Proximal femoral fractures are associated with increased morbidity and mortality. Pre-existing malnutrition and weight loss amongst this patient group is of primary concern, with conventional nutrition support being largely ineffective. The inflammatory response post proximal femoral fracture surgery and the subsequent risk of cachexia may explain the inability of conventional high energy high protein management to produce an anabolic response amongst these patients. Omega-3 fatty acids derived from fish oils have been extensively studied for their anti-inflammatory benefits. Due to their anti-inflammatory properties, the benefit of fish oil combined with individualized nutrition support amongst proximal femoral fracture patients post surgery is an attractive potential therapeutic strategy. The aim of the ATLANTIC trial is to assess the potential benefits of an anti-inflammatory dose of fish oil within the context of a 12 week individualised nutrition program, commencing seven days post proximal femoral fracture surgery.This randomized controlled, double blinded trial, will recruit 150 community dwelling elderly patients aged ≥65 years, within seven days of surgery for proximal femoral fracture. Participants will be randomly allocated to receive either a 12 week individualized nutrition support program complemented with 20 ml/day anti-inflammatory dose fish oil , or, a 12 week individualized nutrition support program complemented with 20 ml/day low dose fish oil .The ATLANTIC trial is the first of its kind to provide fish oil combined with individualized nutrition therapy as an intervention to address the inflammatory response experienced post proximal femoral fracture surgery amongst elderly patients. The final outcomes of this trial will assist clinicians in the development of effective and alternative treatment methods post proximal femoral fracture surgery which may ultimately result in a reduction in systemic inflammation, loss of weight and lean muscle and improvements in nutritional status, mobility, independence and quality of life among elderly patients.ACTRN12609000241235 Osteoporotic fractures and injurious accidental falls are associated with increased morbidity and mortality in older adults -4. ProxiMalnutrition in the elderly is commonly overlooked in a clinical setting ,9. ThereConventional nutritional management of PFF patients involves the provision of high energy, high protein diets, however the evidence for this approach is largely unconvincing. A systematic review of the literature highlighted that most nutrition support provided for PFF patients is based on the provision of a standard volume of high caloric oral supplement rather than individualised dietary requirements . One of Weight loss in older adults, particularly loss of lean muscle, is highly predictive of increased morbidity and mortality -19. FurtAs a biomarker of cachexia, the magnitude of the inflammatory response post PFF surgery, and interventions to reduce this response, has not been adequately investigated. The normal physiological response to a major insult, such as the trauma of PFF and the subsequent surgical repair, is characterized by the activation of the hypothalamic pituitary adrenal axis and sympathetic nervous system with simultaneous activation of the immune system and systemic inflammation . PersistDue to their anti-inflammatory properties and potential to suppress the metabolic consequences of PFF, fish oils are a relatively simple and promising therapeutic strategy for the treatment of cachexia in this population group. Provision of adequate fish oil in conjunction with adequate energy and protein could theoretically improve outcomes for PFF patients. Fish oils, more specifically eicosapentaenoic (EPA) and docosahexanoic (DHA) acids, have been extensively studied for their anti-inflammatory properties in inflammatory conditions including rheumatoid arthritis  and cardThe aim of the present randomised controlled trial (RCT) is to implement a 12 week, individualised nutrition program complemented with an anti-inflammatory dose of fish oil (20 ml/day containing 3.6 g EPA and 2.4 g DHA), commencing 7 days post PFF surgery that will result in clinically important and statistically significant improvements in terms of quality of life, appetite, body composition and physical function. Comparisons will be drawn with a control group receiving 10% of the active fish oil dose.intervention), or, a 12 week individualized nutrition program complemented with 20 ml/day low dose fish oil  (control). An overview of the recruitment method, randomisation process and follow-up procedures is provided in Figure This is a double blinded randomized controlled trial of 150 adults aged ≥65 years, recruited within seven days of surgery for PFF and followed post discharge for up to 12 months. Participants identified with cachexia will be randomly allocated to receive either a 12 week individualized nutrition program complemented with an anti-inflammatory dose of fish oil (20 ml/day providing ~3.6 g EPA and ~2.4 g DHA per day)  heparin, patients receiving treatment doses of any antithrombotic agent, including those taking anti-platelet functioning drugs, will not be eligible to participate in the study. To identify preliminary evidence of cachexia, patient serum CRP levels >6 mg/L will be used as the standard in screening prospective participants.A validated fish food frequency questionnaire (FFQ)  will be Risk of subsequent weight loss will be assessed in the recruitment of participants using the validated Simplified Nutrition Appetite Questionnaire (SNAQ), a four item questionnaire derived from the eight item Council on Nutrition Appetite Questionnaire . SNAQ inThe Mini Mental State Examination (MMSE)  will be All patients who meet the eligibility criteria will be invited to participate in this trial. Project personnel will provide potential participants with a detailed description of the study and the procedures to be performed. If research personnel are satisfied that the potential participant completely comprehends the information and the implications of their involvement in the study, written informed consent will be obtained prior to commencement of baseline measures and randomisation. If study personnel have any doubts that a participant has the capacity to give informed consent, third party consent will be obtained from a relative or immediate caregiver.Project personnel will assess the selected outcome measures (outlined below) at baseline, 6 weeks and 12 weeks with selected measures at 12 months. Project personnel will remain masked to treatment allocation for the assessment of all outcome measures. A telephone follow-up will be performed at 12-months to collect information on quality of life, physical autonomy, changes in level of accommodation and mortality. Outcome measures have been selected based on their suitability for older adults following PFF surgery, strength of the evidence to support validity and reliability, and significance to rehabilitation. All outcome assessments will be conducted in a clinic setting. For all participants who have been discharged post PFF surgery, transportation will be provided by project personnel. It is anticipated that outcome assessments will take approximately 90 minutes in duration.Lean body mass and bone mineral density will be measured using Dual Energy X-ray Absorptiometry . Loss of lean body mass is a key feature in the development of cachexia therefore assessment of the effect of fish oil on body composition is important. Bone mineral density (Anterio-Posterior (AP) spine and hip) will also be examined.Weight change is a key feature in the monitoring of recovery from cachexia. Body weight will be measured to the nearest 0.1 kg following an overnight fast, using calibrated electronic digital scales  with patients in light clothing and without footwear. Alternatively, for inpatients at baseline, a calibrated weigh chair will be used. Percent weight change will be determined by calculating the difference from baseline weight, divided by baseline weight, multiplied by 100. Research Dietitians visiting participants fortnightly will also weigh participants routinely as a means of monitoring patient progress and nutritional status.The Mini Nutritional Assessment (MNA), a validated nutrition screening and assessment tool, will be used to classify patients as well-nourished, at risk of malnutrition or malnourished . This asTriceps skinfold thickness will be assessed using calibrated skinfold calipers  and combined with mid-arm circumference to determine corrected arm muscle area (CAMA) and thereby estimate skeletal muscle mass .Resting energy expenditure (REE) will be measured using a hand held portable indirect calorimeter . REE will be assessed following a fasting period of at least 4 hours. While sitting in a relaxed and upright position, participants will be required to breathe normally into a disposable "scuba-type" mouthpiece where oxygen consumption will be measured until steady state breathing is detected.The ability to participate in activities of daily living (ADL) will be assessed using a validated instrumental and physical ADL tool . The insThis assessment correlates with lower limb muscle strength, which is an integral component of physical independence amongst the elderly population . ParticiFasting blood samples will be collected by a trained research nurse at each of the outcome assessments. Serum samples will be obtained, processed and stored frozen at -70°C. When stored at such temperatures, there is evidence to suggest inflammatory cytokines such as IL-6 remain stable in serum for many years . The anaWhole blood samples will be collected and processed allowing for the separation of plasma from red blood cells. Fatty acids will subsequently be extracted from the erythrocyte phospholipid membrane and analysed to evaluate adherence to the fish oil intervention.Additionally, study participants will be required to maintain a diary outlining their consumption of fish oil, which will then be monitored by the research Dietitian at fortnightly visits; any remaining fish oil will be measured to monitor participant adherence.Health-related quality of life will be assessed using the Assessment of Quality of Life Instrument (AQoL) , a 15 itFrailty will be assessed using the Edmonton Frailty Index  a valid Any gastrointestinal side effects of the fish-oil, although unlikely at the proposed dose, will be self-reported by participants at fortnightly visits, and include the monitoring of gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and steatorrhoea. If participants are unable to tolerate the proposed dose, fish oil capsules will be offered at the equivalent dose. Alternatively the dose will be progressively reduced until any side effects have been resolved.Prophylactic use of LMW heparin or low-dose aspirin will be carefully monitored by research personnel at baseline and throughout fortnightly visits. If any adverse events are observed, such as frequent bruising or increased bleeding time, these will be documented and reviewed by the trial safety management board and further reported to the human research ethics committee. If prophylactic doses for any anticoagulant medication increases to a treatment dose, the administration of fish oil will cease immediately. However, in a previous clinical trial of cardiac patients who were taking an anti-inflammatory dose of fish oil, in addition to aspirin and Warfarin therapy, no increase in bleeding episodes were observed . AlthougParticipants will be randomly assigned to either an intervention or control group following the completion of all baseline measurements. Allocation to groups will be managed by the Flinders University statistician who provides a randomisation service using computerised randomisation software. Allocation will be stratified by hospital admission site due to the likely difference in services provided across the public and private settings. Allocation will also be stratified by fish intake  as determined by the validated fish FFQ . This isAll participants, independent of group allocation, will receive a 12 week well-integrated, coordinated, individualised nutrition care plan in addition to a daily dose of either an anti-inflammatory dose or low dose of fish oil. The provision of the nutrition care plan is designed to ensure that both groups receive best available nutrition care for the prevention of starvation-related muscle wasting and hence will allow the study to evaluate whether an anti-inflammatory dose of fish oil improves outcomes beyond those achieved through ideal nutrition alone.The research Dietitian will perform a comprehensive nutritional assessment upon each participant's entry into the study as a basis for developing a nutrition care plan consistent with estimated nutritional requirements and nutritional rehabilitation goals. As a basis for developing a nutrition program that will achieve positive energy balance, and therefore prevent clinically significant weight loss, REE of each participant will be measured. A factorial method, accounting for injury and weight gain factors, will be used to estimate the total energy expenditure for each participant. Nutrient Reference Values  will be To assess dietary intake, the research Dietitian will perform a standardised dietary interview  with each participant to determine total energy and nutrient intake. Strategies for achieving energy and nutrient requirements will include dietary counselling with attention to timing, size and frequency of meals, recommendations for nutrient dense foods, provision of recipes and referral to community meal programs and providers. Supplementation with commercial high-energy, high-protein supplements as well as multi-vitamins will also be considered to achieve optimal nutritional status.For maximum adherence and minimal cost, administration of EPA and DHA will occur via unencapsulated fish oil taken on fruit juice or vegetable juice. Participants will be required to float 20 ml fish oil  on 30-40 ml juice, or any other flavoured, non-fizzy drink. The fish oil concentrate is flavoured with lemon and lime to mask the fish scent and taste. To avoid any potential side effects associated with the consumption of fish oil, participants are asked to consume the fish oil on juice with breakfast to avoid consumption on an empty stomach. If this dosage is not tolerated, the frequency and volume may be adjusted in conjunction with the research Dietitian, or alternatively fish oil capsules will be offered as an alternative to provide similar concentrations of EPA and DHA as the liquid oil .The anti-inflammatory dose of fish oil selected for the intervention group provides ~3.6 g EPA and ~2.4 g DHA per 20 ml. The low-dose fish oil selected for the control group will be prepared to contain 10% of the active dose, which is also flavoured with lemon and lime to assist in maintaining participant blinding (~0.36 g EPA and ~0.24 g DHA per 20 ml). As with the intervention group, those participants in the control group who refuse to continue with the allocated dose of liquid oil will be offered fish oil capsules providing the equivalent dosage of EPA and DHA.As an inpatient, at baseline, the participant's fish oil will be dispensed by each hospital's pharmacy and administered on the inpatient medication round. The pharmacy will also dispense outpatient supplies alongside other discharge medications.The research Dietitian will perform fortnightly home visits to all participants (intervention and control) over 12 weeks to perform dietetic care and maximise participant nutritional status by way of reviewing the nutrition care plan, dietary counselling and education, monitoring participant weight, ensuring energy and nutrient requirements are achieved as well as monitoring potential gastrointestinal side effects from the dose of fish oil.Quality of life is the primary outcome in this study and was selected because quality of life is an important determinant of future outcomes. It is recommended that half the baseline standard deviation of raw scores provides an appropriate estimate of the minimally clinically important difference for quality of life, and this form of estimation is useful in the absence of direct measurements of important change . Using thttp://www.caresearch.com.au) and will subsequently be exported into SPSS software for analyses. Primary analysis for this study will be undertaken using intention to treat principles. Independent samples t-tests, Mann-Whitney U test and Chi-square test of association will be used as appropriate to compare groups at baseline. To determine differences between the groups at the primary end-point (12 weeks), ANCOVA or logistic regression will be used with models adjusted according to potential confounders.All statistical analyses will be performed using SPSS for Windows, version 18 . Data will be entered into a centralised secure database with remote web access (CareSearch Research Data Management System - This study has a 3.5-year time frame. It is expected that recruitment will commence late 2010 and continue until mid 2012. An additional 12 months will then be required to finalise data collection and six months to complete data analysis and prepare manuscripts for submission to peer reviewed scientific journals.To the best of our knowledge, the ATLANTIC trial is the first of its kind to provide fish oil and individualised nutrition therapy as an intervention to address the deterioration in nutritional status which commonly occurs in PFF patients. This trial will explore more detailed information about the key markers of cachexia than previous work in this population group, particularly concerning the magnitude of inflammation experienced post PFF.This trial will commence earlier than previous research where fish oil has been explored in the treatment of cancer cachexia. Given that the natural process of bone healing is influenced by a variety of systemic and local factors, including an early inflammatory phase , the intEvidence exploring the inflammatory response post PFF surgery in this population group is scant. Previous research using fish oil as an intervention for cachexia has used the model of pancreatic cancer, however there have been considerable limitations in this research including heterogeneous samples representing mixed tumour types and severity, the use of variable and largely insufficient doses of EPA, and in some cases, the administration of fish oil for short durations . FurtherIt is rare that PFF patients receive any significant level of nutrition support as part of standard care following their acute care admission. A major strength of the ATLANTIC trial is that it takes a comprehensive approach to nutrition management where all participants receive individual dietary counselling and nutrition education from an Accredited Practicing Dietitian. This includes the provision of dietary education and counselling in the way of dietary modifications, food fortification and oral supplementation to ensure individual energy, protein and other nutrient requirements are achieved. This is particularly critical given the lack of evidence that oral supplementation alone is effective at improving clinical outcomes in this patient group .To minimize the devastating consequences of cachexia as well as secondary hospital admissions, it is critical that adequate rehabilitation and nutrition support services post PFF surgery are provided. The results of this trial will assist clinicians in the development of more effective and alternative treatment methods, such as an anti-inflammatory dose of fish oil post PFF surgery which may ultimately result in a reduction in systemic inflammation, weight loss, particularly muscle mass, improvements in nutritional status, mobility, independence and quality of life among these patients.The authors declare that they have no competing interests.MM, AY, LCo, RF, LCl, MJ, MC all contributed to the design of the study. MM co-ordinated and prepared drafts of the grant application and manuscript while AY and AV contributed to drafts of the manuscript and LCo, RF, LCl, MJ and MC all reviewed drafts for the grant application and manuscript. All authors have read and approve the publication of the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/10/76/prepub


The new study, the first to examine PBDE neurotoxicity in a human cell–based system, links the brain cell alterations to endocrine disruption.A new laboratory study demonstrating that polybrominated diphenyl ethers (PBDEs) can alter human fetal brain cells may explain at least in part the neurotoxicity recently documented in epidemiologic studies of young children exposed to PBDEs and previously shown in animal models A wealth of data demonstrates that babies can be exposed to significant amounts of PBDE flame retardants both in the womb and through breastfeeding. Although all 3 PBDE formulations—penta, octa, and deca—are banned in Europe, and the penta and octa formulations were discontinued in the United States , PBDEs may still be used in some new U.S. products and in wares manufactured elsewhere. They also are found in a wide variety of older plastic consumer goods that remain in use in many homes, businesses, and automobiles. The PBDEs are known to migrate into indoor dust, posing a particularly high exposure risk to infants and toddlers because of their characteristic hand-to-mouth behavior.EHP 117:1131–1138] as an alternative to animal testing. This method uses primary fetal human neural progenitor cells (hNPCs) cultured to produce complex 3-dimensional cellular systems called neurospheres. Neurospheres undergo the same basic processes that occur during the early stages of normal human brain development: cell proliferation, differentiation, and migration. Tests conducted with neurospheres may help identify exogenous substances that disturb these basic processes in vivo.To investigate how PBDEs may impact the developing fetal brain, the team of scientists employed a method for evaluating human developmental neurotoxicity they had recently developed , and the authors say additional studies are needed to assess these associations.Other work has shown the tendency of PBDEs to accumulate in brain and neuronal cells, and the researchers used radiolabeled BDE-47 to measure an accumulation in test cells of approximately 60-fold. Considered with available human exposure data, these data suggest current PBDE exposure levels are likely to be of concern for human health, the authors write. Two recent studies have linked PBDEs with subtle changes in childrens’ IQs and behavior [


Over the last 30 years options for collecting self-reported data in health surveys and questionnaires have increased with technological advances. However, mode of data collection such as face-to-face interview or telephone interview can affect how individuals respond to questionnaires. This paper adapts a framework for understanding mode effects on response quality and applies it to a health research context.Data collection modes are distinguished by key features . Psychological appraisal of the survey request will initially entail factors such as the cognitive burden upon the respondent as well as more general considerations about participation. Subsequent psychological response processes will further determine how features of the data collection mode impact upon the quality of response provided. Additional antecedent factors which may further interact with the response generation process are also discussed. These include features of the construct being measured such as sensitivity, and of the respondent themselves (e.g. their socio-demographic characteristics). How features of this framework relate to health research is illustrated by example.Mode features can affect response quality. Much existing evidence has a broad social sciences research base but is of importance to health research. Approaches to managing mode feature effects are discussed. Greater consideration must be given to how features of different data collection approaches affect response from participants in studies. Study reports should better clarify such features rather than rely upon global descriptions of data collection mode. Understanding the unique experience of both users and providers of health services requires a broad range of suitably robust qualitative and quantitative methods. Both observational  and interventional  studies may collect data in a variety of ways, and often require self-report from study participants. Increasingly in clinical studies, clinical indicators and outcomes will form part of an assessment package where patient lifestyle choices and behaviour, attitudes and satisfaction with healthcare provision are a major focus. Health researchers need to both be re-assured and provide re-assurance that the measurement tools available are fit-for-purpose across a wide range of contexts. This applies not only to the survey instrument itself, but also to the way it is delivered and responded to by the participant.Options for collecting quantitative self-report data have expanded substantially over the last 30 years, stimulated by technological advances in telephony and computing. The advent of remote data capture has led to the possibility of clinical trials being conducted over the internet ,2. ConceThis article applies a conceptual framework to examine the differences generated by the use of different modes of data collection. Whilst there is considerable evidence about the effect of different data collection modes upon response rates, the article addresses the processes that may ultimately impact upon response quality -8. The frate as well as response content, that is not the focus of this paper. Similarly, approaches that integrate modes of data collection within a study or synthesise data collected by varying modes across studies are only addressed in passing. Although these are important issues for health researchers, this review concentrates on how mode of data collection affects the nature of the response provided by respondents with a particular emphasis on research within the health sciences.It is important to clarify what lies outside the scope of the current review. Whilst mode of data collection can impact upon response Variance attributable to measurement method rather than the intended construct being measured has been well recognised in the psychological literature and includes biases such as social desirability and acquiescence bias . This naEarly options for survey data collection were either face-to-face interview, mail, or telephone. Evolution within each of these three modes led to developments such as computer-assisted personal interview (CAPI), web-delivered surveys and interactive voice response (IVR) . Approaches such as item response theory (IRT) modelling allow for survey respondents to receive differing sets of calibrated question items when measuring a common underlying construct  . CombineThe choice of mode has natural consequences for how questions are worded. Face-to-face interviews, for example, may use longer and more complex items, more adjectival scale descriptors and show cards . In contThe inherent complexity of any one data collection approach  and increasing technological innovation means that trying to categorise all approaches as one or other mode may be too simplistic. Attention has therefore been focused upon survey design features that might influence response. Two recent models by Groves and by Tourangeau illustrate this ,9. TouraCommon to several information processing models of how respondents answer survey questions are four basic stages: comprehension of the question; retrieval of information from autobiographical memory; use of heuristic and decision processes to estimate an answer; and response formulation . At eachOf the features that might vary across data collection method, Tourangeau and others proposed four which may be particularly influential in affecting response: whether a survey schedule is self- or interviewer-administered, the use of a telephone, computerisation, and whether survey items are read by (or to) the respondent . Althougmediate the impact of mode feature: degree of impersonality, the sense of legitimacy engendered by the survey approach and level of cognitive burden imposed. Both impersonality and legitimacy represent the respondent's perceptions of the survey approach and instrument. Cognitive burden, impersonality and legitimacy are a function of the interaction between data collection method and individual respondent . Nevertheless, the level of cognitive burden experienced by individuals is less dependent upon the respondent's psychological appraisal of the survey task than perceptions of either impersonality or legitimacy.Tourangeau considered three variables to The relationships between these mode features, mediating variables, and three response quality indicators  are shown in figure Other features may also modify response and are added to the article framework. They include features of the Respondent (the information provider) and Construct (what is being measured). These features are not directly related to the method of data collection. Some of these features are implied by the mediators described by Tourangeau . Nevertheless, we consider it important to separate out these features in this framework. Examples of both sets of features are provided but are intended to be indicative rather than exhaustive listings. Finally, whilst there may be no unique feature to distinguish between data collection in health and other research contexts, we have used where we can examples of particular relevance to health.The need for approval may restrict disclosure of certain information. Static or dynamic cues  provide a social context which may affect interaction . Self-adThe greater expected privacy for methods such as ACASI (audio computer assisted self-interview) has been associated with increased reporting of sensitive and stigmatising behaviours . It is tSome methods restrict opportunities for establishing researcher credentials, for example, when there is no interviewer physically present. A respondent's perception of survey legitimacy could also be enhanced, albeit unintentionally, by the use of computers. Whilst this may be only a transient phenomenon as computers become more familiar as data collection tools, other technological advances may produce similar effects .Burden may be influenced by self-administration, level of computerisation and channel of presentation. Survey design that broadly accommodates the natural processes of responding to questions across these features is likely to be less prone to error.survey participation was proposed by Groves and colleagues and evaluates the balance of various attributes contributing to a decision to participate in a survey [This general model of a survey . Each atThis theory views the probability of an action being completed as dependent upon an individual's perception of the rewards gained and the costs incurred in complying, and their trust in the researcher. Dillman applied the theory to explaining response to survey requests - mostly in terms of response rate, rather than quality . HoweverUnlike the first three appraisal processes described above, both leverage-saliency and social exchange address broader participation decisions. Features of different data collection modes may affect such decision-making for example, through perceived legitimacy. Other features in the framework considered to modify response may also influence participation decisions according to these theories (e.g. the sensitivity of the construct being measured).Initial appraisal of survey stimulus will result in a response process which further mediates response quality. Several explanatory psychological theories have been proposed. We focus upon three general theories of response formulation .information retrieval and judgement completely (examples of weak and strong satisficing respectively). In either situation, respondents may use a variety of decision heuristics when responding. Three factors are considered to influence the likelihood of satisficing: respondent ability, respondent motivation and task difficulty [Krosnick described optimizing and satisficing as two ends of a continuum of thoroughness of the response process ,29. Fullfficulty ,30. Krosfficulty . Optimizfficulty .Mode feature effects may influence optimizing through differences in non-verbal communication, interview pace (speed) and multitasking. First, the enthusiastic non-verbal behaviour of an interviewer may stimulate and maintain respondent motivation. Experienced interviewers react to non-verbal cues  and respond appropriately. Such advantages are lost in a telephone interview with interviewers relying on changes in verbal tones to judge respondent engagement. Whilst the role of an interviewer to enhance the legitimacy of the survey request was highlighted in Tourangeau's framework, this additional motivation and support function was not clarified . Second,Optimizing/Satisficing has been used to explain a variety of survey phenomena, for example, response order effects  . Visual The tendency for individuals to present themselves in a socially desirable manner in the face of sensitive questions has long been inferred from discrepancies between behavioural self-report and documentary evidence. Response effects due to self-presentation are more likely when respondents' behaviour or attitudes differ from their perception of what is socially desirable . This maMost existing data syntheses of mode feature effects relate to social desirability bias. Sudman and Bradburn found a large difference between telephone- or self-administered surveys compared to face-to-face interviews . DiffereIt is worth noting that Sudman and Bradburn developed a comprehensive coding scheme for their review which was later extended in de Leeuw's work. Difficulties in coding variables with their respective frameworks were noted by Sudman and Bradburn and by Richman and colleagues and is a ubiquitous problem. A greater theoretically-driven emphasis upon mode features should aid both future empirical research and also such data syntheses. The Richman review is particularly notable for its attempt to test explicit a priori hypotheses, its operational definition of sensitivity and its focus upon features rather than overarching modes.Collectively, these reviews provide support for the importance of self-administration and consequently impersonality. Richman and colleagues concluded that there was no overall difference between computer and paper-and-pencil scales. This is consistent with Tourangeau's original model which directly links computerisation to legitimacy and cognitive burden but not to impersonality. From Sudman and Bradburn's review, and from de Leeuw's subsequent review it is clear that other factors may significantly modify the relationship between mode feature and social desirability bias. For example, Whitener and Klein found a significant interaction between the respondent's social environment at the time of data collection  and method of administration . SimilarAsking respondents to agree or disagree with attitudinal statements may be associated with acquiescence - respondents agreeing with items regardless of their content . AcquiesThere is mixed evidence for a mode feature effect for acquiescence. De Leeuw reported no difference in acquiescence between mail, face-to-face and telephone interviews . Howevermissing data [reliability of self-reported data may be affected by the cognitive burden placed upon the respondent [Several mode feature effects on response quality are listed in figure ing data . Computespondent . De Leeuspondent . The relaccuracy  of the data may be affected by impersonality and legitimacy. Both unreliable and inaccurate reporting will be represented by variations in the level of an attribute being reported. For example, a consequence of socially desirable responding will be under- or over-reporting of attitudes and behaviour. This may vary depending upon the degree of impersonality and perceived legitimacy.Tourangeau and colleagues highlight how Two further sets of variables are considered in the article framework presented in figure Constructs being measured will vary according to whether they are subjective or objectively verifiable. Health-related quality of life and health status are increasingly assessed using standardised self-report measures . Whilst the construct being assessed by such measures may in some cases be externally verified  for other constructs (e.g. pain) this may not be possible. Furthermore, the subjective perspective of the individual may be an intrinsic component of the construct being measured ,47. CoteCertain clinical topics are more likely to induce social desirability response bias - potentially accentuating mode feature effects. Such topics include sensitive clinical conditions  and health-related behaviours . An illustrative example is provide by Ghanem and colleagues who found more frequent self-reports of sensitive sexual behaviours  using ACASI compared to face to face interview amongst attendees of a public sexually transmitted diseases clinic .In much of the research contributing to meta-analyses of mode effects on social desirability, the outcome of the assessment was not personally important for study subjects  . FurtherIn a review of satisfaction with healthcare, the location of data collection was found to moderate the level of satisfaction reported, with on site surveys generating less critical response . Crow anAnother role consideration involves the relationship between respondent and researcher. The relationship between patient and healthcare professional may be more influential than that between social survey respondent and researcher. A survey request may be viewed as particularly legitimate in the former case, and less so in the latter . ResponsThere is some indication of differential mode feature effects across demographic characteristics. For example, Hewitt reports variation in sexual activity reporting between modes  by age, ethnicity, educational attainment and income . The epiIn considering modes and mode feature effects we will focus upon three issues that may be of particular relevance to those collecting data in a health context: antecedent features, constraints in choice of mode and the use to which the data is being put.Certain antecedent conditions and aspects of the construct being measured may be particularly relevant in health-related studies. Consider the example of quality of life assessment in clinical trials of palliative care patients from the perspective of response optimising. Motivation to respond may be high, but may be compromised by an advanced state of illness. Using a skilled interviewer may increase the likelihood of optimizing over an approach offering no such opportunity to motivate and assist the patient. Physical ability to respond  may be substantially impaired. This may affect response completeness but if the overall response burden (including cognitive burden) is increased it may also lead to satisficing. In practice, choice of data collection method will be driven as much by ethical considerations about what is acceptable for vulnerable respondents.Are there features of self-reported data collection in health that are particularly different from other settings of relevance to mode feature effects? Surveys will be applied in health research in a wide variety of ways, and some will be indistinguishable in method from some social surveys . Some contexts for data collection in health research may though be very different from elsewhere. Data collection in randomised controlled trials of therapeutic interventions may often include patient-reported outcome measures to assess differences in outcome. How antecedent features in the trial - in particular those associated with respondent role - may influence psychological appraisal and response is hypothesised in table As in social surveys, mode feature effects will be one of several design considerations when collecting health survey data. Surveying patients introduces ethical and logistical considerations which, in turn, may determine or limit choice of data collection method. Quality criteria such as appropriateness and acceptability may be important design drivers . For exaEvaluating mode feature effects will be particularly important as survey instruments start to play a bigger role in the provision of clinical care, rather than solely in research. Patient reported outcome measures are increasingly being applied and evaluated in routine clinical practice -61. BenePerceived benefits of using such patient reported outcomes include assessing the impact on patients of healthcare interventions, guiding resource allocation, and enhancing clinical governance . ComputeIn this clinical service context, psychological responses such as social desirability bias may vary according to whether patient data is being collected to inform treatment decision-making or clinical audit. Method of data collection may similarly play a role in varying the quality of response provided. However, routinely using subjective outcome measures in clinical practice will require a clear theoretical basis for their use and implementation, may require additional training and support for health professionals, and investment in the technology to support its effective implementation which is preferably cost neutral -70 OveraManaging mode feature effects requires identification of their potential impact. This paper has focused upon response quality as one source of error in data collection. Two other sources of error influenced by mode are coverage error and non-response error . In the Social surveys commonly blend different modes of data collection to reduce cost (e.g. by a graduated approach moving from cheaper to more expensive methods ). MixingIn the long term it may prove possible to correct statistically for mode feature effects if consistent patterns emerge from meta-analyses of empirical studies. Alternatively, approaches to reducing socially desirable responding have targeted both the question threat and confidentiality. An example of the latter is the Randomised Response Technique which guarantees privacy ,75. AnotAs described above, the evaluation of data collection method within individual studies is usually complicated by the package of features representing any one mode. Groves and colleagues described two broad approaches to the evaluation of effects due to mode features . The firAs global descriptions of data collection method can obscure underlying mode features, comparative studies should describe these features more fully. This would enable data synthesis, providing greater transparency of method and aid replication .This article has considered how features of data collection mode may impact upon response quality and key messages are summarised below. It has added to a model proposed by Tourangeau and colleagues by drawing apart psychological appraisal and response processes in mediating the effect of mode features. It has also considered other antecedent features that might influence response quality. Mode feature response effects have been most thoroughly reviewed empirically in relation to social desirability bias. Overall effects have been small, although evidence of significant effect modifiers emphasises the need to evaluate mode features rather than simply overall mode. A consistent finding across the reviews is the important moderating effect of year of publication for comparisons involving both telephone and computers. Therefore, mode feature comparisons are likely to remain important as new technologies emerge for collecting data. Although much of the empirical research underpinning the reviewed model has been generated within other academic domains, the messages are nonetheless generally applicable to clinical and health research. Future evidence syntheses may confirm or amend the proposed model but this requires as a precursor greater attention to theoretically driven data collection about mode features.• Choice of data collection mode can introduce measurement error, detrimentally affecting accurate and reliable survey response.• Surveys in health service and research posses similar features to surveys in other settings.• Features of the clinical setting, the respondent role and the health survey content may emphasise psychological appraisal and psychological responses implicated in mode feature effects.• The extent to which these features of health surveys result in consistent mode effects which are different from other survey context requires further evaluation.• Evaluation of mode effects should identify and report key features of data collection method, not simply categorise by overall mode.• Mode feature effects are primarily important when data collected via different modes are combined for analysis or interpretation. Evidence for consistent mode effects may nevertheless permit routine adjustment to help manage such effects.The authors declare that they have no competing interests.MR and DI have been in charge of developing the main arguments presented in the article, have led initial drafting of the article and written the final manuscript. GG, AS, CS, LS, IR, JW and KH have made substantial contributions to developing the arguments in the article, have critically revised the article for substantive intellectual content and have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/10/180/prepub


Lymphocyte apoptosis prevention may improve survival. Bacillus anthracis, the cause of anthrax; Yersinia pestis, the cause of plague; and Ebola virus. Prevention of lymphocyte apoptosis, through either genetic modification of the host or treatment with specific inhibitors, markedly improves survival in murine sepsis models. These findings suggest that interventions aimed at reducing the extent of immune cell apoptosis could improve outcomes for a variety of severe human infections, including those caused by emerging pathogens and bioterrorism agents.Some labile cell types whose numbers are normally controlled through programmed cell death are subject to markedly increased destruction during some severe infections. Lymphocytes, in particular, undergo massive and apparently unregulated apoptosis in human patients and laboratory animals with sepsis, potentially playing a major role in the severe immunosuppression that characterizes the terminal phase of fatal illness. Extensive lymphocyte apoptosis has also occurred in humans and animals infected with several exotic agents, including  Despite success in controlling many infectious diseases, efforts to defend against the wide range of microbes that threaten human health continue to be challenged by the unexpected emergence of novel pathogens and possible use of a variety of virulent agents as biologic weapons. A defensive strategy based solely on developing new vaccines and antimicrobial and antiviral drugs, each specific for only 1 or a few agents, is unlikely to be successful in dealing with potential microbial threats and will be exceedingly expensive. An alternative approach attempts to identify mechanisms shared by most or all severe infections that could be targets for pharmacologic intervention. Such generic therapies could supplement agent-specific treatment by increasing resistance to infection, potentially improving outcomes for patients in a variety of disease states.One physiologic process that characterizes several severe infections is a massive loss of lymphocytes, dendritic cells, gastrointestial epithelial cells, and other cell types through apoptosis, or programmed cell death. This process is an apparent acceleration or dysregulation of the same process by which these cell populations are regulated during normal health  superfamily death ligands, including TNF-α and Fas ligand. Although the intrinsic pathway involves early activation of caspase-9, and the extrinsic pathway is mediated through caspase-8, both lead to activation of the executioner caspase-3 and a variety of proteases and endonucleases. Once begun, apoptosis may be described as an orderly disassembly of the cell from within. Chromosomal DNA is cleaved into oligonucleosomal segments, the nucleus is divided into discrete subunits, and the cell itself is partitioned into multiple membrane-bound fragments whose outer surfaces are marked by large numbers of phosphatidylserine molecules, leading to their rapid uptake by phagocytes. Because all multicellular organisms use programmed cell death to maintain or modify their tissues, this process does not evoke an inflammatory response, and its end products actually serve as antiinflammatory stimuli. Apoptosis thus differs markedly from necrosis, the chaotic breakdown resulting from trauma and other types of damage, in its morphologic and immunologic features . NecrosiA large number of cell-surface and cytoplasmic proteins participate in the detection and processing of signals that tip the balance toward or away from programmed cell death. These include members of the Bcl-2 protein family, which have both proapoptotic and antiapoptotic activity (Bcl-2 is antiapoptotic), and other inhibitors . DespiteDuring normal health, the immediate fate of each lymphocyte is determined through continuous summation of a stream of proapoptotic and antiapoptotic signals that arrive from its external environment and from its internal cytoplasmic milieu. A shift toward initiation of apoptosis should therefore be expected during the early phase of sepsis, when bacteria or their byproducts stimulate macrophages to release proapoptotic substances such as TNF-α, nitric oxide, and glucocorticoids. As the disease develops, accumulating products of lymphocyte apoptosis can act as antiinflammatory stimuli, which contribute to the immunosuppression commonly observed as sepsis progresses to septic shock, and which can lead to a state of immune paralysis before death (Numerous studies have demonstrated a massive apoptotic loss of lymphocytes during sepsis. A prospective investigation in adult patients compared spleens obtained either intraoperatively or within 6 hours after death from sepsis or trauma and found that those from sepsis patients showed a marked decrease in B cells and CD4 T cells  (1). TheThese findings were closely paralleled in another postmortem study, which showed that B and T cells and dendritic cells were markedly depleted in lymphoid organs of children dying of sepsis and that >3% of cells exhibited histologic signs of apopotosis  in mice have shown profound lymphocyte apoptosis in multiple organs, including the thymus and spleen  staining of LT-treated human monocyte–derived dendritic cells found activation of apoptotic pathways , an important virulence factor encoded by Yersinia pestis causes 2 principal forms of illness in humans, a localized infection of lymph nodes (bubonic plague) and a highly lethal septicemia that is a particularly fulminant form of septic shock (Y. pestis in humans is attributable to a collection of outer membrane proteins (Yops) that cause immune suppression and trigger apoptosis . Bcl-2 transgenic mice that overexpressed Bcl-2 in T and B lymphocytes had a marked decrease in splenocyte apoptosis at 72 hours after Y. pestis infection compared with wild-type animals (In addition to these reports that used the CLP model, preliminary studies have shown that Bcl-2 overexpression prevents lymphocyte apoptosis in mice infected with  animals . These fPharmacologic interventions have also been used to prevent initiation of lymphocyte apoptosis in murine models of sepsis . One appL, an absence of apoptosis of B cells, a decrease in loss of T cells, and a resistance to CLP (Another strategy aims to influence intracellular signaling networks in a direction opposing the initiation of programmed cell death. A recent publication by the Hotckhiss group showed that this could be achieved by exploiting the normal CD40 regulatory pathway through which lymphocytes are stimulated in antiapoptotic directions to produce clonal expansion and functional maturation (L fused to carrier peptides to facilitate its transport into cells. In a murine CLP model, treatment resulted in a decrease in lymphocyte apoptosis, but the effect was less marked than that observed in transgenic animals constitutively expressing the same protein (Efforts have also been made to alter intracellular signaling by introducing active portions of Bcl-xEfforts to block completion of the programmed cell death process by blocking executioner caspases have also been reported. Studies with the broad-spectrum caspase inhibitor zVAD showed decreased apoptosis and improved survival in a mouse CLP model (Although the proof-of-concept studies described above have shown promising results, deliberate inhibition of apoptosis during severe infections might have unexpected and undesired consequences. One potential adverse effect of antiapoptotic therapy involves its effects on pathogen replication. Some intracellular agents, such as poxviruses, actively inhibit apoptosis of their host cells so as to permit their own continued replication. Theoretically, pharmacologic inhibition of apoptosis in those situations could actually worsen the clinical outcome by providing an advantage to the pathogen. It may therefore be essential to identify the causative agent of infection before initiating antiapoptotic therapy. An alternative approach that may offer several advantages is targeted delivery of antiapoptotic molecules. Similar to current immune-based therapies, apoptosis inhibitors could be directed to specific classes of immune cells, for example by conjugating them to antibodies to CD4 or CD20, thus avoiding adverse consequences (Other potential limitations of antiapoptotic therapy relate to possible undesired effects of the use of caspase inhibitors. First, because only a small amount of activated caspase-3 is sufficient to initiate genomic DNA breakdown and lead to apoptotic cell death, a high degree of inhibition would be needed to achieve therapeutic effectiveness (A massive loss of lymphocytes and other cells through apoptosis is a proven component of the physiologic changes that occur over the course of septic shock. This process appears also to occur in a variety of other severe infections, including anthrax, plague, and Ebola hemorrhagic fever, which are of major concern for biodefense. A variety of proof-of-concept studies with murine sepsis models have demonstrated that this host response worsens disease outcome because its prevention through genetic modification or pharmacologic intervention improves survival. Research is needed to assess the possible contribution of lymphocyte apoptosis to immune impairment in other disease processes, including a variety of newly emerging infections. By helping to bolster immune function, the development of antiapoptotic therapies could mitigate the consequences of infection by a wide variety of pathogenic agents.


It has been more than a year since ophthalmologists and scientists under Dr. Robin Ali′s team at the Moorsfield Eye Hospital and the Institute of Ophthalmology, University College London, successfully treated patients with a severely blinding disease, Leber′s congenital amaurosis (LCA) using gene therapy. This success does not look to be transient, and this achievement in gene replacement therapy clinical trial for LCA has instilled hope in numerous families with patients suffering from this and similar retinal degenerative diseases, for whom restoration of lost vision has remained a distant dream so far. The encouragement that this success has given is expected to also lead to start of clinical trials for other blinding ocular diseases for which gene therapy experiments at the laboratory and animal levels have been successful. This article reviews the various studies that have led to the understanding of gene therapy outcomes in human ocular diseases and attempts to provide a brief sketch of successful clinical trials. Although history of genetics dates back to more than a century, only the last few decades, encompassing the DNA and genomics era, have witnessed breakthrough research work that have revolutionized various fields including medicine. The only possible treatment that was predicted to become available for untreatable genetic disorders was gene therapy. The first ray of hope came in 1990, through successful retroviral transduction of the gene coding for adenosine deaminase in four-year-old Ashanti De Silva, who suffered from severe combined immunodeficiency (SCID). However, the trust in gene therapy was shaken by the death of 18-year-old Jesse Gelsinger in 1999 due to multiple organ failure following systemic administration of an adenoviral vector having ornithine transcarbamylase gene. Despite this, continued success in treating SCID patients and hemophilia are quite encouraging.[Ocular gene therapy research has made rapid progress in the past few years. Although laboratory and animal experiments started were successful many years ago, the application in human beings took very long due to several biological and regulatory hurdles. However, the recent successful gene therapy clinical trials are promising and encouraging. There arLeber′s congenital amaurosis (LCA), both copies of the same gene are mutated resulting in defective protein production, similar to a knockout animal model. In gene replacement therapy, a defective gene (protein) causing loss of function is replaced by a normal copy of the gene (protein) delivered to site of action through an attenuated viral vector [et al performed successful RPE65 gene replacement therapy in natural canine models of LCA that resulted in restoration of vision, a landmark experiment that prompted clinical scientists to adopt the strategy to restore vision in humans with recessive retinal degenerative diseases.[In autosomal recessive disorders like l vector . Acland diseases.RPE65 gene were administered single subretinal injection of recombinant adeno-associated virus vector that expressed RPE65 complementary DNA (cDNA) in one eye, which had worse visual acuity; the contralateral eye was used as a control. Visual function and immune status were assessed after two, four and six months and graded as predefined end points for toxic effects and efficacy for improved visual function.[The first gene therapy clinical trial was started in May 2007 at the Institute of Ophthalmology and Moorfields Eye Hospital, London, UK. Three young adult LCA patients with early onset, severe retinal dystrophy, who had missense mutation in function.5 After tet al, developed a mutation independent-suppression replacement strategy, which has been evaluated in in vitro cell cultures with transcripts derived from rhodopsin and RDS-peripherin genes.[While gene replacement is the most suitable method for autosomal recessive diseases where there is no normal protein production, it is not a method of choice for autosomal-dominant (AD) diseases. In AD diseases there is one defective copy that produces mutant protein and one that produces normal protein, resulting in a dominant-negative effect, where the wild type and mutant protein interact with each other resulting in blocking of normal protein function. RNA silencing aims at preventing the mutant gene either from getting transcribed into messenger RNA (mRNA) or preventing mutant mRNA transcript from being translated into a protein . Silenciin genes.+/−rds mice, was shown to result in significant structural and biochemical rescue of the disease. ERG showed significant improvement in cone function and fairly good rod response.[et al showed in a rat model of retinal degeneration that intravitreal injection of glial cell-derived neorotrophic factor (GDNF) secreting embryonic stem cells could sustain neuroprotective effect on retinal structures for at least three months.[Animal experiments are underway for delivery of DNA using nanoparticles. Recently, nanoparticle-mediated transfer of retinal degeneration slow (Rds) gene in response. In 2009,retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR) and age-related macular degeneration (AMD).[Ocular neovascularization is the central feature in the pathogenesis of ischemic ocular diseases such as on (AMD). While neon (AMD).11 Similaon (AMD). An AAV-mon (AMD). Pre-clinThe recent success of gene replacement therapy for LCA is a big step forward in the field of genomic medicine. These results have enthused the medical community and basic scientists equally and have unveiled the potentials that is in store for the future of medicine. Once these experiments are refined and tailored to the needs of these patients with unambiguous success, nearly 500 eye genetic diseases and 1500 genetic diseases in other parts of the body could be potentially cured.


Shared genetic and environmental risk factors have been identified for autistic spectrum disorders (ASD) and schizophrenia. Social interaction, communication, emotion processing, sensorimotor gating and executive function are disrupted in both, stimulating debate about whether these are related conditions. Brain imaging studies constitute an informative and expanding resource to determine whether brain structural phenotype of these disorders is distinct or overlapping. We aimed to synthesize existing datasets characterizing ASD and schizophrenia within a common framework, to quantify their structural similarities. In a novel modification of Anatomical Likelihood Estimation (ALE), 313 foci were extracted from 25 voxel-based studies comprising 660 participants  and 801 controls. The results revealed that, compared to controls, lower grey matter volumes within limbic-striato-thalamic circuitry were common to ASD and schizophrenia. Unique features of each disorder included lower grey matter volume in amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for autism. Thus, in terms of brain volumetrics, ASD and schizophrenia have a clear degree of overlap that may reflect shared etiological mechanisms. However, the distinctive neuroanatomy also mapped in each condition raises the question about how this is arrived in the context of common etiological pressures. Autistic spectrum disorders  and schizophrenia have a substantial number of features in common. People with autism, have a strong family history of schizophrenia and bipolar disorder Resisting this position is an influential hypothesis recently proposed by Crespi and Badcock (2008). In their conceptualization, autism reflects a bias towards paternally expressed genes, brain overgrowth and underdevelopment of social brain systems. Schizophrenia, on the other hand, is said to involve maternally expressed genes, brain undergrowth and maladaptive ‘hyper-development’ of social systems. These two disorders therefore have abnormalities in the same set of traits but are ‘diametrically’ opposite, with opposing phenotypes. Thus the field is ripe for investigation of shared or unique characteristics of these two disorders, with the hope that this can inform the search for aetiological mechanisms driving neurodevelopmental dysfunction as well as possible fresh approaches to each condition.The explosion in brain imaging studies over the past decade has greatly expanded our knowledge of brain biology in autistic disorders and schizophrenia. However, with the exception of one recent study which looked at autism and psychosis The initial step of ALE is to generate a Gaussian probability distribution around the peak or central coordinates of significant foci reported in voxel-based studies. The probability that any given voxel is involved in the disorder(s) can be estimated from this whole brain ‘likelihood’ map. ALE retains foci that are close in proximity (regions most consistently reported across studies) to generate resultant or summary 3D clusters. The novelty of our current approach is to combine datasets for joint entry into a single analysis, therefore the resultant ALE map will contain clusters comprising foci from one or other or both conditions, and the contribution each disorder made to every resultant cluster can be estimated. This should help to clarify the extent to which ASD and schizophrenia cause similar brain structural phenotype. The prediction is that there will be considerable overlap across these conditions, a result that will point towards potentially common causal mechanisms.A search was carried out using PubMed, Scopus, and PsycINFO databases with the keywords including: autism, high functioning autism, Asperger, schizophrenia, first-episode, psychosis, MRI, voxel, VBM, and SPM . A branch search was conducted from the retrieved studies, and also existing meta-analysis studies on autistic spectrum disorders and schizophrenia. Schizophrenia studies included studies comparing groups with schizophrenia, to controls balanced for IQ, gender, and handedness were selected. Autistic Disorder studies included studies comparing groups with autism, or autism-spectrum conditions such as high-functioning autism (HFA) and Asperger, to controls. Our definition of autism is when the subject's IQ is below 70 and has a speech acquisition delay of 36 months. Subjects with HFA and Asperger have IQ above 70, and the latter has no delay in speech acquisition.VBM studies of schizophrenia comprise a heterogeneous collection of samples recruited at varying stages of illness with variable medication exposure. Since antipsychotic medication has been clearly shown to affect brain volume even early in treatment Co-ordinates in Montreal Neurological Institute (MNI) format were transformed into Talairach using the “Lancaster transform”, icbm2tal. Co-ordinates transformed to Talairach space by using the Brett transformation, mni2tal, were transformed to the original MNI using Brett transformation, and reconverted to Talairach using icbm2tal http://csl.georgetown.edu/software/3 were retained. Clusters generated from a single studies only were not reported in the resultant joint ALE. The ‘intensity’ ratio of the mean disorder maps to the final joint map at each resultant cluster was calculated. In this way the contribution of each condition to the final ALE result could be estimated (Matlab and SPM5 scripts available on request). For example, for a resultant cluster, high percentage contribution from one condition implied a high chance that foci from studies of that condition would be found therein. A 50% contribution from each condition suggested an equal chance that foci from either condition formed the cluster. Separate ALE analyses were conducted for grey matter deficits (188 foci) and excesses (133 foci).There were a total of 313 co-ordinates  extracted from the studies listed in Global grey matter volumes were generally found to be no different from control samples. The exceptions were 1 study of ASD reporting greater total GM in ASD than controls There were a total of 15 resultant ALE clusters showing lower grey matter volume compared to typical controls across schizophrenia-ASD studies. Brain structures that commonly affected by the two conditions included the right parahippocampal gyrus, posterior cingulate, putamen, insula and left thalamus. ‘Schizophrenia-only’ clusters were mostly located in the left hemisphere  except for two regions  in the right hemisphere. One cluster of lower grey matter volume in the left putamen was uniquely generated from ASD studies , and total foci included. We describe a technique to calculate the percentage contribution of each condition to regional grey matter differences across the whole brain.Our findings summarized in This pattern of grey matter differences in schizophrenia and autism fits well with Middleton and Strick's prediction (2000) that abnormalities within basal ganglia loop systems may underlie neuropsychiatric symptoms Disruption within basal ganglia loop systems is also thought to explain impaired sensorimotor gating in both ASD Medial temporal lobe structures have long been postulated to play a role in autism and schizophrenia. In his seminal review in 1991, Delong conceived of autism as a ‘developmental syndrome of hippocampal dysfunction’ Similarly the amygdala has been implicated in both ASD and schizophrenia. The role of the amygdala has been emphasized as central in autism The present meta-analysis, showing overlapping grey matter abnormalities in brain regions in 2 conditions with shared behavioural traits, supports the position that schizophrenia and autism are related and not entirely polar opposites as proposed by Crespi and Badcock We emphasize that, although we interpret our findings as indicative of overlapping neuroanatomical phenotype, we do not imply that schizophrenia and autism constitute a common entity. Our study indicates a number of brain regions discretely affected by schizophrenia or autism. The result is largely consistent with the findings of Toal et al. 2009, in which the authors compared two autistic groups (with psychosis or without psychosis) separately to controls, and reported coincident lowering of grey matter in many brain areas in both groups The Toal et al (2009) study also found cerebellar volume differences in autistic groups with and without psychosis and controls The major challenge for further study is to try to understand how shared genetic and environmental risk factors acting to elicit such similar grey matter deficits in autism and schizophrenia have quite different illness progression. There are very clear clinical distinctions to be made between the 2 disorders, not least of which lies in their developmental trajectories. Autism is evident in early childhood and is pervasive. Schizophrenia tends to present in late adolescence or early adulthood, and is relatively quiescent during childhood. Therefore one important potential confounder in the present study is that schizophrenia samples were slightly older than autism samples included in the analysis. Numbers of children presenting with childhood onset schizophrenia are limited, making it a practical challenge to study these groups. The available VBM evidence suggests that the brain structural phenotype in early onset schizophrenia is much the same as that reported in older patients In common with all meta-analytic approaches, a major limitation of our study is the ‘file drawer’ problem. That is, studies with negative findings are less likely to be written up and published. Even if there exist studies reporting no significant group differences, the ALE analysis method cannot take account of absent foci. Another possible limitation to the present analysis is that VBM methodology changes over time. Grey matter differences have been quantified in terms of intensity or modulated to yield volume measures. This difficulty for meta-analysis of VBM data has recently received attention In conclusion, we find an appreciable brain structural concordance between schizophrenia and autism. Specifically, lower volumes within the limbic basal ganglia loop system appear to be common to both schizophrenia and autism, while lower grey matter volume in the left putamen (autism) and left fronto-striatal-temporal regions (schizophrenia) appears to distinguish the conditions in terms of grey matter circuitry. Thus our results lend support to theories that schizophrenia and autism have important similarities


Stuart Rennie and colleagues argue that while unlinked anonymous HIV testing is valuable and ethical, such surveillance can be conducted in ethically questionable ways in certain circumstances. Decades into the pandemic, the public health value of HIV surveillance is obvious. Surveillance is traditionally depicted as the “radar” or “eyes” of public health ,2. The WHowever, several approaches to surveillance remain controversial, including the methods used to target populations for surveillance, the statistical tools through which surveillance data are translated into HIV incidence data, and, in the light of existing, highly effective therapies, the obligations of public health agencies to identify infected individuals for follow-up treatment and care. In particular, unlinked, anonymous HIV testing (UAT), which typically involves the use of residual sera normally discarded from blood specimens collected from persons for routine clinical purposes, commonly does not involve obtaining consent from the person whose blood is tested for HIV. The blood tested for HIV is irrevocably anonymized and unlinked from the person providing the sample and hence the testing results cannot be reported back to patients. The main reason to waive consent is methodological: asking persons to volunteer their blood samples for HIV testing could lead to selection and participation bias and compromise the validity of the surveillance data . As noteData collected from HIV surveillance are crucial to guide public health interventions, planning, and prevention efforts.The practice of UAT, an important form of HIV surveillance, raises ethical, epidemiological, and public health challenges in low-income countries.Some ways of conducting UAT in the field violate the spirit and/or the letter of international ethical guidelines.Vulnerable populations, such as sex workers, may be subject to unjust treatment by local health authorities during HIV surveillance initiatives.Conducting UAT in ethically and epidemiologically sound ways in low-income countries requires a multifaceted approach including local capacity building, community engagement, and increased access to HIV and STI testing.We believe that while UAT in itself is valuable and ethical, such surveillance can be conducted in ethically questionable ways in certain circumstances. In what follows, we will briefly compare international ethical guidelines on UAT with ethical and public health challenges encountered with HIV sentinel surveillance in sub-Saharan Africa, among populations usually targeted by UAT efforts. Accompanying this discussion, we propose practical approaches, informed by field research in southern Africa, to improve the quality of HIV surveillance data, strengthen the ethics of surveillance activities, and enhance the capacity of public health systems.Surveying the scientific literature, the ethical justification for the practice of UAT appears to consist in (1) the greater epidemiological utility of “unconsented” testing through avoidance of selection and participation bias; (2) the confidentiality protections afforded by anonymous, unlinked testing; (3) the fact that the residual blood collected for other purposes would be discarded anyway and no one is harmed by its use; and (4) the view that UAT takes place as part of a response to a public health emergency .In developed world settings, these ethical conditions are commonly fulfilled, though the appropriateness of these conditions themselves merits independent ethical scrutiny . The sitDebates about the conduct of UAT leads to questions about decision makers and decision processes. According to WHO/UNAIDS guidelines, UAT activities should be reviewed by a national ethics review board and involve a process of community consultation . It is uapproval for HIV surveillance activities is important, but insufficient. Given the existing power imbalances between international agencies and developing countries, gaining local approval for surveillance activities can be relatively easy. Beyond approval lies the fundamental ethical requirement to strengthen in-country capacity in epidemiological surveillance, ethics, and health care systems.We see three broad strategies to harmonize quality surveillance with ethical concerns. First, justifications for unlinked, anonymous HIV testing should be reviewed in local contexts with local stakeholders. The justifications should be directly addressed in surveillance protocols, discussed with local ethics review boards, and communicated in community awareness meetings. Second, one ethical concern surrounding UAT—namely that persons whose blood tests positive for HIV do not know their HIV status—could be addressed by providing confidential voluntary testing in close conjunction with UAT activities. Local stakeholders should play a central role in designating where such testing should best take place and whether it should take the form of “opt out” or “opt in” testing. Third, gaining local Elsewhere, we have discussed “implementation ethics,” i.e., the ethical issues arising from the implementation of proven interventions or programs, as distinguished from research ethics or clinical ethics . UAT canA key ethical question is to what extent these successes can be reproduced within fragile health systems in developing countries. One small example from our own field experience evokes some of the larger challenges. Two midwives were assisting with blood collection from sex workers at an HIV serosurveillance site. The midwives knew that a woman's HIV test was positive, because the blood was collected in the same room where behavioral interviews and HIV testing took place. The test tubes containing blood were labeled to achieve unlinking, but the lab technician remembered the person whose blood was collected. The midwives reported the woman's name to members of the local organization that provides care to sex workers, because they thought the woman needed counseling and referral to care. The significance of this single incident goes beyond that of a protocol violation. Even in the United States, there is not always a clear recognition among the lay public or health professionals of the public health significance of surveillance, with a related inability (or unwillingness) to distinguish between the clinical context of HIV case finding and public health context of HIV surveillance . ThroughIn some approaches to HIV surveillance, both behavioral data and blood are collected from participants. UNAIDS/WHO guidelines state that if UAT is used in HIV serosurveillance activities, “[n]o additional information should be requested from the participant; only the socio-demographic or clinical information required on the clinic form should be collected” . In our We suggest three strategies to improve confidentiality of HIV results and limit potential abuses that may occur during UAT-based HIV surveillance. First, the importance of surveillance, and the distinction between HIV case finding and HIV surveillance, must be clearly communicated to everyone on the front line of participant interaction and sera collection. Second, field conditions at each sentinel site should be reviewed, and detailed site-specific operational procedures should be developed to allow genuine unlinked anonymous HIV testing. Third, protocol enforcement mechanisms should be established, including independent monitoring boards, field supervisions, and requirements for scheduled written reports. Appropriate training of all persons involved in HIV surveillance  is essential for optimal and responsible implementation.Pregnant women are a special target group for HIV surveillance activities in the developing world. Access to women who attend antenatal clinics is usually easy, and pregnant women may be fairly representative of the sexually active adult population . Women pIn the background of this ethical discussion is another debate about the current and future utility of UAT at antenatal care sites. As prevention of mother-to-child transmission of HIV programs are increasingly implemented and strengthened in developing countries, and greater use is made of general population-based behavioral surveys incorporating HIV testing, the need for unlinked anonymous testing may be gradually phased out, along with its associated ethical issues . For ethIn many settings in sub-Saharan Africa, relatively few persons with symptoms suggestive of sexually transmitted infections (STIs) seek care in public clinics . Since aThe anecdote suggests that efforts to increase demand for STI testing for HIV surveillance purposes must be coupled with mechanisms enabling those tested to receive their STI results. But the larger question is whether such “inducements” are ethically acceptable. Is it justified to induce potential STI patients to a clinic with the primary purpose of using their residual blood, without their consent, for HIV surveillance? What would be the likely reaction of those tested for STIs, if they discovered this? Can such responses be dismissed as irrational or based on public ignorance about the need for HIV surveillance? Inducing individuals to come to the STI clinic for free testing may additionally bias the results and defeat the HIV surveillance purpose. This example highlights the importance of regularly reviewing methodological and ethical justifications for UAT with key local stakeholders and ethical review boards, and exploring alternative approaches that can generate quality data with less risk to public trust in HIV prevention and control efforts.In our field research, local public health authorities were instructed to provide about 300 serum samples from sex workers for unlinked, anonymous surveillance in public health clinics. However, since few sex workers attend these clinics, an organization providing STI prevention and care services for sex workers was asked to collaborate in surveillance activities. The sex worker organization's routine procedures included syphilis testing by rapid plasma reagin (RPR) every three months, except when women tested positive by RPR and were effectively treated, in which case they were retested six months later. This procedure conflicted with the local health authority's desire to collect the required number of samples in a short time span. Local health authorities pressured the sex worker organization to perform blood draws with women not scheduled to have RPR tests according to routine procedures. The sex worker organization insisted that, according to their procedures and international guidelines, such blood collection required informed consent. However, the priorities of local public health authorities ultimately prevailed: blood was drawn for HIV surveillance without consent.In Bangladesh, there have been a number of negative incidents reported about HIV surveillance among sex workers. Unofficial HIV testing of sex workers led to the incarceration of sex workers through breaches of confidentiality. Dissemination of surveillance results by public health officials led to social welfare agencies and police forcefully evicting women from the surveyed brothels, spreading them through the city and compromising existing HIV prevention efforts .Obtaining meaningful sentinel surveillance data representative of the sex worker populations requires knowledge of these women's health-seeking behaviors and the institutions that provide sex workers with STI prevention and treatment services. However, sex workers, being a highly stigmatized group, may be reluctant to seek STI care at public clinics. Surveillance agencies attempting to gain access to this “hard-to-reach” population may enter into ethically murky territory. Two examples:There are additional concerns about social justice. Sex work is either illegal or socially undesirable in most countries. Special care must be taken in order that surveillance data collection or dissemination has a positive and lasting impact on this vulnerable group rather than posing additional burdens. Supportive collaborations between sex workers, sex worker organizations, gatekeepers (such as brothel owners and pimps), law enforcement authorities, Ministries of Women's Affairs, local human rights groups, and agencies planning surveillance activities can usefully customize epidemiological methods to the local context , and canAttempts to implement methodologically and ethically sound surveillance practices currently encounter a number of significant challenges that may be widespread and under-reported in the developing world. Of the 167 HIV surveillance systems for which data were collected worldwide, one analysis found only 47 of these programs (28%) adequate in terms of the frequency and timeliness of data collection, the appropriateness of the populations under surveillance, the consistency of sites, locations, and groups being measured over time, and the coverage and representativeness of those groups to measure adult HIV prevalence . EffectiAlternative Language Summary S1(20 KB DOC).Click here for additional data file.


Several reasons have been advanced to support the view that schizophrenia is a neurodevelopmental disorder. The primThe main neurodevelopmental hypotheses for schizophrenia set forth in the last 10 years are relatively restricted and share three assumptions:The primary pathogenetic defect is an early derangement of the orderly development of the central nervous system that occurs in the pre- or perinatal period;The period of active operation of the causative agent is of short duration, meaning that it is essentially static;The behavioral consequences of this static process remain relatively latent until long after the primary pathogenetic process has run its course.Furthermore, aspects of illness suggesting neurodevelopmental deviation may not apply to all individuals and some authors have argued for neurodevelopmental and non-neurodevelopmental subtypes of the disorder and evenHowever, neurodegenerative hypotheses of schizophrenia have been criticized mainly because of the following reason: gliosis, which is regarded as a necessary neuropathological hallmark of neuronal degeneration, has not been found in a number of carefully controlled postmortem studies in patients with schizophrenia. These neuropathological studies provide strong evidence against a classic neurodegenerative pathogenesis of schizophrenia.4 In addiSome researchers have proposed another alternative that schizophrenia is a progressive neurodevelopmental disorder. This postulates that developmental mechanisms, such as apoptosis and pruning, can continue to go awry over many years without resulting in excessive gliosis. This accounts for both the neuropathological findings implicating prenatal pathology and the imaging findings . Thus, al61The tenets of the neurodevelopmental hypothesis of schizophrenia derive from observations of epidemiological, clinical and brain imaging evidence for neurodevelopmental deviance. These inthe underlying brain and the overlying face are inexorably intertwined” in the course of early development.[Minor physical anomalies are defined as minor structural deviations, which are found in numerous areas of the body  and which are of little general physiological or cosmetic importance. MPAs areelopment. An increelopment.At least 12 different studies have found increased rates of MPAs in adults with schizophrenia, whereas 14Neurodevelopmental disorders tend to have more severe manifestations in males compared to females, i.e., the AAO being earlier in males with comparatively worse outcome. The AAO et al.,[18In addition, the definition of a developmental phenomenon has been reserved to those characteristics that show a nonlinear mean developmental function across age in some group that is relatively consistent across birth cohorts. In the Aet al.,21 based et al.,1822et al.,[In a study by Green et al., schizophet al., These fiClinical neurological abnormalities in schizophrenia have been described since the time of Kraepelin. These abRecent findings provide new evidence suggesting the so-called “soft” neurological signs might have some measure of neuroanatomical validity. Cerebell30Indian study examining CSS in antipsychotic-naïve schizophrenia patients has shown interesting results. CSS scores were significantly higher in patients in comparison with healthy controls. Discriminant analysis revealed two CSS subscores to be significant accounting for 78% of classification. CSS total score, posture subscore and oculomotor subscore had significant positive correlation with a negative syndrome score.NSS may be an intrinsic component of schizophrenia because of their presence even in first-episode patients without antipsychotic treatment.2833 In a28et al.,[The modern era of neurodevelopmental research in schizophrenia began in 1976, when Johnstone et al., showed tet al.,In the late 1980s, the first wave of MRI studies essentially aimed at replicating the findings already established with CT. A second wave of MRI studies reported a measurable reduction in gray matter volume in medial temporal lobe structures including hippocampus-amygdala and parahippocampal gyrus. Another meta-analysis of 40 volumetric MRI studies concluded that regions, such as the amygdala and hippocampus, were probably smaller. In addition, volumes of the frontal lobe, parahippocampus, thalamus and superior temporal gyri are decreased in patients when compared with controls. Recent sCurrent thinking about the mechanisms of schizophrenia postulates a disruption in distributed functional circuits rather than a single abnormality in a single brain region such as prefrontal cortex. SchizophNo specific group of regions has yet emerged as the “schizophrenia circuit”, but a consensus is developing on some of the nodes that may be involved. These nodes include various subregions within the frontal cortex , the anterior cingulate gyrus, the thalamus, several temporal lobe subregions, basal gaCorpus callosum is the major interhemispheric connecting tract with definitely connections with multiple heteromodal association areas. Clinical and experimental data suggest that the CC is part of the highest order-latest maturing neural network of the brain. Reports Most of the prior neuroimaging studies have examined chronic schizophrenia patients on long-term neuroleptic treatment. In addition, they have used thicker MRI slices, which might have resulted in potential partial volume effects. In an attempt to avoid these potential confounds and to examine the status of brain structure in Indian schizophrenia patients, MRI and MRS studies using 1 mm slices (compared to 3 and 5 mm slices used in most of the western studies) were performed on antipsychotic-naïve, first contact schizophrenia patients in comparison with age, sex, education, handedness matched healthy volunteers were performed at the National Institute of Mental Health and Neurosciences, Bangalore. These studies have examined the following brain structures using semi-automated morphometric techniques in antipsychotic-naïve schizophrenia patients in comparison with matched healthy subjects:Corpus callosum45–47Cerebellar vermisCaudate nucleus50Very recently, another Indian study has utilized a fully automated, unbiased brain image analysis technique called Voxel Based Morphometry (VBM) to examine antipsychotic-naïve Indian schizophrenia patients. Further,52et al.[The areas of CC and cerebellar vermis were found to be smaller in patients when compared with controls. This is et al. The CC aet al.45 In addet al.50 A receet al.31P MRS were limited and produced conflicting findings, perhaps due to differences in the MRS methodology and medication status of the patients studied among other reasons. A 31P MRS study examining basal ganglia metabolism in antipsychotic-naïve Indian schizophrenia patients showed statistically significant decreased phosphocreatine/total phosphorous and phosphocreatine/total ATP ratios in both basal ganglia of the patient group as compared to the matched normal subjects suggesting increased metabolism in the basal ganglia.[Earlier efforts at detecting metabolic changes in the striatum with  ganglia. These me ganglia. Another  ganglia. A recent ganglia.None of these brain structural abnormalities had significant correlation with illness duration pointing towards nonprogressive probably developmental pathogenesis. The observation of these brain structural abnormalities at the time of illness onset prior to the antipsychotic treatment and lack of correlation with illness duration supports neurodevelopmental pathogenesis in schizophrenia.Neurophenomenology proposes that the phenomenological accounts of the structure of experience and their counterparts in cognitive science relate to each other through reciprocal constraints.Such a phenomenological approach that is informed by neuroscience would help in synthesizing neurocognitive models of schizophrenia. Perhaps the most widely cited and influential of these is the neurocognitive model proposed by Christopher Frith. This modInterestingly, both these brain areas  are among those that have been reported to be at high risk for being affected by neurodevelopmental insult. Frontal lobe one of the important neo-cortical area is also among the latest to mature and hence is at high risk for neurodevelopmental insult. The func64In addition to positive and negative symptoms, obsessive-compulsive symptoms in schizophrenia might also indicate neurodevelopmental insult. Schizophrenia patients with obsessive-compulsive symptoms have been reported to have significantly earlier AAO that those without obsessive-compulsive symptoms. Obsessiv66In conclusion, selective review of relevant studies shows schizophrenia patients to have more MPAs, NSS, CSS, structural and neurochemical brain abnormalities in comparison with matched healthy controls. Neurophenomenological correlates of schizophrenia point towards abnormalities involving brain regions that are at high risk for neurodevelopmental insult. Observation of these abnormalities in multiple domains of aberrant neurodevelopmental indicators with lack of correlation with illness duration strongly suggests neurodevelopmental etiopathogenesis in schizophrenia.Future studies are required in the following areas to establish and explore the clinical utility of neurodevelopmental model of schizophrenia:Longitudinal studies to elucidate the exact trajectorial profile of these brain changes;Studies on high risk subjects to examine for the predictive validity of clinical  and brain structural indicators of aberrant neurodevelopment with relevance to the future occurrence of psychosis;Pharmacological imaging studies to explore the potential and the neural basis for the beneficial effects of novel molecules  in improving the course and possibly to prevent the onset of schizophrenia.While these “ontogeny” related studies might help in understanding the “proximal” mechanisms of schizophrenia pathogenesis, it is important that the “distal” mechanisms need to be understood. Thus, one needs to apply the principles of “evolutionary psychiatry” to enable comprehensive understanding of the “Human Ontogenic and Phylogenic Evolutionary” basis of schizophrenia.