Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries

Background: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decisionmaking. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peerreviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. Copyright:Methods and Findings: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2594.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2598.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6- 2.5). The probability of publication within two years after study completion ranged from 7% to 30%.Conclusions: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased

Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries

BACKGROUND: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decision-making. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peer-reviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. METHODS AND FINDINGS: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2 = 94.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2 = 98.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6-2.5). The probability of publication within two years after study completion ranged from 7% to 30%. CONCLUSIONS: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased

The scientific impact of commercial and non-commercial clinical trials in Portuguese lnstitutions

Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019Background: The pharmaceutical industry is the lead promoter of clinical studies across the world and its focus is on the company’s molecules which are patented. Although there are fewer non-commercial clinical trials, the information provided in these studies is vastly important for the wellbeing of the society, not aiming at the protection of commercial interests. Concerning the impact of both types of clinical trials, commercial studies are frequently published in high-impact scientific journals, given the complexity and dimension of the study, which is mandatory to achieve a meaningful result. On the other hand, non-commercial trials, that are initiated by the investigators, capacitate them, contributing to a general capacity for the research, clinical study and impact. Objectives: This study aims to identify the scientific impact of the commercial and non-commercial clinical trials with Portuguese institutions as sponsors or/and participating country. Design and Methods: A systematic search of trial registrations from 01/10/2004 to 30/09/2018 – using four clinical trials registries (CTRs) – was carried out to identify the interventional clinical trials with Portugal as sponsor or participating country. Information about the sponsor, funders, intervention type, and therapeutic area was obtained from each CTR. Every completed study was screened for publications and data collected from databases were complemented with data contained in publications. The impact factor of each journal and quartile in the respective publication year was also registered. Outcome: For the first time, the scientific impact and characteristics of both commercial and non-commercial clinical trials implemented in Portugal were assessed considering four different clinical trials registries and the information gathered from publications of completed studies. It was a great achievement conducting this analysis on a high number of clinical trials, implicating an exhaustive methodological approach. Results: The number of commercial clinical trials (n= 1402) registered was higher than the non-commercial clinical trials (n= 339). A total of 970 commercial clinical trials were completed and only 280 (28.87%) were published, from those, only 24 (8.57%) had Portuguese authorship. On the other hand, 170 non-commercial clinical trials were completed studies, 54 (31.76%) were published and 38 (70.37%) of them had Portuguese authorship. Oncology is the therapeutic area with more commercial studies published (20.71%) and chemical drugs the most applied interventions (65.71%). Considering the publications of the non-commercial clinical trials, Cardiology/Vascular Diseases is the main area of concern (16.67%) and behavioral interventions the most studied (31.48%). Eighty-three percent of the clinical trials published were sponsored by the pharmaceutical industry. Nevertheless, the publications with Portuguese authorship (43.55%) had universities as lead sponsors. Commercial clinical trials took 1.82 ± 0.10 years to publish their results while non-commercial trials took 2.13 ± 0.21 years. These results were not statistically different (p > 0.05). Commercial clinical trials were published in journals with a higher mean impact factor than non-commercial clinical trials (21.65 ± 1.33 and 15.63 ± 3.27, respectively; p < 0.05). Also, commercial clinical trials with Portuguese authors have a mean impact factor higher than non-commercial trials (17.09 ± 4.80 and 6.42 ± 1.93, respectively; p < 0.05). Conclusions: In this study, we conclude that commercial and non-commercial trials are published in similar percentages (around 30%). Portuguese authorship in non-commercial clinical trials has a higher percentage of publications when compared to those from commercial clinical trials (70.37% vs 8.57%). Oncology is the therapeutic area of higher number of registered trials, but it is not the most target one in the publications of non-commercial clinical trials. The mean time from the end of a clinical trial to the publication of its results is around 2 years both for commercial and non-commercial clinical trials. On average, commercial trials are published in journals with higher Impact Factors, when compared to those from non-commercial trials. A higher difference is observed in publications with Portuguese authors (17.09 vs 6.42). The scientific output of this work so far: - Preliminary conclusions from part of this research project were previously presented as an oral communication (selected by abstract) at the Portuguese Society of Pharmacology annual meeting (February 2019) in Porto entitled: The scientific impact of investigator-initiated clinical trials in Portuguese institutions: a systematic search in clinical trials databases. - By invitation, the same work was presented in a class of the "Clinical Trials Monitor Career Initiation Course", which was held at the Faculty of Pharmacy of the University of Porto (February 2019).Introdução: A investigação clínica ou estudos clínicos, que faz parte do ramo das ciências da saúde, é qualquer tipo de investigação médica que envolva participantes humanos. Estes estudos têm como objetivo primário responder a questões científicas específicas e produzir conhecimento valioso para a compreensão de doenças humanas, prevenção ou tratamento de doenças e promoção da saúde. Os ensaios clínicos são muito importantes uma vez que providenciam as ferramentas essenciais para traduzir descobertas científicas em terapias inovadoras, permitem a comercialização de novos fármacos e têm um papel crucial na resposta a questões médicas e científicas. Estes estudos podem ser divididos em ensaios comerciais (promovidos por organizações comerciais como as indústrias farmacêuticas) e ensaios não comerciais (geralmente promovidos por uma organização sem fins lucrativos). Nos ensaios comerciais, os investigadores limitam-se a executar um protocolo definido pela indústria, capacitando o investigador para a execução e prestação de serviços. Por outro lado, nos ensaios não comerciais, os investigadores ou a instituição são os responsáveis pelo desenho e execução do protocolo do ensaio clínico, contribuindo para uma capacitação geral de investigação, de estudo clínico e de impacto científico. De facto, hoje em dia a indústria farmacêutica é a principal promotora de ensaios clínicos em todo mundo apesar do seu foco primário se prender com a comercialização das suas terapias. A proporção de ensaios clínicos não comerciais (ou seja, ensaios clínicos da iniciativa do investigador) é consideravelmente inferior. Ainda assim, a informação proveniente destes estudos é extremamente importante para o bem-estar geral da sociedade, uma vez que é imparcial e não existe nenhum interesse comercial associado. Considerando o impacto científico que ambos os tipos de ensaios clínicos promovem, existem ainda algumas divergências. Os estudos comerciais são frequentemente publicados em jornais com fatores de impacto elevados devido à grande complexidade e dimensão dos estudos que é essencial para atingir resultados relevantes e significativos. Por outro lado, os ensaios não comerciais são normalmente ensaios de menores dimensões, com restrições financeiras e cujos resultados são publicados em artigos científicos ou são apresentados em conferências, sendo associados a fatores de impacto inferiores. Objetivos: Este estudo tem como objetivo principal identificar o impacto científico dos ensaios comerciais e não comerciais que tenham instituições Portuguesas como promotores e /ou Portugal como país participante. Os objetivos secundários prendem-se com comparação nos ensaios comerciais e não comerciais relativamente à: identificação de autores portugueses nas publicações, verificação das áreas terapêuticas de maior interesse onde existe um maior número de publicações e também no tempo médio que decorre desde o término de um ensaio até a publicação dos seus resultados. Metodologia: Uma pesquisa sistemática desde 01/10/2004 a 30/09/2018 foi realizada utilizando quatro plataformas de registo online de ensaios clínicos – Clinicaltrials.gov, EU-CTR, ISRCTN, ANZCTR - para identificar os ensaios clínicos a incluir neste trabalho de investigação. Os três critérios de inclusão utilizados foram: ter como país participante Portugal, ser um estudo de intervenção e ter data de início entre 01/10/2004 a 30/09/2018. A informação relativa ao número de identificação do ensaio, promotor, financiador, tipo de intervenção, área terapêutica, data de início e título do estudo foi obtida através das plataformas de registo referidas acima. A classificação relativa à natureza dos ensaios clínicos (comerciais ou não comerciais) foi feita manualmente, através do nome do promotor do ensaio, uma vez que os registos de ensaios clínicos não possuem essa informação (à exceção da EU-CTR). Para selecionar as publicações, apenas foram considerados os ensaios completos. Para além disso, só a primeira publicação de resultados após o término dos ensaios é que foi considerada. Tendo em conta apenas os ensaios completos, as possíveis publicações foram procuradas através do número de identificação dos ensaios numa pesquisa na base de dados MEDLINE (PubMed). A informação recolhida foi utilizada para complementar a informação obtida nos registos online. Em cada publicação, o ano de publicação, o jornal onde o artigo foi publicado, o fator de impacto e o percentil do respetivo ano de publicação foram registados. Para analisar toda a informação obtida, foi efetuada uma análise descritiva dos resultados. Quando adequado, foi realizada uma análise estatística. As amostras utilizadas não seguiam uma distribuição normal pelo que foi utilizado um teste não paramétrico (teste de Mann-Withney para amostras independentes) com uma confiança de 95%. Relevância: Pela primeira vez, foi conduzido um estudo relativo ao impacto científico com informação detalhada das características dos ensaios comerciais e não comerciais em Portugal utilizando quatro plataformas de registos clínicos e cruzando essa informação com as publicações dos ensaios completos. Foi uma grande conquista conduzir essa análise num número tão elevado de ensaios clínicos, implicando uma abordagem metodológica exaustiva. A relevância de aceder ao impacto científico de ensaios clínicos comerciais e não comerciais de maneira comparativa é muito significativa. Não há dúvida de que as informações fornecidas pelos ensaios da iniciativa do investigador são extremamente importantes, uma vez que os dados clínicos gerados poderão ter um grande impacto nas políticas de saúde na Europa e inovar áreas clínicas que são desconsideradas pela indústria devido à sua lucratividade muito baixa ou inexistente. Além disso, ainda existem poucos ensaios não comerciais publicados em jornais científicos com fator de impacto mais alto quando comparados com os comerciais havendo uma necessidade urgente de entender e superar esse revés. Resultados: Foram identificados um maior número de ensaios clínicos comerciais registados (n= 1402) em comparação com o número de ensaios não comerciais (n= 339). Dentro dos ensaios comerciais, 970 estão completos e apenas 280 (28.87%) publicados, dos quais, 24 (8.57) têm autoria portuguesa. Por outro lado, 170 ensaios não comerciais estão completos, dos quais 54 (31.76%) estão publicados e 38 (70.37%) têm autoria portuguesa. A área oncológica é a área terapêutica mais estudada nos ensaios comerciais publicados (20.71%) e os fármacos químicos as intervenções mais estudadas (65.71%). Em relação aos ensaios não comerciais publicados, a cardiologia é a área de terapêutica de maior interesse (16.67%) e as intervenções comportamentais as mais aplicadas (31.48%). Relativamente à média dos fatores de impacto dos jornais onde os resultados dos ensaios são publicados, esta é significativamente superior (p 0.05). Conclusões: Quando comparados com os ensaios comerciais, os ensaios não comerciais têm uma maior percentagem de publicações e de publicações com autores portugueses. No entanto, é claro que os promotores comerciais publicam mais frequentemente em jornais com fatores de impacto e quartis mais elevados sobre áreas da medicina que são consideradas as mais prevalentes e incidentes no mundo. Os ensaios não comerciais dedicam-se sobretudo a estudos de cardiologia. Relativamente ao tempo médio para a publicação dos resultados, este é semelhante tanto para os ensaios comerciais como não comerciais (aproximadamente 2 anos). Ao comparar as médias dos fatores de impacto dos ensaios comerciais e não comerciais, existem algumas divergências significativas: embora os ensaios clínicos comercias sejam publicados em jornais com fatores de impacto superiores, a maioria destas publicações não tem autores portugueses, ao contrário do que se passa com a publicação de estudos não comercias. Será relevante, no futuro, desenvolver estratégias nacionais que passem pela inclusão de investigadores portugueses em estudos comercias desde uma fase inicial de preparação do estudo, bem como estimular a realização de estudos não comerciais com financiamento substancial para aumentar o impacto científico dos mesmos. Produção científica deste trabalho até à data: - As conclusões preliminares de parte deste projeto foram apresentadas anteriormente, numa comunicação oral (selecionada pelo Resumo) na reunião anual da Sociedade Portuguesa de Farmacologia (fevereiro 2019) no Porto, intitulada: O impacto científico dos ensaios clínicos iniciados por investigadores em instituições portuguesas: uma pesquisa sistemática em plataformas online de ensaios clínicos. - Por convite, o mesmo trabalho foi apresentado numa aula do "Curso de Iniciação à Carreira de Monitor de Ensaios Clínicos", que se realizou na Faculdade de Farmácia da Universidade do Porto (fevereiro 2019)

Effects of obstructive sleep apnea and its treatment over the erectile function: a systematic review

Erectile dysfunction (ED) is considered a condition with a broad range of etiologies. Obstructive sleep apnea (OSA) syndrome is one of the lesser studied risk factors for ED. We intend to summarize the current evidence on the relationship between OSA and sexual impairment, focusing on the results in terms of erectile function of the different therapies offered to OSA patients. A systematic review was conducted, selecting articles related to the physiology of OSA and ED, and to the treatments of OSA syndrome and their reported outcomes in erectile and sexual function. Higher prevalences of ED in the OSA groups have been published. However, whether this effect on the erectile function occurs in the entire range of OSA severities remains unclear. Several hypotheses were proposed to explain the physiology of this association. Continuous Positive Airway Pressure as a treatment for OSA patients with ED has achieved a significative improvement in the sexual parameters in most of the studies. Phosphodiesterase type 5 inhibitors (iPDE5) on demand are useful as a treatment for ED in this subgroup of patients, with high satisfaction rates. The surgical treatment for the OSA evidenced benefits over the erectile function, and the effect on the sexual satisfaction of the therapy using Mandibular Advancement Devices is still undefined

Dental Research Waste in Design, Analysis, and Reporting: A Scoping Review.

Research waste is highly prevalent across biomedical investigations. We aimed to assess the evidence on the extent of research waste in dental research. We performed a scoping review of empirical evaluations of dental studies assessing the prevalence and impact of limitations in design, conduct, analysis, and reporting of research. PubMed was searched using specific terms to retrieve studies dealing with design, conduct, analysis, and reporting of studies in dentistry, with no year or language restrictions. Of the 1,807 publications identified from the search and from manual searches, 71 were included in this review. The topic and article selection was based on the expert opinion of the authors. The existing evidence suggests that, although there are improvements over time, substantial deficiencies in all areas (design, conduct, analysis, reporting) were prevalent in dental research publications. Waste in research is a multifaceted problem without a simple solution. However, an appreciation of optimal research design and execution is a prerequisite and should be underpinned by policies that include appropriate training in research methods and properly aligned incentives

Lumbar facet joint injections for the management of chronic low back pain

Background: Low back pain is a leading cause of disability worldwide and has a significant economic burden. Targeted lumbar facet joint injections may be used to relieve this pain and aid rehabilitation, but high quality clinical evidence to support their use is lacking. The National Institute for Health and Care Excellence (NICE) does not recommend spinal injections for the management of chronic low back pain. Critical appraisal of systematic reviews: A critical appraisal of systematic reviews of randomised controlled trials concluded that the existing evidence to support the use of facet joint injections in low back pain management is equivocal, with methodological variability detected across the studies and reviews. FACET feasibility study: The FACET feasibility study was a blinded parallel two-arm pilot randomised controlled trial to assess the feasibility of carrying out a definitive study evaluating the effectiveness of lumbar facet joint injections compared with a sham procedure, in patients with non-specific low back pain of more than three months’ duration. The study recruited from the pain and spinal orthopaedic clinics at Barts Health NHS Trust only, although a multicentre study was planned. Adult patients referred to the specialist clinics with non-specific low back pain despite NICE-recommended best non-invasive care were randomised and blinded to receive either intra-articular lumbar facet joint injections with steroid or a sham procedure, following a positive response to diagnostic medial branch nerve blocks. Both groups were invited to attend a combined physical and psychological programme. Measures of feasibility included the recruitment and retention rate, and adherence to the study protocol. Questionnaires were used to assess a range of pain- and disability-related issues. Of 628 participants screened for eligibility, nine were randomised to receive the study intervention and eight participants completed the study. Failure to recruit sufficient participants led to early closure of the study by the funder, and no conclusions were drawn on the clinical effectiveness of lumbar facet joint injections for the management of non-specific low back pain in this sub-group of patients. Although the target recruitment rate was not achieved, a robust study protocol was developed and the intended interventions delivered safely, thus addressing many of the feasibility objectives. Conclusions: Further high quality randomised controlled trials and systematic reviews are required to inform decision makers, with implications for both clinical practice and policy. Stronger collaborations with primary care may improve the recruitment of patients earlier in their pain trajectory, suitable for inclusion in a future trial. Study registration: EudraCT 2014-003187-20 and Current Controlled Trials ISRCTN12191542. Funding details: The FACET feasibility study was funded by the National Institute for Health Research Health Technology Assessment programme (reference number HTA 11/31/02)

The clinical effectiveness and cost-effectiveness of ablative therapies in the management of liver metastases: systematic review and economic evaluation

Background: Many deaths from cancer are caused by metastatic burden. Prognosis and survival rates vary, but survival beyond 5 years of patients with untreated metastatic disease in the liver is rare. Treatment for liver metastases has largely been surgical resection, but this is feasible in only approximately 20–30% of people. Non-surgical alternatives to treat some liver metastases can include various forms of ablative therapies and other targeted treatments.Objectives: To evaluate the clinical effectiveness and cost-effectiveness of the different ablative and minimally invasive therapies for treating liver metastases.Data sources: Electronic databases including MEDLINE, EMBASE and The Cochrane Library were searched from 1990 to September 2011. Experts were consulted and bibliographies checked.Review methods: Systematic reviews of the literature were undertaken to appraise the clinical effectiveness and cost-effectiveness of ablative therapies and minimally invasive therapies used for people with liver metastases. Studies were any prospective study with sample size greater than 100 participants. A probabilistic model was developed for the economic evaluation of the technologies where data permitted.Results: The evidence assessing the clinical effectiveness and cost-effectiveness of ablative and other minimally invasive therapies was limited. Nine studies of ablative therapies were included in the review; each had methodological shortcomings and few had a comparator group. One randomised controlled trial (RCT) of microwave ablation versus surgical resection was identified and showed no improvement in outcomes compared with resection. In two prospective case series studies that investigated the use of laser ablation, mean survival ranged from 41 to 58 months. One cohort study compared radiofrequency ablation with surgical resection and five case series studies also investigated the use of radiofrequency ablation. Across these studies the median survival ranged from 44 to 52 months. Seven studies of minimally invasive therapies were included in the review. Two RCTs compared chemoembolisation with chemotherapy only. Overall survival was not compared between groups and methodological shortcomings mean that conclusions are difficult to make. Two case series studies of laser ablation following chemoembolisation were also included; however, these provide little evidence of the use of these technologies in combination. Three RCTs of radioembolisation were included. Significant improvements in tumour response and time to disease progression were demonstrated; however, benefits in terms of survival were equivocal. An exploratory survival model was developed using data from the review of clinical effectiveness. The model includes separate analyses of microwave ablation compared with surgery and radiofrequency ablation compared with surgery and one of radioembolisation in conjunction with hepatic artery chemotherapy compared with hepatic artery chemotherapy alone. Microwave ablation was associated with an incremental cost-effectiveness ratio (ICER) of £3664 per quality-adjusted life-year (QALY) gained, with microwave ablation being associated with reduced cost but also with poorer outcome than surgery. Radiofrequency ablation compared with surgical resection for solitary metastases &lt; 3 cm was associated with an ICER of –£266,767 per QALY gained, indicating that radiofrequency ablation dominates surgical resection. Radiofrequency ablation compared with surgical resection for solitary metastases ? 3 cm resulted in poorer outcomes at lower costs and a resultant ICER of £2538 per QALY gained. Radioembolisation plus hepatic artery chemotherapy compared with hepatic artery chemotherapy was associated with an ICER of £37,303 per QALY gained.Conclusions: There is currently limited high-quality research evidence upon which to base any firm decisions regarding ablative therapies for liver metastases. Further trials should compare ablative therapies with surgery, in particular. A RCT would provide the most appropriate design for undertaking any further evaluation and should include a full economic evaluation, but the group to be randomised needs careful selection.Source of funding: Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research

Do nutritional factors interact with chronic musculoskeletal pain? : A systematic review

Dietary patterns may play an important role in musculoskeletal well-being. However, the link between dietary patterns, the components of patients' diet, and chronic musculoskeletal pain remains unclear. Therefore, the purpose of this review was to systematically review the literature on the link between dietary patterns, the components of patients' diet and chronic musculoskeletal pain. This review was conducted following the "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) guidelines and was registered in PROSPERO with the registration number CRD42018110782. PubMed, Web of Science, and Embase online databases were searched. After screening titles and abstracts of 20,316 articles and full texts of 347 articles, 12 eligible articles were included in this review, consisting of nine experimental and three observational studies. Seven out of nine experimental studies reported a pain-relieving effect of dietary changes. Additionally, protein, fat, and sugar intake were found to be associated with pain intensity and pain threshold. In conclusion, plant-based diets might have pain relieving effects on chronic musculoskeletal pain. Patients with chronic rheumatoid arthritis pain can show inadequate intake of calcium, folate, zinc, magnesium, and vitamin B6, whilst patients with fibromyalgia can show a lower intake of carbohydrates, proteins, lipids, vitamin A-E-K, folate, selenium, and zinc. Chronic pain severity also shows a positive relation with fat and sugar intake in osteoarthritis, and pain threshold shows a positive association with protein intake in fibromyalgia