsies to assess histological activity, including fibrosis stage (scored 0-6 units, 6 representing established cirrhosis), and to calculate fibrosis progression rates in 101 post-transplant specimens from 56 HCV infected LT patients. Univariate and multivariate analyses examined the impact of parameters including recipient and donor age and sex on fibrosis progression rate, and on predicted time to cirrhosis. RESULTS: For the cohort, median fibrosis progression rate was 0.78 units/year, and median interval from transplantation to development of cirrhosis was 7.7 years. In multivariate analysis, donor age (not recipient age) was a powerful determinant (p=0.02) of fibrosis progression rate. When the liver donor was younger than 40 years, median progression rate was 0.6 units/year and interval to cirrhosis was 10 years. When the donor was aged 50 years or more, median progression rate was 2.7 units/year and interval to cirrhosis only 2.2 years. During the observation period there has been a significant increase in donor age (p=0.01) but date of transplantation per se is not a determinant of progression rate when included in multivariate analyses. CONCLUSIONS: Donor age has a major influence on graft outcome following transplantation for HCV. The changing organ donor profile will affect the long term results of LT for HCV. These observations have important implications for donor liver allocation.

Day 5 inhibin B levels in a treatment cycle are predictive of IVF outcome.

BACKGROUND: Day 5 serum inhibin B during IVF treatment has been investigated as a predictor of outcome. METHODS: A total of 54 women (< or = 39 years, normal menses and endocrine profiles) were treated with urinary gonadotrophins or recombinant FSH following pituitary down-regulation. Serum day 3 FSH in a preceding cycle was <8.5 IU/l. Plasma inhibin B, inhibin A and estradiol were determined after 4 days of gonadotrophin administration (day 5). RESULTS: Day 5 inhibin B was the most highly correlated with the number of mature follicles (>14 mm), oocytes retrieved and fertilized. Receiver operating characteristic analysis gave high accuracy for day 5 inhibin B in predicting ovarian response and indicated that a threshold of 400 pg/ml may be helpful in the decision as to whether to continue treatment. Women with <400 pg/ml (n = 16) had lower numbers of follicles, mature follicles, oocytes retrieved, fertilized and cleaved compared with those >400 pg/ml (n = 36) and this threshold gave a positive likelihood ratio of 30, 92.9% sensitivity, 95.0% specificity and 86.7% positive predictive value to detect poor ovarian response. Day 5 inhibin B was the best predictor of pregnancy (no live births and four cycles cancelled, low inhibin group; nine live births and no cancelled cycles, high inhibin group). CONCLUSIONS: Normogonadotrophic, normogonadal women with day 5 inhibin B <400 pg/ml in down-regulated cycles have a poor response to ovarian stimulation and are less likely to conceive compared with women with higher day 5 inhibin B.