Immune Checkpoint Blockade in Lower Gastrointestinal Cancers: A Systematic Review.

BACKGROUND: Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours. PATIENTS AND METHODS: Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy. RESULTS: In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment.

Association of Markers of Proinflammatory Phenotype and Beige Adipogenesis with Metabolic Syndrome in Chinese Centrally Obese Adults.

BACKGROUND: Visceral adiposity is associated with higher productions of C-reactive protein (CRP) and interleukin-6 (IL-6). Inflammation of obese adipose tissues could contribute to systemic metabolic dysregulation, especially thermogenic activity of white adipose tissues, namely, beige adipogenesis, characterized by altered irisin expression. Thus, we investigated the roles of inflammation and adipocyte beiging in Chinese centrally obese (CO) adults with metabolic syndrome (MetS). METHODS: This cross-sectional study was conducted on 54 CO and 58 non-CO subjects drawn from 1492 Chinese people with age and sex matched during November 2010 and August 2013. Twenty (37.0%) of the CO subjects fulfilled the IDF worldwide definition of MetS. Serum CRP, IL-6, and irisin levels were examined. RESULTS: Higher CRP and IL-6, but lower irisin, levels were manifested in MetS versus non-MetS subjects with or without CO. Multiple linear regression identified high-density lipoprotein cholesterol level as the only independent risk factor for irisin level. Categorized by median of CRP and IL-6 levels, a lower irisin level was only observed in high CRP group. CONCLUSION: Under the condition of central obesity, chronic inflammation and impaired beige adipogenesis are associated with MetS in Chinese adults.

Sonographic evaluation of the immediate effects of eccentric heel drop exercise on Achilles tendon and gastrocnemius muscle stiffness using shear wave elastography.

BACKGROUND: Mechanical loading is crucial for muscle and tendon tissue remodeling. Eccentric heel drop exercise has been proven to be effective in the management of Achilles tendinopathy, yet its induced change in the mechanical property (i.e., stiffness) of the Achilles tendon (AT), medial and lateral gastrocnemius muscles (MG and LG) was unknown. Given that shear wave elastography has emerged as a powerful tool in assessing soft tissue stiffness with promising intra- and inter-operator reliability, the objective of this study was hence to characterize the stiffness of the AT, MG and LG in response to an acute bout of eccentric heel drop exercise. METHODS: Forty-five healthy young adults (36 males and nine females) performed 10 sets of 15-repetition heel drop exercise on their dominant leg with fully-extended knee, during which the AT and gastrocnemius muscles, but not soleus, were highly stretched. Before and immediately after the heel drop exercise, elastic moduli of the AT, MG and LG were measured by shear wave elastography. RESULTS: After the heel drop exercise, the stiffness of AT increased significantly by 41.8 + 33.5% (P < 0.001), whereas the increases in the MG and LG stiffness were found to be more drastic by 75 + 47.7% (P < 0.001) and 71.7 + 51.8% (P < 0.001), respectively. Regarding the AT, MG and LG stiffness measurements, the inter-operator reliability was 0.940, 0.987 and 0.986, and the intra-operator reliability was 0.916 to 0.978, 0.801 to 0.961 and 0.889 to 0.985, respectively. DISCUSSION: The gastrocnemius muscles were shown to bear larger mechanical loads than the AT during an acute bout of eccentric heel drop exercise. The findings from this pilot study shed some light on how and to what extent the AT and gastrocnemius muscles mechanically responds to an isolated set of heel drop exercise. Taken together, appropriate eccentric load might potentially benefit mechanical adaptations of the AT and gastrocnemius muscles in the rehabilitation of patients with Achilles tendinopathy.

Anxiety and anxious-depression in Parkinson's disease over a 4-year period: a latent transition analysis.

BACKGROUND: Depression and anxiety in Parkinson's disease are common and frequently co-morbid, with significant impact on health outcome. Nevertheless, management is complex and often suboptimal. The existence of clinical subtypes would support stratified approaches in both research and treatment. METHOD: Five hundred and thirteen patients with Parkinson's disease were assessed annually for up to 4 years. Latent transition analysis (LTA) was used to identify classes that may conform to clinically meaningful subgroups, transitions between those classes over time, and baseline clinical and demographic features that predict common trajectories. RESULTS: In total, 64.1% of the sample remained in the study at year 4. LTA identified four classes, a 'Psychologically healthy' class (approximately 50%), and three classes associated with psychological distress: one with moderate anxiety alone (approximately 20%), and two with moderate levels of depression plus moderate or severe anxiety. Class membership tended to be stable across years, with only about 15% of individuals transitioning between the healthy class and one of the distress classes. Stable distress was predicted by higher baseline depression and psychiatric history and younger age of onset of Parkinson's disease. Those with younger age of onset were also more likely to become distressed over the course of the study. CONCLUSIONS: Psychopathology was characterized by relatively stable anxiety or anxious-depression over the 4-year period. Anxiety, with or without depression, appears to be the prominent psychopathological phenotype in Parkinson's disease suggesting a pressing need to understanding its mechanisms and improve management.

Wnt/ß-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion.

Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence-free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down-regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients.

An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults

RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.(AU)

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.(AU)

Palliative care for dementia--time to think again?

It is estimated that there are 35.6 million people with dementia worldwide and this is projected to increase to over 115 million by the year 2050. Dementia is a progressive neurodegenerative disease that significantly reduces survival. End-of-life care received by this group is often poor and does not equate to that offered in other life limiting illnesses. This review highlights results from a large UK study of informal carers of people with dementia to explore what are determinants of care for people with dementia and their family carers. New perspectives as to models of care for end-of-life care for patients with dementia are discussed together with how these may be implemented and delivered within wider community settings and contexts, where many people with dementia may be cared for in the future.

Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.

OBJECTIVE: To examine the prevalence, incidence and risk factors associated with visual hallucinations (VHs) amongst people suffering from Parkinson's disease (PD). METHODS: We recruited 513 patients with PD from movement disorder and PD clinics within three sites in the UK. Patients were interviewed using a series of standardised clinical rating scales at baseline, 12, 24 and 36 months. Data relating to VHs were collected using the North-East Visual Hallucinations Interview. Prevalence rates for VHs at each assessment were recorded. Associations were determined using multiple regression analysis. RESULTS: Cross-sectional prevalence rates for VHs at baseline, 12, 24 and 36 months indicated VHs in approximately 50% of patients. A cumulative frequency of 82.7% of cases at the end of the study period exhibited VHs. The incidence rate for VHs was 457 cases per 1000 population. Longer disease duration, greater impairment in activities of daily living and higher rates of anxiety were most commonly associated with VHs. No factors predictive of VHs could be ascertained. CONCLUSIONS: When examined longitudinally, VHs affect more patients than is commonly assumed in cross-sectional prevalence studies. Clinicians should routinely screen for VHs throughout the disease course. Disease duration, impairment in activities of daily living and anxiety presented as co-morbidities associated with VHs in PD, and therefore those presenting with VHs should be screened for anxiety disorder and vice versa.

Pre-clinical evaluation of ceramic femoral head resurfacing prostheses using computational models and mechanical testing.

Ceramic-on-ceramic hip resurfacing can potentially offer the bone-conserving advantages of resurfacing while eliminating metal ion release. Thin-walled ceramic resurfacing heads are conceivable following developments in the strength and reliability of ceramic materials, but verification of new designs is required. The present study aimed to develop a mechanical pre-clinical analysis verification process for ceramic resurfacing heads, using the DeltaSurf prosthesis design as a case study. Finite element analysis of a range of in vivo scenarios was used to design a series of physiologically representative mechanical tests, which were conducted to verify the strength of the prosthesis. Tests were designed to simulate ideal and worst-case in vivo loading and support, or to allow comparison with a clinically successful metallic device. In tests simulating ideal loading and support, the prosthesis sustained a minimum load of 39 kN before fracture, and survived 10 000 000 fatigue cycles of 0.534 kN to 5.34 kN. In worst-case tests representing a complete lack of superior femoral head bone support or pure cantilever loading of the prosthesis stem, the design demonstrated strength comparable to that of the equivalent metal device. The developed mechanical verification test programme represents an improvement in the state of the art where international test standards refer largely to total hip replacement prostheses. The case study's novel prosthesis design performed with considerable safety margins compared with extreme in vivo loads, providing evidence that the proposed ceramic resurfacing heads should have sufficient strength to perform safely in vivo. Similar verification tests should be designed and conducted for novel ceramic prosthesis designs in the future, leading the way to clinical evaluation.

Novel therapeutic potential in targeting microtubules by nanoparticle albumin-bound paclitaxel in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) shows low response to most conventional chemotherapies. To facilitate target identification for novel therapeutic development, we deployed gene expression profiling on 43 paired HCC tumors and adjacent non-tumoral liver, which is also considered as the pre-malignant liver lesion. In conjunction with ontology analysis, a major functional process found to play a role in the malignant transformation of HCC was microtubule-related cellular assembly. We further examined the potential use of microtubule targeting taxane drugs, including paclitaxel and docetaxel, and compared with findings to results from doxorubicin, a common chemotherapeutic agent used in HCC. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, the nanoparticle albumin-bound (nab)-paclitaxel was also examined. In a panel of HCC cell lines studied, a high sensitivity towards taxane drugs was generally found, although the effect from nab-paclitaxel was most profound. The nab-paclitaxel showed an effective IC50 dose at 15-fold lower than paclitaxel alone or the derivative analogue docetaxel, and ~450-fold less compared to doxorubicin. Flow cytometric analysis confirmed a cell cycle blockade at the G2/M phase and increased apoptosis following nab-paclitaxel treatment. In vivo animal studies also showed that nab-paclitaxel readily inhibited xenograft growth with less toxicity to host cells compared to other anti-microtubule drugs and doxorubicin. Gene silencing of the microtubule regulatory gene STMN1 by RNAi suggested a distinct synergistic effect in the combined treatment with nab-paclitaxel. Our findings in this study highly suggest that the microtubule assembly represents a promising therapeutic target development in HCC.

Phosphorylation of Caldesmon by PFTAIRE1 kinase promotes actin binding and formation of stress fibers.

Caldesmon (CaD) is an actin-binding protein that is capable of stabilizing actin filaments. Phosphorylation of CaD is widely accepted in the actin cytoskeletal modeling and promotion of cell migration. In this study, we show that CaD is a downstream phosphorylation substrate of PFTK1, a novel Cdc-2-related ser/thr protein kinase. Our study stemmed from an earlier investigation where we demonstrated that PFTK1 kinase conferred cell migratory advantages in human hepatocellular carcinoma (HCC) cells. Here, we showed that PFTK1-knockdown cells exhibited much reduced CaD phosphorylation and consequently caused dissociation of CaD from the F-actin fibers. The cellular localization of CaD was also altered in the absence of PFTK1. Immunofluorescence analysis revealed that PFTK1-abrogated cells exhibited a diffused and blurred appearance of CaD localization, whereas intact co-localization with F-actins was apparent in PFTK1-expressing cells. Without the binding of CaD to actin, disappearance of actin stress fibers was also evident in PFTK1-abrogated cells. In addition, we found that CaD is also commonly up-regulated in HCC tumors when compared to adjacent non-malignant liver (P = 0.022). Taken together, our results highlight a novel biological cascade that involved the phosphorylation activation of CaD by PFTK1 kinase in promoting formation of actin stress fibers.

Coping in Parkinson's disease: an examination of the coping inventory for stressful situations.

BACKGROUND: Parkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings from coping studies in PD remain inconsistent. The variety of coping scales used without validation in PD has been cited as a possible cause of this inconsistency. The present study sought to examine the validity of the coping inventory for stressful situations (CISS) in a sample of patients with PD. METHODS: Five hundred and twenty-five patients with PD were recruited as part of a longitudinal investigation of mood states in PD. Four hundred and seventy-one participants completed the CISS. Confirmatory factor analysis was used to explore the structural validity of the scale. Internal reliability, test-retest reliability, convergent validity and discriminant validity were assessed using Cronbach's alpha, intraclass correlations and Pearson's correlations. RESULTS: Both three and four factor solutions were examined. The four factor model was found to provide a better fit of the data than the three factor model. The internal reliability, discriminant validity, convergent validity, and test-retest reliability of the CISS scales were shown to be good. Use of emotion-focused coping was associated with greater depression and anxiety whilst, task-oriented coping was associated with better psychological well-being. CONCLUSION: The results provide support for the validity and reliability of the CISS as a measure of coping in patients with PD. Further research into the relationship between coping and well-being is warranted. The identification of helpful and unhelpful coping strategies may guide the development of evidence-based therapies to improve well-being in patients with PD.

Psychotherapeutic treatments for older depressed people.

BACKGROUND: Despite a number of reviews advocating psychotherapy for the treatment of depression, there is relatively little evidence based on randomised controlled trials that specifically examines its efficacy in older people. OBJECTIVES: To examine the efficacy of psychotherapeutic treatments for depression in older people. SEARCH STRATEGY: CCDANCTR-Studies and CCDANCTR-References were searched on 11/9/2006. The International Journal of Geriatric Psychiatry and Irish Journal of Psychiatry were handsearched. Reference lists of previous published systematic reviews, included/excluded trial articles and bibliographies were scrutinised. Experts in the field were contacted.. SELECTION CRITERIA: All randomised controlled trials that included older adults diagnosed as suffering from depression (ICD or DSM criteria) were included. All types of psychotherapeutic treatments were included, categorised into cognitive behavioural therapies (CBT), psychodynamic therapy, interpersonal therapy and supportive therapies. DATA COLLECTION AND ANALYSIS: Meta-analysis was performed, using odds ratios for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes, with 95% confidence intervals. Primary outcomes were a reduction in severity of depression, usually measured by clinician rated rating scales. Secondary outcomes, including dropout and life satisfaction, were also analysed. MAIN RESULTS: The search identified nine trials of cognitive behavioural and psychodynamic therapy approaches, together with a small group of 'active control' interventions. No trials relating to other psychotherapeutic approaches and techniques were found. A total of seven trials provided sufficient data for inclusion in the comparison between CBT and controls. No trials compared psychodynamic psychotherapy with controls. Based on five trials (153 participants), cognitive behavioural therapy was more effective than waiting list controls (WMD -9.85, 95% CI -11.97 to -7.73). Only three small trials compared psychodynamic therapy with CBT, with no significant difference in treatment effect indicated between the two types of psychotherapeutic treatment. Based on three trials with usable data, CBT was superior to active control interventions when using the Hamilton Depression Rating Scale (WMD -5.69, 95% CI -11.04 to -0.35), but equivalent when using the Geriatric Depression Scale (WMD -2.00, 95% CI -5.31 to 1.32). AUTHORS' CONCLUSIONS: Only a small number of studies and patients were included in the meta-analysis. If taken on their own merit, the findings do not provide strong support for psychotherapeutic treatments in the management of depression in older people. However, the findings do reflect those of a larger meta-analysis that included patients with broader age ranges, suggesting that CBT may be of potential benefit.

Clinical pharmacology of old age syndromes.

Several syndromes occur in old age. They are often associated with increased mortality and in all there is a paucity of basic and clinical research. The recent developments in the clinical pharmacology of three common syndromes of old age (delirium, urinary incontinence, and falls) are discussed along with directions for future research.

Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.

BACKGROUND: Despite a growing use of selective serotonin reuptake inhibitors in older people, only one trial has examined their prophylactic efficacy in people aged 65 years and over. AIMS: To examine the efficacy of sertraline in preventing the recurrence of depression in older people living in the community. METHOD: Participants were openly treated with sertraline and then randomised into a double-blind, placebo-controlled continuation/maintenance study of about 2 years duration. Drug dosage was maintained at levels that achieved remission. RESULTS: No significant difference between the sertraline and placebo groups was found in the proportion of recurrences (-7.9%; 95% CI -28.06 to 12.23). Increased age and minor residual symptoms during the continuation phase were associated with recurrence. CONCLUSIONS: Sertraline at therapeutic dosage does not provide significant protection against recurrence.

The Geriatric Mental State Examination in the 21st century.

The Geriatric Mental State Examination (GMS) is now established as one of the most commonly used mental health assessments for older people. Its strengths lie in extensive validity studies, high inter-rater reliability, accessibility to trained raters, irrespective of professional background and its continual evolution and adaptation. Its computerisation, association with supplementary instruments and support by a diagnostic algorithm provides a comprehensive diagnostic system and syndrome profile for each subject. The instrument has been validated against most major diagnostic systems and has been used as outcome measures in intervention studies. It has been translated into numerous languages and validated as a diagnostic instrument in various cultures. Such studies have exposed weaknesses, including the over diagnoses of organic states in populations with poorly developed education. On-going studies continue to address these issues, providing a culture sensitive instrument enabling unique trans-cultural research in a relatively under-researched field.

The clinical profile of older patients' response to antidepressants--an open trial of sertraline.

BACKGROUND: A number of studies have examined the predictive utility and time to response of rating scales and demographic variables. Very few community samples have been examined in this way, and no studies examining the prognostic validity of early symptomatic response have been found in the literature. OBJECTIVES: This study aims to describe how treatment response is reflected in rating scales in older community residents treated with sertraline and to explore the utility of these instruments in predicting response. METHODS: The study examines the open label therapeutic and continuation phases of a maintenance trial. RESULTS: 225 older depressed community residents were treated (openly) with sertraline. Fifty-three percent had a good outcome, 13% did not respond to sertraline and had a poor long-term prognosis. Increased age was associated with poor outcome and increased anxiety symptoms with a good outcome. In the compliant sub-sample, GMS/AGECAT schizophrenia symptoms were associated with poor response to treatment. Baseline HDRS items and related symptom clusters were not of predictive utility, however early changes in HDRS score (improvement from baseline of four or more by four weeks) was associated with good outcome. All symptom clusters improved within two weeks of treatment with sleep symptoms improving by six weeks. Optimum symptomatic improvement was achieved by eight weeks. CONCLUSIONS: Clinicians in primary care can expect 53% response to treatment. In the absence of symptomatic improvement by one month (HDRS score of four or more) treatment should be reviewed. Optimum treatment response is usually achieved within eight weeks.

Depression in Europe. Geographical distribution among older people.

BACKGROUND: This is the first report of results from the EURODEP Programme. AIMS: To assess the prevalence of depression judged suitable for intervention in randomised samples of those aged > or = 65 in nine European centres. METHOD: The GMS-AGECAT package. RESULTS: Differences in prevalence are apparent, 8.8% (Iceland) to 236% (Munich). When sub-cases and cases are added together, five high- and four low-scoring centres emerge. Women predominated over men. Proportions of sub-cases to cases revealed striking differences but did not explain prevalence. There was no constant association between prevalence and age. A meta-analysis (n = 13,808) gave an overall prevalence of 12.3%, 14.1% for women and 8.6% for men. CONCLUSIONS: Considerable variation occurs in the levels of depression across Europe, the cause for which is not immediately obvious. Case and sub-case levels taken together show greater variability, suggesting that it is not a matter of case/sub-case selection criteria, which were standardised by computer. Substantial levels of depression are shown but 62-82% of persons had no depressive level. Opportunities for treatment exist.