Cancer-related fatigue in patients treated with mistletoe extracts: a systematic review and meta-analysis.

PURPOSE: Cancer-related fatigue remains one of the most prevalent and distressing symptoms experienced by cancer patients. Effective treatments for cancer-related fatigue are needed. The objective of this meta-analysis is to determine the impact of mistletoe extracts as a pharmacological treatment for the management of cancer-related fatigue. METHODS: We included randomized clinical trials (RCTs) and non-randomized studies of interventions (NRSIs) in cancer patients. Inclusion criteria were cancer-related fatigue severity or prevalence as an outcome and testing of mistletoe extracts compared to control groups. We searched Medline (EuropePMC), Embase, the Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and opengrey.org through October 2020. We assessed the risk of bias using the Cochrane risk of bias tools for RCTs and NRSIs and conducted a meta-analysis. RESULTS: We performed one meta-analysis with 12 RCTs, including 1494 participants, and one meta-analysis with seven retrospective NRSIs, including 2668 participants. Heterogeneity between the studies was high in both meta-analyses. Most studies had a high risk of bias. A random-effects model showed for RCTs a standardized mean difference of -0.48 (95% confidence interval -0.82 to -0.14; p = 0.006) and for NRSIs an odds ratio of 0.36 (95% confidence interval 0.20 to 0.66; p = 0.0008). CONCLUSION: Treatment with mistletoe extracts shows a moderate effect on cancer-related fatigue of similar size to physical activity. These results need to be confirmed by more placebo-controlled trials. Future trials should investigate different treatment durations and their effect on cancer-related fatigue in post-treatment cancer survivors. TRIAL REGISTRATION: This meta-analysis has been registered under the PROSPERO registration number CRD42020191967 on October 7, 2020.

Searching for Real-World Effectiveness of Health Care Innovations: Scoping Study of Social Prescribing for Diabetes.

BACKGROUND: Social prescribing is a process whereby primary care patients are linked or referred to nonmedical sources of support in the community and voluntary sector. It is a concept that has arisen in practice and implemented widely in the United Kingdom and has been evaluated by various organizations. OBJECTIVE: The aim of our study was to characterize, collate, and analyze the evidence from evaluation of social prescribing for type 2 diabetes in the United Kingdom and Ireland, comparing information available on publicly available websites with the published literature. METHODS: We used a broad, pragmatic definition of social prescribing and conducted Web-based searches for websites of organizations providing potentially relevant services. We also explored linked information. In parallel, we searched Medline, PubMed, Cochrane Library, Google Scholar, and reference lists for relevant studies published in peer-reviewed journals. We extracted the data systematically on the characteristics, any reported evaluation, outcomes measured and results, and terminology used to describe each service. RESULTS: We identified 40 UK- or Ireland-based projects that referred people with type 2 diabetes and prediabetes to nonmedical interventions or services provided in the community. We located evaluations of 24 projects; 11 as published papers, 12 as Web-based reports, and 1 as both a paper and a Web-based report. The interventions and services identified included structured group educational programs, exercise referral schemes, and individualized advice and support with signposting of health-related activities in the community. Although specific interventions such as community-based group educational programs and exercise referral have been evaluated in randomized controlled trials, evaluation of individualized social prescribing services involving people with type 2 diabetes has, in most cases, used pre-post and mixed methods approaches. These evaluations report generic improvement in a broad range of outcomes and provide an insight into the criteria for the success of social prescribing services. CONCLUSIONS: Our study revealed the varied models of social prescribing and nonmedical, community-based services available to people with type 2 diabetes and the extent of evaluation of these, which would not have been achieved by searching databases alone. The findings of this scoping study do not prove that social prescribing is an effective measure for people with type 2 diabetes in the United Kingdom, but can be used to inform future evaluation and contribute to the development of the evidence base for social prescribing. Accessing Web-based information provides a potential method for investigating how specific innovative health concepts, such as social prescribing, have been translated, implemented, and evaluated in practice. Several challenges were encountered including defining the concept, focusing on process plus intervention, and searching diverse, evolving Web-based sources. Further exploration of this approach will inform future research on the application of innovative health care concepts into practice.

Quality of Life in Breast Cancer Patients Treated With Mistletoe Extracts: A Systematic Review and Meta-Analysis.

BACKGROUND: Breast cancer is the most common cancer type in women and quality of life an essential part of patients' well-being. Although the treatment with mistletoe extracts is covered by multiple cancer guidelines and reviews, it is uncertain whether mistletoe extracts can improve the quality of life in breast cancer patients. We therefore performed a systematic review and meta-analysis on this topic. METHODS: This systematic review included randomized clinical trials (RCTs) and non-randomized studies of intervention (NRSIs) comparing the quality of life in breast cancer patients treated with mistletoe extracts as add-on therapy to control groups treated conventionally. We searched previous systematic reviews and multiple databases until January 2023. We conducted a meta-analysis and assessed the risk of bias according to the Cochrane Handbook via RoB 2 and ROBINS-I and the certainty of evidence via GRADE, respectively. RESULTS: Nine RCTs and 7 NRSIs with 833 and 2831 participants, respectively, were included. The pre-post changes for the quality of life resulted in a pooled standardized mean difference for RCTs of SMD = 0.61 (95% CI 0.47-0.75; P < .0001) and for retrospective NRSIs of SMD = 0.46 (95% CI 0.10-0.82; P = .01). The risk of bias was low to high for the RCTs and serious for all NRSIs. The certainty of evidence was moderate for RCTs and very low for NRSIs. DISCUSSION: Our results indicate a clinically relevant, medium-sized effect of mistletoe extracts on the quality of life in breast cancer patients which may be based on the immunomodulating effects of mistletoe extracts during chemotherapy. The limitations of evidence include the risk of bias which is mainly caused by the difficulty of blinding. Further RCTs and real-world evidence need to confirm this result, especially in the setting of neoadjuvant chemotherapy and in breast cancer survivors.

Bibliography of Homeopathic Intervention Studies (HOMIS) in Human Diseases.

Objectives: Homeopathy (HOM) is a therapeutic method, which is widely used by patients and medical professionals. The medical conditions as well as the homeopathic medical products investigated vary strongly. There is an extensive amount of research, and this necessitates a bibliography that comprehensively presents the entire body of clinical evidence grouped according to medical conditions. Design: Thirty-seven online sources as well as print libraries were searched for HOM and related terms in eight languages (1980 to March 2021). We included studies that compared a homeopathic medicine or intervention with a control regarding the therapeutic or preventive outcome of a disease (classified according to International Classification of Diseases-10). The data were extracted independently by two reviewers and analyzed descriptively. Results: A total of 636 investigations met the inclusion criteria, of which 541 had a therapeutic and 95 a preventive purpose. Seventy-three percent were randomized controlled trials (n = 463), whereas the rest were non-randomized studies (n = 173). The leading comparator was placebo (n = 400). The type of homeopathic intervention was classified as multi-constituent or complex (n = 272), classical or individualized (n = 176), routine or clinical (n = 161) and isopathic (n = 19), or various (n = 8). The potencies ranged from 1X (dilution of -10,000) to 10 M (100-10.000). The included studies explored the effect of HOM in 223 medical indications. We present the evidence in an online database. Conclusions: This bibliography maps the status quo of clinical research in HOM. The data will serve for future targeted reviews, which may focus on the most studied conditions and/or homeopathic medicines, clinical impact, and the risk of bias of the included studies.

The combined effects of healthy lifestyle behaviors on all cause mortality: a systematic review and meta-analysis.

OBJECTIVE: Lifestyle factors are related to mortality. Although much is known about the impact of single factors, the current evidence about the combined effects of lifestyle behaviors on mortality has not yet been systematically compiled. METHOD: We searched Medline, Embase, Global Health, and Somed up to February 2012. Prospective studies were selected if they reported the combined effects of at least three of five lifestyle factors (obesity, alcohol consumption, smoking, diet, and physical activity). The mean effect sizes that certain numbers of combined lifestyle factors have on mortality were compared to the group with the least number of healthy lifestyle factors by meta-analysis. Sensitivity analyses were conducted to explore the robustness of the results. RESULTS: 21 studies (18 cohorts) met the inclusion criteria of which 15 were included in the meta-analysis that comprised 531,804 people with a mean follow-up of 13.24 years. The relative risks decreased proportionate to a higher number of healthy lifestyle factors for all cause mortality. A combination of at least four healthy lifestyle factors is associated with a reduction of the all cause mortality risk by 66% (95% confidence interval 58%-73%). CONCLUSION: Adherence to a healthy lifestyle is associated with a lower risk of mortality.

Copper and iron in Alzheimer's disease: a systematic review and its dietary implications.

Fe and Cu could represent dietary risk factors for Alzheimer's disease (AD), which has become a global health concern. To establish the relationship between diets high in Cu and Fe and cognitive decline or AD, we have conducted a systematic review of the literature (up to January 2011). We identified two meta-analyses, two systematic reviews, eleven placebo-controlled trials, five observational studies, forty-five case-control studies, thirty autopsy and five uncontrolled studies, and one case report. There were eleven interventional trials that tried to either supplement or deplete Fe and Cu, but none of them provided clear evidence of a beneficial effect on cognitive performance in patients with AD. The prospective studies revealed an association between a diet simultaneously high in SFA and Cu and cognitive decline. Case-control and autopsy studies showed elevated Fe levels in the brains of AD patients, whereas the evidence was less consistent for Cu. In most of the studies, Cu concentrations were unchanged in the cerebrospinal fluid and the brain but increased in the serum. In conclusion, the existing data suggest that diets excessive in Fe or Cu, together with a high intake of SFA, should be avoided in the elderly who are not at risk of anaemia. Basic studies and, building on this, clinical investigations are needed to further elucidate in which dietary patterns and in which patient groups an Fe- and Cu-rich diet might foster the risk of developing AD.

Zinc diet and Alzheimer's disease: a systematic review.

OBJECTIVES: This paper reviews evidence of an association between zinc (Zn) nutrition and Alzheimer's disease (AD) or age-associated cognitive decline. The involvement of zinc in the pathology of AD has been reported hundreds of times. It is, however, still a matter of debate whether the disease progression can be influenced by modifying zinc in the diet. METHODS: We searched Medline, Embase, Biosis, ALOIS, the Cochrane central register of controlled trials, the Cochrane database of systematic reviews, and different publisher databases, and included studies that dealt with zinc in the diet and AD or cognitive decline in elderly subjects. RESULTS: Fifty-five studies met the inclusion criteria. Neither randomized-controlled trials nor observational studies provide conclusive evidence whether Zn in the diet is associated with cognitive decline or AD. Case-control and autopsy studies suggest decreased systemic and increased brain Zn levels, respectively. DISCUSSION: The current state of evidence does not allow conclusions to be drawn on whether supplementation of Zn is beneficial for the prevention or treatment of AD, although a subclinical deficiency appears common in the elderly and subjects with AD. Dietary studies with animals suggest that the impact of dietary Zn on cognitive performance depend on additional nutrients. Further studies are necessary to determine whether Zn deficiency is a risk factor for AD in general terms or under certain dietary circumstances only.

Survival of Cancer Patients Treated with Non-Fermented Mistletoe Extract: A Systematic Review and Meta-Analysis.

BACKGROUND: Mistletoe extracts (ME) are used in integrative cancer care to improve quality of life and to prolong survival. ME are available from different producers and differ in pharmaceutical processing, such as fermentation. In contrast to fermented ME, the impact of unfermented extracts on the survival of cancer patients has not yet been assessed in a meta-analysis. METHODS: We searched the databases Embase, CENTRAL, Europe PMC, Clinicaltrials.gov, Opengrey and Google Scholar, and selected controlled studies on cancer patients treated with non-fermented ME. We included randomized controlled trials (RCTs) and non-randomized studies of intervention (NRSIs). The risk of bias was assessed with Cochrane's ROB2 and ROBINS-I; a meta-analysis was conducted. RESULTS: Eleven RCTs and eight NRSIs met the inclusion criteria. The studies were heterogeneous and their ROB2 and ROBINS-I displayed a moderate and high risk of bias, respectively. For RCTs, the pooled effect estimate of non-fermented ME on survival was HR = 0.81 (95% CI 0.69-0.95, P = .01). Subgroup analyses as well as the NRSIs estimation support the robustness of the finding. When active comparators are added to the analysis, the effect estimates become non-significant. CONCLUSION: The results may indicate a positive impact of non-fermented ME on the overall survival of cancer patients. High quality RCTs are necessary to substantiate our results. PROSPERO REGISTRATION: CRD42021233177.

Most healthcare interventions tested in Cochrane Reviews are not effective according to high quality evidence: a systematic review and meta-analysis.

OBJECTIVE: To estimate the proportion of healthcare interventions tested within Cochrane Reviews that are effective according to high-quality evidence. METHODS: We selected a random sample of 2,428 (35%) of all Cochrane Reviews published between 1 January 2008 and 5 March 2021. We extracted data about interventions within these reviews that were compared with placebo, or no treatment, and whose outcome quality was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We calculated the proportion of interventions whose benefits were based on high-quality evidence (defined as having high quality GRADE rating for at least one primary outcome, statistically significant positive results, and being judged by review authors as effective. We also calculated the proportion of interventions that suggested harm. RESULTS: Of 1,567 eligible interventions, 87 (5.6%) had high-quality evidence supporting their benefits. Harms were measured for 577 (36.8%) interventions. There was statistically significant evidence for harm in 127 (8.1%) of these. Our dependence on the reliability of Cochrane author assessments (including their GRADE assessments) was the main potential limitation of our study. CONCLUSION: More than 9 in 10 healthcare interventions studied within recent Cochrane Reviews are not supported by high-quality evidence, and harms are under-reported.

Effects of open-label placebos in clinical trials: a systematic review and meta-analysis.

Open-label placebos (OLPs) are placebos without deception in the sense that patients know that they are receiving a placebo. The objective of our study is to systematically review and analyze the effect of OLPs in comparison to no treatment in clinical trials. A systematic literature search was carried out in February 2020. Randomized controlled trials of any medical condition or mental disorder comparing OLPs to no treatment were included. Data extraction and risk of bias rating were independently assessed. 1246 records were screened and thirteen studies were included into the systematic review. Eleven trials were eligible for meta-analysis. These trials assessed effects of OLPs on back pain, cancer-related fatigue, attention deficit hyperactivity disorder, allergic rhinitis, major depression, irritable bowel syndrome and menopausal hot flushes. Risk of bias was moderate among all studies. We found a significant overall effect (standardized mean difference = 0.72, 95% Cl 0.39-1.05, p < 0.0001, I2 = 76%) of OLP. Thus, OLPs appear to be a promising treatment in different conditions but the respective research is in its infancy. More research is needed, especially with respect to different medical and mental disorders and instructions accompanying the OLP administration as well as the role of expectations and mindsets.

Quality of life in cancer patients treated with mistletoe: a systematic review and meta-analysis.

BACKGROUND: Mistletoe extracts are used as an adjunct therapy for cancer patients, but there is dissent as to whether this therapy has a positive impact on quality of life (QoL). METHODS: We conducted a systematic review searching in several databases (Medline, Embase, CENTRAL, CINAHL, PsycInfo, Science Citation Index, clinicaltrials.gov, opengrey.org ) by combining terms that cover the fields of "neoplasm", "quality of life" and "mistletoe". We included prospective controlled trials that compared mistletoe extracts with a control in cancer patients and reported QoL or related dimensions. The quality of the studies was assessed with the Cochrane Risk of Bias tool version 2. We conducted a quantitative meta-analysis. RESULTS: We included 26 publications with 30 data sets. The studies were heterogeneous. The pooled standardized mean difference (random effects model) for global QoL after treatment with mistletoe extracts vs. control was d = 0.61 (95% CI 0.41-0.81, p < 0,00001). The effect was stronger for younger patients, with longer treatment, in studies with lower risk of bias, in randomized and blinded studies. Sensitivity analyses support the validity of the finding. 50% of the QoL subdomains (e.g. pain, nausea) show a significant improvement after mistletoe treatment. Most studies have a high risk of bias or at least raise some concern. CONCLUSION: Mistletoe extracts produce a significant, medium-sized effect on QoL in cancer. Risk of bias in the analyzed studies is likely due to the specific type of treatment, which is difficult to blind; yet this risk is unlikely to affect the outcome. PROSPERO REGISTRATION: CRD42019137704 .

The quality of evidence for medical interventions does not improve or worsen: a metaepidemiological study of Cochrane reviews.

OBJECTIVES: The objective of the study was to determine the change in quality of evidence in updates of Cochrane reviews that were initially published between January 1, 2013 and June 30, 2014. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to document evidence quality. STUDY DESIGN AND SETTING: We searched the Cochrane Database of Systematic Reviews on March 20, 2020 to identify which of the reviews from the initial (2013/14) sample had been updated. Using the same methods to determine the quality of evidence in the previous analysis, we assessed the quality of evidence for the first-listed primary outcomes in the updated reviews. RESULTS: Of the 608 reviews in the original sample, 154 had been updated with and 151 contained available data for both original and updated systematic reviews (24.8%). The updated reviews included: 15 (9.9%) with high-quality evidence, 56 (37.1%) with moderate-quality evidence, 47 (31.1%) with low-quality evidence, and 33 (21.9%) with very low-quality evidence. No change in the GRADE quality of evidence was found for most (103, 68.2%) of the updated reviews. The quality of evidence rating was downgraded in 28 reviews (58.3%) and upgraded in 20 (41.7%), although only six reviews were promoted to high quality. CONCLUSION: Updated systematic reviews continued to suggest that only a minority of outcomes for health care interventions are supported by high-quality evidence. The quality of the evidence did not consistently improve or worsen in updated reviews.

Using a matrix-analytical approach to synthesizing evidence solved incompatibility problem in the hierarchy of evidence.

OBJECTIVES: The hierarchy of evidence presupposes linearity and additivity of effects, as well as commutativity of knowledge structures. It thereby implicitly assumes a classical theoretical model. STUDY DESIGN AND SETTING: This is an argumentative article that uses theoretical analysis based on pertinent literature and known facts to examine the standard view of methodology. RESULTS: We show that the assumptions of the hierarchical model are wrong. The knowledge structures gained by various types of studies are not sequentially indifferent, that is, do not commute. External validity and internal validity are at least partially incompatible concepts. Therefore, one needs a different theoretical structure, typical of quantum-type theories, to model this situation. The consequence of this situation is that the implicit assumptions of the hierarchical model are wrong, if generalized to the concept of evidence in total. CONCLUSION: The problem can be solved by using a matrix-analytical approach to synthesizing evidence. Here, research methods that produce different types of evidence that complement each other are synthesized to yield the full knowledge. We show by an example how this might work. We conclude that the hierarchical model should be complemented by a broader reasoning in methodology.

The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence.

It has been suggested that the intake of certain fatty acids may influence the risk of dementia. However, current reviews have focused only on the therapeutic effects of omega-3 fatty acids, mostly as supplements. To date, the evidence for the relevance of the omega-6/omega-3 ratio has been neglected. Therefore, we searched the databases Alois, Medline, Biosis, Embase, Cochrane Central Register of Controlled Trials, and The Cochrane Database of Systematic Reviews for "essential fatty acids" and "dementia" and aimed to conduct a comprehensive review across study types. All studies that reported on the association between the n-6/n-3 ratio and dementia or cognitive decline were selected. In the 13 animal studies we examined, the dietary n-6/n-3 ratio was shown to affect brain composition, Alzheimer's disease pathology, and behavior. Our review of the 14 studies in humans that fulfilled the selection criteria (7 prospective studies, 3 cross-sectional studies, 1 controlled trial, 3 case-control studies) provided evidence, albeit limited, supporting an association between the n-6/n-3 ratio, cognitive decline, and incidence of dementia. This review supports growing evidence of a positive association between the dietary n-6/n-3 ratio and the risk of Alzheimer's disease.

Midlife obesity and dementia: meta-analysis and adjusted forecast of dementia prevalence in the United States and China.

OBJECTIVE: Obesity is a risk factor of dementia. Current forecasts of dementia prevalence fail to take the rising obesity prevalence into account. DESIGN AND METHODS: Embase and Medline were searched for observational studies on the association between overweight (BMI 25-30 kg/m(2)) or obesity (BMI > 30 kg/m(2)) and dementia and pooled the effect sizes by meta-analysis. The population attributable risk (PAR) was calculated for different time points and adjusted them for confounders. Based on current prevalence rates of dementia and demographic forecasts, patient numbers were calculated and adjusted by the growth rates of PAR. RESULTS: Compared to normal weight, midlife obesity increases the risk of dementia later in life (BMI 25-30: RR = 1.34 [95% CI 1.08, 1.66], BMI > 30: RR = 1.91 [1.4, 2.62]). If obesity is included into forecast models, the prevalence of dementia is estimated to be 7.1 million (6.9, 7.3) and 11.3 million (10.9, 11.7) for the United States in 2030 and 2050, respectively. In China, the estimate is 13.1 million (12.8, 13.3) in 2030 and 26.2 million (25.1, 27.4) in 2050. These figures are 9% and 19% higher for the United States and China, respectively, than forecasts that rely solely on the demographic change. CONCLUSION: The past and ongoing increase in midlife obesity prevalence will contribute significantly to the future prevalence of dementia and public health measures to reduce midlife obesity are simultaneously primary prevention measures to reduce the risk of dementia.

Selenium and Alzheimer's disease: a systematic review.

Preventing Alzheimer's disease (AD) would require knowledge about its etiology to a degree of detail not yet available. The major hurdle in understanding the disease lies in teasing out the various causes and their complex interactions. Since considerable data have accrued showing that the essential trace element selenium (Se) might play different roles in the progression of AD, we conducted a systematic review of the literature regarding Se and AD. We identified 9 placebo-controlled studies (6 were multiple supplement trials including Se, 1 was ongoing), 4 prospective, 4 cross-sectional, 15 case control, 24 autopsy studies, as well studies in animals and cells. There is an absence of consistent clinical evidence as to whether supplementation of Se is beneficial in the treatment of AD and how Se levels are altered in brain, cerebrospinal fluid, and blood of patients with AD. Some longitudinal and cross-sectional studies, however, show an association of Se status and cognitive function. Findings from molecular biology reveal a decisive role of Se in the pathogenesis of AD. In summary, the current state of knowledge provides no evidence for a role of Se in the treatment of AD, but allows speculation on a potential preventive relevance. Large trials of long-term duration could provide definitive answers.