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1.  Why Are Medical and Health-Related Studies Not Being Published? A Systematic Review of Reasons Given by Investigators 
PLoS ONE  2014;9(10):e110418.
About half of medical and health-related studies are not published. We conducted a systematic review of reports on reasons given by investigators for not publishing their studies in peer-reviewed journals.
MEDLINE, EMBASE, PsycINFO, and SCOPUS (until 13/09/2013), and references of identified articles were searched to identify reports of surveys that provided data on reasons given by investigators for not publishing studies. The proportion of non-submission and reasons for non-publication was calculated using the number of unpublished studies as the denominator. Because of heterogeneity across studies, quantitative pooling was not conducted. Exploratory subgroup analyses were conducted.
We included 54 survey reports. Data from 38 included reports were available to estimate proportions of at least one reason given for not publishing studies. The proportion of non-submission among unpublished studies ranged from 55% to 100%, with a median of 85%. The reasons given by investigators for not publishing their studies included: lack of time or low priority (median 33%), studies being incomplete (median 15%), study not for publication (median 14%), manuscript in preparation or under review (median 12%), unimportant or negative result (median 12%), poor study quality or design (median 11%), fear of rejection (median 12%), rejection by journals (median 6%), author or co-author problems (median 10%), and sponsor or funder problems (median 9%). In general, the frequency of reasons given for non-publication was not associated with the source of unpublished studies, study design, or time when a survey was conducted.
Non-submission of studies for publication remains the main cause of non-publication of studies. Measures to reduce non-publication of studies and alternative models of research dissemination need to be developed to address the main reasons given by investigators for not publishing their studies, such as lack of time or low priority and fear of being rejected by journals.
PMCID: PMC4198242  PMID: 25335091
2.  Supplemental plant sterols and stanols for serum cholesterol and cardiovascular disease 
This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effects of phytosterols, phytostanols or their esters, ingested in supplemented foods, on blood cholesterol concentrations and cardiovascular disease;To look for adverse effects e.g. on nutritional status or physiological function;To study/comment on, possible effects of cost.
PMCID: PMC4178528  PMID: 25278808
3.  Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases 
This is the protocol for a review and there is no abstract. The objectives are as follows:
The primary objective is to determine the effectiveness of i) advice to increase fruit and vegetable consumption ii) the provision of fruit and vegetables to increase consumption, for the primary prevention of CVD.
PMCID: PMC4176664  PMID: 25267919
4.  Omega 3 fatty acids for prevention and treatment of cardiovascular disease 
It has been suggested that omega 3 (W3, n-3 or omega-3) fats from oily fish and plants are beneficial to health.
To assess whether dietary or supplemental omega 3 fatty acids alter total mortality, cardiovascular events or cancers using both RCT and cohort studies.
Search methods
Five databases including CENTRAL, MEDLINE and EMBASE were searched to February 2002. No language restrictions were applied. Bibliographies were checked and authors contacted.
Selection criteria
RCTs were included where omega 3 intake or advice was randomly allocated and unconfounded, and study duration was at least six months. Cohorts were included where a cohort was followed up for at least six months and omega 3 intake estimated.
Data collection and analysis
Studies were assessed for inclusion, data extracted and quality assessed independently in duplicate. Random effects meta-analysis was performed separately for RCT and cohort data.
Main results
Forty eight randomised controlled trials (36,913 participants) and 41 cohort analyses were included. Pooled trial results did not show a reduction in the risk of total mortality or combined cardiovascular events in those taking additional omega 3 fats (with significant statistical heterogeneity). Sensitivity analysis, retaining only studies at low risk of bias, reduced heterogeneity and again suggested no significant effect of omega 3 fats.
Restricting analysis to trials increasing fish-based omega 3 fats, or those increasing short chain omega 3s, did not suggest significant effects on mortality or cardiovascular events in either group. Subgroup analysis by dietary advice or supplementation, baseline risk of CVD or omega 3 dose suggested no clear effects of these factors on primary outcomes.
Neither RCTs nor cohorts suggested increased relative risk of cancers with higher omega 3 intake but estimates were imprecise so a clinically important effect could not be excluded.
Authors’ conclusions
It is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population. There is no evidence we should advise people to stop taking rich sources of omega 3 fats, but further high quality trials are needed to confirm suggestions of a protective effect of omega 3 fats on cardiovascular health.
There is no clear evidence that omega 3 fats differ in effectiveness according to fish or plant sources, dietary or supplemental sources, dose or presence of placebo.
PMCID: PMC4170890  PMID: 15495044
*Dietary Supplements; Cardiovascular Diseases [*diet therapy; mortality; prevention & control]; Fatty Acids, Omega-3 [*therapeutic use]; Randomized Controlled Trials as Topic; Humans
5.  Reduced or modified dietary fat for preventing cardiovascular disease 
Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol), but their effects on important health outcomes are less clear.
To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration.
Search methods
For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, were searched through to June 2010. References of Included studies and reviews were also checked.
Selection criteria
Trials fulfilled the following criteria: 1) randomised with appropriate control group, 2) intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions), 3) not multi factorial, 4) adult humans with or without cardiovascular disease, 5) intervention at least six months, 6) mortality or cardiovascular morbidity data available.
Data collection and analysis
Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed.
Main results
This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I2 50%). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides), of at least two years duration and in studies of men (not of women). There were no clear effects of dietary fat changes on total mortality (RR 0.98, 95% CI 0.93 to 1.04, 71,790 participants) or cardiovascular mortality (RR 0.94, 95% CI 0.85 to 1.04, 65,978 participants). This did not alter with sub-grouping or sensitivity analysis.
Few studies compared reduced with modified fat diets, so direct comparison was not possible.
Authors’ conclusions
The findings are suggestive of a small but potentially important reduction in cardiovascular risk on modification of dietary fat, but not reduction of total fat, in longer trials. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups, should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturates. The ideal type of unsaturated fat is unclear.
PMCID: PMC4163969  PMID: 21735388
*Diet, Fat-Restricted; Cardiovascular Diseases [epidemiology; *prevention & control]; Dietary Fats [administration & dosage]; Randomized Controlled Trials as Topic; Risk Factors; Adult; Aged; Humans; Middle Aged
6.  Reduced dietary salt for the prevention of cardiovascular disease 
An earlier Cochrane review of dietary advice identified insufficient evidence to assess effects of reduced salt intake on mortality or cardiovascular events.
To assess the long term effects of interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity.
To investigate whether blood pressure reduction is an explanatory factor in any effect of such dietary interventions on mortality and cardiovascular outcomes.
Search methods
The Cochrane Library (CENTRAL, Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effect (DARE)), MEDLINE, EMBASE, CINAHL and PsycInfo were searched through to October 2008. References of included studies and reviews were also checked. No language restrictions were applied.
Selection criteria
Trials fulfilled the following criteria: (1) randomised with follow up of at least six-months, (2) intervention was reduced dietary salt (restricted salt dietary intervention or advice to reduce salt intake), (3) adults, (4) mortality or cardiovascular morbidity data was available. Two reviewers independently assessed whether studies met these criteria.
Data collection and analysis
Data extraction and study validity were compiled by a single reviewer, and checked by a second. Authors were contacted where possible to obtain missing information. Events were extracted and relative risks (RRs) and 95% CIs calculated.
Main results
Six studies (including 6,489 participants) met the inclusion criteria - three in normotensives (n=3518), two in hypertensives (n=758), and one in a mixed population of normo- and hypertensives (n=1981) with end of trial follow-up of seven to 36 months and longest observational follow up (after trial end) to 12.7 yrs. Relative risks for all cause mortality in normotensives (end of trial RR 0.67, 95% CI: 0.40 to 1.12, 60 deaths; longest follow up RR 0.90, 95% CI: 0.58 to 1.40, 79 deaths) and hypertensives (end of trial RR 0.97, 95% CI: 0.83 to 1.13, 513 deaths; longest follow up RR 0.96, 95% CI; 0.83 to 1.11, 565 deaths) showed no strong evidence of any effect of salt reduction. Cardiovascular morbidity in people with normal blood pressure (longest follow-up RR 0.71, 95% CI: 0.42 to 1.20, 200 events) or raised blood pressure at baseline (end of trial RR 0.84, 95% CI: 0.57 to 1.23, 93 events) also showed no strong evidence of benefit. We found no information on participants health-related quality of life.
Authors’ conclusions
Despite collating more event data than previous systematic reviews of randomised controlled trials (665 deaths in some 6,250 participants), there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or cardiovascular morbidity in normotensive or hypertensive populations. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small blood pressure reduction achieved.
PMCID: PMC4160847  PMID: 21735439
*Diet, Sodium-Restricted; Cardiovascular Diseases [mortality; *prevention & control]; Randomized Controlled Trials as Topic; Sodium Chloride, Dietary [*administration & dosage]; Adult; Humans
7.  Accuracy of prediction equations for serum osmolarity in frail older people with and without diabetes1234 
Background: Serum osmolality is an accurate indicator of hydration status in older adults. Glucose, urea, and electrolyte concentrations are used to calculate serum osmolarity, which is an indirect estimate of serum osmolality, but which serum osmolarity equations best predict serum osmolality in the elderly is unclear.
Objective: We assessed the agreement of measured serum osmolality with calculated serum osmolarity equations in older people.
Design: Serum osmolality was measured by using freezing point depression in a cross-sectional study. Plasma glucose, urea, and electrolytes were analyzed and entered into 38 serum osmolarity-prediction equations. The Bland-Altman method was used to evaluate the agreement and differential bias between measured osmolality and calculated osmolarity. The sensitivity and specificity of the most-promising equations were examined against serum osmolality (reference standard).
Results: A total of 186 people living in UK residential care took part in the Dehydration Recognition In our Elders study (66% women; mean ± SD age: 85.8 ± 7.9 y; with a range of cognitive and physical impairments) and were included in analyses. Forty-six percent of participants had impending or current dehydration (serum osmolality ≥295 mmol/kg). Participants with diabetes (n = 33; 18%) had higher glucose (P < 0.001) and serum osmolality (P < 0.01). Of 38 predictive equations used to calculate osmolarity, 4 equations showed reasonable agreement with measured osmolality. One [calculated osmolarity = 1.86 × (Na+ + K+) + 1.15 × glucose + urea +14; all in mmol/L] was characterized by narrower limits of agreement and the capacity to predict serum osmolality within 2% in >80% of participants, regardless of diabetes or hydration status. The equation's sensitivity (79%) and specificity (89%) for impending dehydration (≥295 mmol/kg) and current dehydration (>300 mmol/kg) (69% and 93%, respectively) were reasonable.
Conclusions: The assessment of a panel of equations for the prediction of serum osmolarity led to identification of one formula with a greater diagnostic performance. This equation may be used to predict hydration status in frail older people (as a first-stage screening) or to estimate hydration status in population studies. This trial was registered at the Research Register for Social Care ( as 122273.
PMCID: PMC4135495  PMID: 25030781
10.  The diagnostic accuracy of multi-frequency bioelectrical impedance analysis in diagnosing dehydration after stroke 
Non-invasive methods for detecting water-loss dehydration following acute stroke would be clinically useful. We evaluated the diagnostic accuracy of multi-frequency bioelectrical impedance analysis (MF-BIA) against reference standards serum osmolality and osmolarity.
Patients admitted to an acute stroke unit were recruited. Blood samples for electrolytes and osmolality were taken within 20 minutes of MF-BIA. Total body water (TBW%), intracellular (ICW%) and extracellular water (ECW%), as percentages of total body weight, were calculated by MF-BIA equipment and from impedance measures using published equations for older people. These were compared to hydration status (based on serum osmolality and calculated osmolarity). The most promising Receiver Operating Characteristics curves were plotted.
27 stroke patients were recruited (mean age 71.3, SD10.7). Only a TBW% cut-off at 46% was consistent with current dehydration (serum osmolality >300 mOsm/kg) and TBW% at 47% impending dehydration (calculated osmolarity ≥295–300 mOsm/L) with sensitivity and specificity both >60%. Even here diagnostic accuracy of MF-BIA was poor, a third of those with dehydration were wrongly classified as hydrated and a third classified as dehydrated were well hydrated. Secondary analyses assessing diagnostic accuracy of TBW% for men and women separately, and using TBW as a percentage of lean body mass showed some promise, but did not provide diagnostically accurate measures across the population.
MF-BIA appears ineffective at diagnosing water-loss dehydration after stroke and cannot be recommended as a test for dehydration, but separating assessment by sex, and using TBW as a percentage of lean body weight may warrant further investigation.
PMCID: PMC3711909  PMID: 23839255
dehydration; electric impedance; osmolar concentration; body water; sensitivity and specificity; serum osmolality
11.  Climate Change and Food Security: Health Impacts in Developed Countries 
Environmental Health Perspectives  2012;120(11):1520-1526.
Background: Anthropogenic climate change will affect global food production, with uncertain consequences for human health in developed countries.
Objectives: We investigated the potential impact of climate change on food security (nutrition and food safety) and the implications for human health in developed countries.
Methods: Expert input and structured literature searches were conducted and synthesized to produce overall assessments of the likely impacts of climate change on global food production and recommendations for future research and policy changes.
Results: Increasing food prices may lower the nutritional quality of dietary intakes, exacerbate obesity, and amplify health inequalities. Altered conditions for food production may result in emerging pathogens, new crop and livestock species, and altered use of pesticides and veterinary medicines, and affect the main transfer mechanisms through which contaminants move from the environment into food. All these have implications for food safety and the nutritional content of food. Climate change mitigation may increase consumption of foods whose production reduces greenhouse gas emissions. Impacts may include reduced red meat consumption (with positive effects on saturated fat, but negative impacts on zinc and iron intake) and reduced winter fruit and vegetable consumption. Developed countries have complex structures in place that may be used to adapt to the food safety consequences of climate change, although their effectiveness will vary between countries, and the ability to respond to nutritional challenges is less certain.
Conclusions: Climate change will have notable impacts upon nutrition and food safety in developed countries, but further research is necessary to accurately quantify these impacts. Uncertainty about future impacts, coupled with evidence that climate change may lead to more variable food quality, emphasizes the need to maintain and strengthen existing structures and policies to regulate food production, monitor food quality and safety, and respond to nutritional and safety issues that arise.
PMCID: PMC3556605  PMID: 23124134
adaptation; climate change; food safety; food security; nutrition; regulation
12.  The effectiveness of manual stretching in the treatment of plantar heel pain: a systematic review 
Plantar heel pain is a commonly occurring foot complaint. Stretching is frequently utilised as a treatment, yet a systematic review focusing only on its effectiveness has not been published. This review aimed to assess the effectiveness of stretching on pain and function in people with plantar heel pain.
Medline, EMBASE, CINAHL, AMED, and The Cochrane Library were searched from inception to July 2010. Studies fulfilling the inclusion criteria were independently assessed, and their quality evaluated using the modified PEDro scale.
Six studies including 365 symptomatic participants were included. Two compared stretching with a control, one study compared stretching to an alternative intervention, one study compared stretching to both alternative and control interventions, and two compared different stretching techniques and durations. Quality rating on the modified Pedro scale varied from two to eight out of a maximum of ten points. The methodologies and interventions varied significantly between studies, making meta-analysis inappropriate. Most participants improved over the course of the studies, but when stretching was compared to alternative or control interventions, the changes only reached statistical significance in one study that used a combination of calf muscle stretches and plantar fascia stretches in their stretching programme. Another study comparing different stretching techniques, showed a statistically significant reduction in some aspects of pain in favour of plantar fascia stretching over calf stretches in the short term.
There were too few studies to assess whether stretching is effective compared to control or other interventions, for either pain or function. However, there is some evidence that plantar fascia stretching may be more effective than Achilles tendon stretching alone in the short-term. Appropriately powered randomised controlled trials, utilizing validated outcome measures, blinded assessors and long-term follow up are needed to assess the efficacy of stretching.
PMCID: PMC3150253  PMID: 21703003
13.  A survey of orthopaedic journal editors determining the criteria of manuscript selection for publication 
To investigate the characteristics of editors and criteria used by orthopaedic journal editors in assessing submitted manuscripts.
Between 2008 to 2009 all 70 editors of Medline listed orthopaedic journals were approached prospectively with a questionnaire to determine the criteria used in assessing manuscripts for publication.
There was a 42% response rate. There was 1 female editor and the rest were male with 57% greater than 60 years of age. 67% of the editors worked in university teaching hospitals and 90% of publications were in English.
The review process differed between journals with 59% using a review proforma, 52% reviewing an anonymised manuscript, 76% using a routine statistical review and 59% of journals used 2 reviewers routinely. In 89% of the editors surveyed, the editor was able to overrule the final decision of the reviewers.
Important design factors considered for manuscript acceptance were that the study conclusions were justified (80%), that the statistical analysis was appropriate (76%), that the findings could change practice (72%). The level of evidence (70%) and type of study (62%) were deemed less important. When asked what factors were important in the manuscript influencing acceptance, 73% cited an understandable manuscript, 53% cited a well written manuscript and 50% a thorough literature review as very important factors.
The editorial and review process in orthopaedic journals uses different approaches. There may be a risk of language bias among editors of orthopaedic journals with under-representation of non-English publications in the orthopaedic literature.
PMCID: PMC3095562  PMID: 21527007
editor; orthopaedic
14.  Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials 
Human Reproduction Update  2010;16(6):745-760.
Isoflavones from soy and red clover exert modest hormonal effects in women, but the relevance to risk of breast cancer is unclear. The aim of this meta-analysis was to assess the effects of isoflavone-rich foods or supplements on a biomarker of breast cancer risk, women's mammographic density.
Electronic searches were performed on The Cochrane Library, Medline and EMBASE (to June 2009), and reference lists and trial investigators were consulted to identify further studies. Randomized controlled trials (RCTs) of isoflavone-rich foods or supplements versus placebo with a duration of at least 6 months were included in our analysis. Inclusion/exclusion, data extraction and validity assessment were carried out independently in duplicate, and meta-analysis used to pool study results. Subgrouping, sensitivity analysis, assessment of heterogeneity and funnel plots were used to interpret the results.
Eight RCTs (1287 women) compared isoflavones with placebo for between 6 months and 3 years. Meta-analysis suggested no overall effect of dietary isoflavones on breast density in all women combined [mean difference (MD) 0.69%, 95% confidence interval (CI) −0.78 to 2.17] or post-menopausal women (MD −1.10%, 95% CI −3.22 to 1.03). However, there was a modest increase in mammographic density in premenopausal women (MD 1.83%, 95% CI 0.25–3.40) without heterogeneity but this effect was lost in one of three sensitivity analyses.
Isoflavone intake does not alter breast density in post-menopausal women, but may cause a small increase in breast density in premenopausal women. Larger, long-term trials are required to determine if these small effects are clinically relevant.
PMCID: PMC2953939  PMID: 20511398
isoflavone; mammographic density; breast cancer risk; meta-analysis; menopause
15.  Health, wellbeing and nutritional status of older people living in UK care homes: an exploratory evaluation of changes in food and drink provision 
BMC Geriatrics  2010;10:28.
Food and drink are important determinants of physical and social health in care home residents. This study explored whether a pragmatic methodology including routinely collected data was feasible in UK care homes, to describe the health, wellbeing and nutritional status of care home residents and assess effects of changed provision of food and drink at three care homes on residents' falls (primary outcome), anaemia, weight, dehydration, cognitive status, depression, lipids and satisfaction with food and drink provision.
We measured health, wellbeing and nutritional status of 120 of 213 residents of six care homes in Norfolk, UK. An intervention comprising improved dining atmosphere, greater food choice, extended restaurant hours, and readily available snacks and drinks machines was implemented in three care homes. Three control homes maintained their previous system. Outcomes were assessed in the year before and the year after the changes.
Use of routinely collected data was partially successful, but loss to follow up and levels of missing data were high, limiting power to identify trends in the data.
This was a frail older population (mean age 87, 71% female) with multiple varied health problems. During the first year 60% of residents had one or more falls, 40% a wound care visit, and 40% a urinary tract infection. 45% were on diuretics, 24% antidepressants, and 43% on psychotropic medication.
There was a slight increase in falls from year 1 to year 2 in the intervention homes, and a much bigger increase in control homes, leading to a statistically non-significant 24% relative reduction in residents' rate of falls in intervention homes compared with control homes (adjusted rate ratio 0.76, 95% CI 0.57 to 1.02, p = 0.06).
Care home residents are frail and experience multiple health risks. This intervention to improve food and drink provision was well received by residents, but effects on health indicators (despite the relative reduction in falls rate) were inconclusive, partly due to problems with routine data collection and loss to follow up. Further research with more homes is needed to understand which, if any, components of the intervention may be successful.
Trial registration
Trial registration: ISRCTN86057119.
PMCID: PMC2890011  PMID: 20507560
16.  The impact of subacromial impingement syndrome on muscle activity patterns of the shoulder complex: a systematic review of electromyographic studies 
Subacromial impingement syndrome (SIS) is a commonly reported cause of shoulder pain. The purpose of this study was to systematically review the literature to examine whether a difference in electromyographic (EMG) activity of the shoulder complex exists between people with SIS and healthy controls.
Medline, CINAHL, AMED, EMBASE, and grey literature databases were searched from their inception to November 2008. Inclusion, data extraction and trial quality were assessed in duplicate.
Nine studies documented in eleven papers, eight comparing EMG intensity and three comparing EMG onset timing, representing 141 people with SIS and 138 controls were included. Between one and five studies investigated each muscle totalling between 20 and 182 participants. The two highest quality studies of five report a significant increase in EMG intensity in upper trapezius during scaption in subjects with SIS. There was evidence from 2 studies of a delayed activation of lower trapezius in patients with SIS. There was otherwise no evidence of a consistent difference in EMG activity between the shoulders of subjects with painful SIS and healthy controls.
A difference may exist in EMG activity within some muscles, in particular upper and lower trapezius, between people with SIS and healthy controls. These muscles may be targets for clinical interventions aiding rehabilitation for people with SIS. These differences should be investigated in a larger, high quality survey and the effects of therapeutically targeting these muscles in a randomised controlled trial.
PMCID: PMC2846868  PMID: 20214817
17.  The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis 
Nutrition Journal  2010;9:4.
In observational studies anaemia and iron deficiency are associated with cognitive deficits, suggesting that iron supplementation may improve cognitive function. However, due to the potential for confounding by socio-economic status in observational studies, this needs to be verified in data from randomised controlled trials (RCTs).
To assess whether iron supplementation improved cognitive domains: concentration, intelligence, memory, psychomotor skills and scholastic achievement.
Searches included MEDLINE, EMBASE, PsychINFO, Cochrane CENTRAL and bibliographies (to November 2008). Inclusion, data extraction and validity assessment were duplicated, and the meta-analysis used the standardised mean difference (SMD). Subgrouping, sensitivity analysis, assessment of publication bias and heterogeneity were employed.
Fourteen RCTs of children aged 6+, adolescents and women were included; no RCTs in men or older people were found. Iron supplementation improved attention and concentration irrespective of baseline iron status (SMD 0.59, 95% CI 0.29 to 0.90) without heterogeneity. In anaemic groups supplementation improved intelligence quotient (IQ) by 2.5 points (95% CI 1.24 to 3.76), but had no effect on non-anaemic participants, or on memory, psychomotor skills or scholastic achievement. However, the funnel plot suggested modest publication bias. The limited number of included studies were generally small, short and methodologically weak.
There was some evidence that iron supplementation improved attention, concentration and IQ, but this requires confirmation with well-powered, blinded, independently funded RCTs of at least one year's duration in different age groups including children, adolescents, adults and older people, and across all levels of baseline iron status.
PMCID: PMC2831810  PMID: 20100340
18.  The expressed needs of people with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A systematic review 
BMC Public Health  2009;9:458.
We aimed to review systematically the needs for support in managing illness and maintaining social inclusion expressed by people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
We carried out a systematic review of primary research and personal ('own') stories expressing the needs of people with CFS/ME. Structured searches were carried out on Medline, AMED, CINAHL, EMBASE, ASSIA, CENTRAL, and other health, social and legal databases from inception to November 2007. Study inclusion, data extraction and risk of bias were assessed independently in duplicate. Expressed needs were tabulated and a conceptual framework developed through an iterative process.
Thirty two quantitative and qualitative studies, including the views of over 2500 people with CFS/ME with mainly moderate or severe illness severity, met the inclusion criteria. The following major support needs emerged: 1) The need to make sense of symptoms and gain diagnosis, 2) for respect and empathy from service providers, 3) for positive attitudes and support from family and friends, 4) for information on CFS/ME, 5) to adjust views and priorities, 6) to develop strategies to manage impairments and activity limitations, and 7) to develop strategies to maintain/regain social participation.
Although the studies were heterogeneous, there was consistent evidence that substantial support is needed to rebuild lives. Gaining support depends - most importantly - on the ability of providers of health and social care, colleagues, friends and relatives, and those providing educational and leisure services, to understand and respond to those needs.
PMCID: PMC2799412  PMID: 20003363
19.  Extent of publication bias in different categories of research cohorts: a meta-analysis of empirical studies 
The validity of research synthesis is threatened if published studies comprise a biased selection of all studies that have been conducted. We conducted a meta-analysis to ascertain the strength and consistency of the association between study results and formal publication.
The Cochrane Methodology Register Database, MEDLINE and other electronic bibliographic databases were searched (to May 2009) to identify empirical studies that tracked a cohort of studies and reported the odds of formal publication by study results. Reference lists of retrieved articles were also examined for relevant studies. Odds ratios were used to measure the association between formal publication and significant or positive results. Included studies were separated into subgroups according to starting time of follow-up, and results from individual cohort studies within the subgroups were quantitatively pooled.
We identified 12 cohort studies that followed up research from inception, four that included trials submitted to a regulatory authority, 28 that assessed the fate of studies presented as conference abstracts, and four cohort studies that followed manuscripts submitted to journals. The pooled odds ratio of publication of studies with positive results, compared to those without positive results (publication bias) was 2.78 (95% CI: 2.10 to 3.69) in cohorts that followed from inception, 5.00 (95% CI: 2.01 to 12.45) in trials submitted to regulatory authority, 1.70 (95% CI: 1.44 to 2.02) in abstract cohorts, and 1.06 (95% CI: 0.80 to 1.39) in cohorts of manuscripts.
Dissemination of research findings is likely to be a biased process. Publication bias appears to occur early, mainly before the presentation of findings at conferences or submission of manuscripts to journals.
PMCID: PMC2789098  PMID: 19941636
20.  Primary prevention of CVD: diet and weight loss 
Clinical Evidence  2007;2007:0219.
Key Points
Diet is an important cause of many chronic diseases. Individual change in behaviour has the potential to decrease the burden of chronic disease, particularly cardiovascular disease (CVD).This review focuses on the evidence that specific interventions to improve diet and increase weight loss lead to changed behaviour, and that these changes may prevent CVD.
Intensive advice to healthy people to reduce sodium intake reduces sodium intake, as measured by sodium excretion.
Reducing sodium intake reduces blood pressure, even in people without hypertension.
Advice to reduce saturated fat intake may reduce the saturated fat intake, and multiple advice components reduce saturated fat intake more.
Reducing saturated fat intake can reduce mortality in the longer term.
Complex combined interventions to lose weight (physical plus dietary plus behavioural) are effective in helping people lose weight. Simpler interventions are less effective. We don't know what lifestyle interventions can maintain weight loss or what lifestyle interventions prevent weight gain, or if training health professionals is effective in promoting weight loss.We don't know whether diets and behavioural interventions to lose weight reduce the risk of cardiovascular disease.
Increasing fruit and vegetable intake may decrease the risk of cardiovascular disease. We don't know whether advising people to increase their fruit and vegetable intake will actually increase their intake.
Taking a high dose of antioxidant supplements (vitamin E and beta carotene) does not reduce mortality or cardiovascular events.
We don't know whether omega 3 oil supplementation or advice to increase omega 3 intake can reduce mortality.
We also don't know how effective a Mediterranean diet is at reducing cardiovascular events or deaths in the general population.
PMCID: PMC2943801  PMID: 19450364
21.  Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review 
BMJ : British Medical Journal  2006;332(7544):752-760.
Objective To review systematically the evidence for an effect of long chain and shorter chain omega 3 fatty acids on total mortality, cardiovascular events, and cancer.
Data sources Electronic databases searched to February 2002; authors contacted and bibliographies of randomised controlled trials (RCTs) checked to locate studies.
Review methods Review of RCTs of omega 3 intake for 3 6 months in adults (with or without risk factors for cardiovascular disease) with data on a relevant outcome. Cohort studies that estimated omega 3 intake and related this to clinical outcome during at least 6 months were also included. Application of inclusion criteria, data extraction, and quality assessments were performed independently in duplicate.
Results Of 15 159 titles and abstracts assessed, 48 RCTs (36 913 participants) and 41 cohort studies were analysed. The trial results were inconsistent. The pooled estimate showed no strong evidence of reduced risk of total mortality (relative risk 0.87, 95% confidence interval 0.73 to 1.03) or combined cardiovascular events (0.95, 0.82 to 1.12) in participants taking additional omega 3 fats. The few studies at low risk of bias were more consistent, but they showed no effect of omega 3 on total mortality (0.98, 0.70 to 1.36) or cardiovascular events (1.09, 0.87 to 1.37). When data from the subgroup of studies of long chain omega 3 fats were analysed separately, total mortality (0.86, 0.70 to 1.04; 138 events) and cardiovascular events (0.93, 0.79 to 1.11) were not clearly reduced. Neither RCTs nor cohort studies suggested increased risk of cancer with a higher intake of omega 3 (trials: 1.07, 0.88 to 1.30; cohort studies: 1.02, 0.87 to 1.19), but clinically important harm could not be excluded.
Conclusion Long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer.
PMCID: PMC1420708  PMID: 16565093
22.  The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review 
BMJ : British Medical Journal  2004;329(7472):948.
Objectives To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)—H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs—in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life.
Data sources The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included.
Review methods Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or no review outcomes were measured. Quality assessment included allocation concealment and baseline similarity.
Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed.
Results Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter).
Conclusions Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
PMCID: PMC524106  PMID: 15475342
23.  Systematic review of long term effects of advice to reduce dietary salt in adults 
BMJ : British Medical Journal  2002;325(7365):628.
To assess the long term effects of advice to restrict dietary sodium in adults with and without hypertension.
Systematic review and meta-analysis of randomised controlled trials.
Data sources
Cochrane library, Medline, Embase, and bibliographies.
Study selection
Unconfounded randomised trials that aimed to reduce sodium intake in healthy adults over at least 6 months. Inclusion decisions, validity and data extraction were duplicated. Random effects meta-analysis, subgrouping, sensitivity analysis, and meta-regression were performed.
Mortality, cardiovascular events, blood pressure, urinary sodium excretion, quality of life, and use of antihypertensive drugs.
Three trials in normotensive people (n=2326), five trials in those with untreated hypertension (n=387), and three trials in people being treated for hypertension (n=801) were included, with follow up from six months to seven years. The large high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported. There were 17 deaths, equally distributed between intervention and control groups. Systolic and diastolic blood pressures were reduced (systolic by 1.1 mm Hg, 95% confidence interval 1.8 to 0.4 mm Hg; diastolic by 0.6 mm Hg, 1.5 to −0.3 mm Hg) at 13 to 60 months, as was urinary 24 hour sodium excretion (by 35.5 mmol/24 hours, 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related.
Intensive interventions, unsuited to primary care or population prevention programmes, provide only small reductions in blood pressure and sodium excretion, and effects on deaths and cardiovascular events are unclear. Advice to reduce sodium intake may help people on antihypertensive drugs to stop their medication while maintaining good blood pressure control.
What is already known on this topicRestricting sodium intake in people with hypertension reduces blood pressureLong term effects (on blood pressure, mortality, and morbidity) of reduced salt intake in people with and without hypertension are unclearWhat this study addsFew deaths and cardiovascular events have been reported in salt reduction trialsMeta-analysis shows that blood pressure was reduced (systolic by 1.1 mm Hg, diastolic by 0.6 mm Hg) at 13 to 60 months, with a reduction in sodium excretion of almost a quarter (35.5 mmol/24 hours)The interventions used were highly intensive and unsuited to primary care or population prevention programmesLower salt intake may help people on antihypertensive drugs to stop their medication while maintaining good control of blood pressure, but there are doubts about effects of sodium reduction on overall health
PMCID: PMC126303  PMID: 12242173
24.  Dietary fat intake and prevention of cardiovascular disease: systematic review 
BMJ : British Medical Journal  2001;322(7289):757-763.
To assess the effect of reduction or modification of dietary fat intake on total and cardiovascular mortality and cardiovascular morbidity.
Systematic review.
Data sources
Cochrane Library, Medline, Embase, CAB abstracts, SIGLE, CVRCT registry, and biographies were searched; trials known to experts were included.
Included studies
Randomised controlled trials stating intention to reduce or modify fat or cholesterol intake in healthy adult participants over at least six months. Inclusion decisions, validity, and data extraction were duplicated. Meta-analysis (random effects methodology), meta-regression, and funnel plots were performed.
27 studies (30 902 person years of observation) were included. Alteration of dietary fat intake had small effects on total mortality (rate ratio 0.98; 95% confidence interval 0.86 to 1.12). Cardiovascular mortality was reduced by 9% (0.91; 0.77 to 1.07) and cardiovascular events by 16% (0.84; 0.72 to 0.99), which was attenuated (0.86; 0.72 to 1.03) in a sensitivity analysis that excluded a trial using oily fish. Trials with at least two years' follow up provided stronger evidence of protection from cardiovascular events (0.76; 0.65 to 0.90).
There is a small but potentially important reduction in cardiovascular risk with reduction or modification of dietary fat intake, seen particularly in trials of longer duration.
What is already known on this topicThe epidemiological relation between dietary fat intake and cardiovascular disease is central in strategies aimed at risk reduction in populations and individualsSystematic review of randomised controlled trials supports manipulation of dietary fat to control serum lipid concentrations, though evidence of effect on one risk factor does not rule out an opposite or reinforced effect on another unstudied risk factorRandomised controlled trials of dietary fat reduction or modification have shown varying results on cardiovascular morbidity and mortalityWhat this study addsSystematic review of trials of modified fat intake shows that reduction or modification of dietary fat intake results in reductions in cardiovascular events, but only in trials of at least two years' durationThere is little effect on total mortalityDespite decades of effort and many thousands of people randomised, there is still only limited and inconclusive evidence of the effects of modification of total, saturated, monounsaturated, or polyunsaturated fats on cardiovascular morbidity and mortality
PMCID: PMC30550  PMID: 11282859
25.  Effect of reducing total fat intake on body weight: systematic review and meta-analysis of randomised controlled trials and cohort studies 
Objective To investigate the relation between total fat intake and body weight in adults and children.
Design Systematic review and meta-analysis of randomised controlled trials and cohort studies.
Data sources Medline, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials to June 2010.
Inclusion criteria Randomised controlled trials and cohort studies of adults or children that compared lower versus usual total fat intake and assessed the effects on measures of body fatness (body weight, body mass index, or waist circumference) after at least six months (randomised controlled trials) or one year (in cohorts). Randomised controlled trials with any intention to reduce weight in participants or confounded by additional medical or lifestyle interventions were excluded.
Data extraction Data were extracted and validity was assessed independently and in duplicate. Random effects meta-analyses, subgroups, sensitivity analyses, and metaregression were done.
Results 33 randomised controlled trials (73 589 participants) and 10 cohort studies were included, all from developed countries. Meta-analysis of data from the trials suggested that diets lower in total fat were associated with lower relative body weight (by 1.6 kg, 95% confidence interval −2.0 to −1.2 kg, I2=75%, 57 735 participants). Lower weight gain in the low fat arm compared with the control arm was consistent across trials, but the size of the effect varied. Metaregression suggested that greater reduction in total fat intake and lower baseline fat intake were associated with greater relative weight loss, explaining most of the heterogeneity. The significant effect of a low fat diet on weight was not lost in sensitivity analyses (including removing trials that expended greater time and attention on low fat groups). Lower total fat intake also led to lower body mass index (−0.51 kg/m2, 95% confidence interval −0.76 to −0.26, nine trials, I2=77%) and waist circumference (by 0.3 cm, 95% confidence interval −0.58 to −0.02, 15 671 women, one trial). There was no suggestion of negative effects on other cardiovascular risk factors (lipid levels or blood pressure). GRADE assessment suggested high quality evidence for the relation between total fat intake and body weight in adults. Only one randomised controlled trial and three cohort studies were found in children and young people, but these confirmed a positive relation between total fat intake and weight gain.
Conclusions There is high quality, consistent evidence that reduction of total fat intake has been achieved in large numbers of both healthy and at risk trial participants over many years. Lower total fat intake leads to small but statistically significant and clinically meaningful, sustained reductions in body weight in adults in studies with baseline fat intakes of 28-43% of energy intake and durations from six months to over eight years. Evidence supports a similar effect in children and young people.
PMCID: PMC3516671  PMID: 23220130

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