case-control study

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This prospective cohort study examined the effects of fish oil supplements on the clinical course of cardiovascular disease, from a healthy state to atrial fibrillation, major adverse cardiovascular events, and subsequently death.

The analysis is based on the UK Biobank study (1 January 2006 to 31 December 2010, with follow-up to 31 March 2021 (median follow-up 11.9 years)) including 415 737 participants, aged 40-69 years. Incident cases of atrial fibrillation, major adverse cardiovascular events, and death, identified by linkage to hospital inpatient records and death registries. Role of fish oil supplements in different progressive stages of cardiovascular diseases, from healthy status (primary stage), to atrial fibrillation (secondary stage), major adverse cardiovascular events (tertiary stage), and death (end stage).

Among 415 737 participants free of cardiovascular diseases, 18 367 patients with incident atrial fibrillation, 22 636 with major adverse cardiovascular events, and 22 140 deaths during follow-up were identified. Regular use of fish oil supplements had different roles in the transitions from healthy status to atrial fibrillation, to major adverse cardiovascular events, and then to death:

  • For people without cardiovascular disease, hazard ratios were 1.13 (95% confidence interval 1.10 to 1.17) for the transition from healthy status to atrial fibrillation and 1.05 (1.00 to 1.11) from healthy status to stroke.
  • For participants with a diagnosis of a known cardiovascular disease, regular use of fish oil supplements was beneficial for transitions from atrial fibrillation to major adverse cardiovascular events (hazard ratio 0.92, 0.87 to 0.98), atrial fibrillation to myocardial infarction (0.85, 0.76 to 0.96), and heart failure to death (0.91, 0.84 to 0.99).

The authors concluded that regular use of fish oil supplements might be a risk factor for atrial fibrillation and stroke among the general population but could be beneficial for progression of cardiovascular disease from atrial fibrillation to major adverse cardiovascular events, and from atrial fibrillation to death. Further studies are needed to determine the precise mechanisms for the development and prognosis of cardiovascular disease events with regular use of fish oil supplements.

I must admit that I am slightly puzzled by this study and its findings. The authors clearly speak of the ‘role’ regular use of fish oil supplements has. This language implies a casual impact. Yet, what we have here are associations, and every 1st year medical student knows that

correlation is not causation.

Other things to note are that:

  • the associations are only very weak;
  • they go in opposite directions depending on the subpopulation that is examined,
  • there is no plausible mechanism of action to explain all this.

Collectively, these facts suggest to me that we are indeed more likely dealing here with a non-causal association and not a causal link. All the more surprising then that the (UK) press took up this paper in a major and occasionally alarmist fashion (the headline in THE TELEGRAPH was Revealed: How cod liver oil could be bad for your health). I learned of it by listening to the BBC headline news.


Conspiracy theories, as often discussed here, plague the realm of so-called alternative medicine (SCAM), e.g.:

In fact, I did recently suggest that so-called alternative medicine is a conspiracy theory in disguise. Previous research has found that individuals who struggle with emotion regulation are more prone to believing in conspiracy theories. Emotional granularity – the ability to differentiate between nuanced emotional states – is a key component of effective emotion regulation, yet its relationship with conspiracy beliefs has not been explored thoroughly.

Psychologists from the Uni Graz in Austria conducted an experience-sampling study (165 participants, mean age = 26.3 years) including measures of emotion regulation and differentiation. The study started with an online survey that assessed participants’ sociodemographic (age, sex, and education) and trait measures. Following this, participants were asked to install an in-house developed app on their smartphones to obtain the emotional granularity specificity index. The app displayed two notifications each day for over a week (14 max.). Notifications were randomly displayed between 08:00 am and 10:00 pm with a minimum of at least 5 h between two notifications. Participants, on average, answered 57% of the notifications.

The findings revealed that individuals who endorse conspiracy theories engage in repetitive thinking about the causes and consequences of events and exhibit a reduced ability to distinguish between negative emotions. This effect, however, was observed only in the performance-based measure of emotion differentiation, not in the self-report measures.

The authors conclused that this suggests that enhancing emotional granularity may help individuals in regulating their emotions more effectively, thereby reducing their vulnerability to adopt conspiracy beliefs.

To reduce belief in conspiracy theories, one might, according to the authors, consider a training program to enhance emotion regulation and differentiation. A combination of cognitive control training on emotion regulation, which has been shown to reduce overthinking, as well as reflecting on and diversifying emotional experiences, could provide simple tools for assessing and regulating emotional experiences. This, in turn, may lead to decreased endorsement of conspiracy theories in the long run.

Perhaps we should recommend this to the chaps who recularly comment on this blog bursting with conspiracy theories?

In the realm of so-called alternative medicine (SCAM), dental amalgam is a big topic. Therefore, we have discussed it several times before, e.g.:

This study evaluated the changes of health complaints after removal of amalgam restorations in patients with health complaints attributed to dental amalgam fillings.

Patients with medically unexplained physical symptoms (MUPS) attributed to dental amalgam (Amalgam cohort) had all their amalgam fillings removed. The participants indicated an intensity of 11 local and 12 general health complaints on numeric rating scales before the treatment and at follow-up after 1 and 5 years.

The comparison groups comprising

  1. a group of healthy individuals
  2. a group of patients with MUPS without symptom attribution to dental amalgam

did not have their amalgam restorations removed.

In the Amalgam cohort, mean symptom intensity was lower for all 23 health complaints at follow-up at 1 year compared to baseline. Statistically significant changes were observed for specific health complaints with effect sizes between 0.36 and 0.68. At the 5-year follow-up, the intensity of symptoms remained consistently lower compared to before the amalgam removal. In the comparison groups, no significant changes of intensity of symptoms of health complaints were observed.

The authors concluded that, after removal of all amalgam restorations, both local and general health complaints were reduced. Since blinding of the treatment was not possible, specific and non-specific treatment effects cannot be separated.

This is an interesting study with a particularly long follow-up. Unfortunately, due to the study’s design, its results tell us very little about causality. The results are perfectly consistent with two entirely different explanations:

  1. Amalgam was the cause of MUPS and therefore removal of amalgam cured the problem permanently.
  2. Amalgam was not the cause of MUPS but the knowledge that the evil substance had finally been removed sufficed for MUPS to disappear.

It is to the credit of the authors that they consider both options.

A word of caution: amalgam removal can lead to a spike in Hg levels in the body!

Many fans of so-called alternative medicine have, as discussed ad nauseam on this blog, an irrational attitude towards vaccinations. They frequently claim that they do more harm than good. I wonder whether the data from a very large study might convince them other wise.

The WHO launched the ‘Expanded Programme on Immunization’ (EPI) in 1974 to make life-saving vaccines available to all globally. To mark the 50-year anniversary of EPI, this analysis sought to quantify the public health impact of vaccination globally since the programme’s inception.

his modelling study used a suite of mathematical and statistical models to estimate the global and regional public health impact of 50 years of vaccination against 14 pathogens in EPI. For the modelled pathogens, we considered coverage of all routine and supplementary vaccines delivered since 1974 and estimated the mortality and morbidity averted for each age cohort relative to a hypothetical scenario of no historical vaccination. These modelled outcomes were then used to estimate the contribution of vaccination to globally declining infant and child mortality rates over this period.

Since 1974, vaccination has averted 154 million deaths, including 146 million among children younger than 5 years of whom 101 million were infants younger than 1 year. For every death averted, 66 years of full health were gained on average, translating to 10·2 billion years of full health gained. Vaccination has thus accounted for 40% of the observed decline in global infant mortality, 52% in the African region. In 2024, a child younger than 10 years is 40% more likely to survive to their next birthday relative to a hypothetical scenario of no historical vaccination. Increased survival probability is observed even well into late adulthood.

The authors concluded that since 1974 substantial gains in childhood survival have occurred in every global region. We estimate that EPI has provided the single greatest contribution to improved infant survival over the past 50 years. In the context of strengthening primary health care, our results show that equitable universal access to immunisation remains crucial to sustain health gains and continue to save future lives from preventable infectious mortality.

>So, will this excellent and compelling analysis concince many irrational anti-vaxers? Somehow, I have my doubts.

Microplastics are tiny polymer fragments that range from less than 0.2 inch to 1/25,000th of an inch. Smaller particles are called nanoplastics and are measured in billionths of a metre. Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for human health and for cardiovascular disease in particular. However, direct evidence that this risk extends to humans has so far been lacking. This investigation is a first step towards filling the gap.

The researchers conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis–gas chromatography–mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs.

A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 μg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 μg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001).

The authors concluded that, in this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected.

This is an impressive study – so much so that I report it here even though it has no connection to so-called alternative medicine, the focus of my blog. The fact that 58% of all plaques contained MNPs seems alarming. The finding that the presence of these MNPs is associated with a poor cardiovascular prognosis seems even more concerning.

MNPs have been found in every environmental compartment on earth. They are ingested not just by humans but by most animals as well. Even though research into these issues is most active, their effects are so far still under-researched and not fully understood.

The authors of the new investigation are rightly cautious: “Our data must be confirmed by other studies and on larger populations,” said Marfella, professor of internal medicine and director of the department of medical and surgical sciences at the University of Campania Luigi Vanvitelli in Naples, Italy. “However, our study convincingly highlights the presence of plastics and their association with cardiovascular events in a representative population affected by atherosclerosis.”

Of course, many questions are as yet unanswered but the subject is as worrying as it is important, e.g.:

  • Should exposure to MNPs be considered a cardiovascular risk factor?
  • What organs in addition to the heart may be at risk?
  • How can we reduce exposure?”

I wish I knew the ansers.

Getting old is not nice – but think of the alternative!

I think it was Woody Allen who said something to that extent. But there is a third way, at least this is waht Tai Chi advocates want us to believe.

Utilizing a hybrid design, this study aimed to test whether both long-term and short-term Tai Chi (TC) training are associated with age-related decline in physical function in healthy older adults.

The authors first conducted cross-sectional comparisons among TC-naïve older adults (n = 60, 64.2 ± 7.7 years), TC-expert older adults (n = 27, 62.8 ± 7.6 years, 24.5 ± 12 years experience), and TC-naïve younger adults (n = 15, 28.7 ± 3.2 years) to inform long-term effects of TC training on physical function, including single leg stance time with eyes closed, grip strength, Timed Up and Go, maximum walking speed, functional reach, and vertical jump for lower-extremity power. There were significant differences among the three groups on all the six tests. For most functional tests, TC-experts performed better than age-matched TC-naïve controls and were statistically indistinguishable from young healthy adult controls. Long-term TC training was associated with higher levels of physical function in older adults, suggesting a potential preventative healthy aging effect.

In the randomized longitudinal trial, TC-naïve subjects were randomized (n = 31 to Tai Chi group, n = 29 to usual care control group) to evaluate the short-term effects of TC over 6 months on all outcomes. TC’s short-term impacts on physical function were small and not statistically significant. The impact of short-term training in healthy adults is less clear.

The authors concluded that both potential longer-term preventive effects and shorter-term restorative effects warrant further research with rigorous, adequately powered controlled clinical trials.

Even though the authors imply that their cross-sectional comparison points to a causal effect, this is clearly not true. For instance, it could easily be that people who are somehow destined to keep fit and agile are the ones who keep up Tai Chi. So, rather than being the result of Tai Chi, the proneness to fitness and agility could be the cause for doing Tai Chi.

The authors laudably were aware of these problems and therefore also did an RCT. Sadly this RCT did not yield significant findings. Essentially this means that eitherTai Chi did not work, or the study was naively inadequate, e.g. too small and too short-term.

Thus the authors finish with the usual statement that MORE RESEARCH IS NEEDED. This might be true, but is a definitive RCT likely?

I don’t think so.

A long time ago I had designed such a definitive study. It needed to be very large considering that many participants might drop out. Crucially, it also had to be long- term, i.e. years, not months.

And what happened to my study?

I never managed to get it funded, mainly because the costs would have been astronomical.

How often have we seen it stated on this blog and elsewhere by enthusiasts of so-called alternative medicine (SCAM) that COVID vaccinations were useless or even harmful? Here is some rather compelling evidence that should make them think again.

This population based cohort study investigated the effectiveness of primary covid-19 vaccination (first two doses and first booster dose within the recommended schedule) against post-covid-19 condition (PCC).

All adults (≥18 years) participated from the Swedish Covid-19 Investigation for Future Insights (a Population Epidemiology Approach using Register Linkage (SCIFI-PEARL) project, a register based cohort study in Sweden) with covid-19 first registered between 27 December 2020 and 9 February 2022 (n=589 722) in the two largest regions of Sweden. Individuals were followed from a first infection until death, emigration, vaccination, reinfection, a PCC diagnosis (ICD-10 diagnosis code U09.9), or end of follow-up (30 November 2022), whichever came first. Individuals who had received at least one dose of a covid-19 vaccine before infection were considered vaccinated.

The primary outcome was a clinical diagnosis of PCC. Vaccine effectiveness against PCC was estimated using Cox regressions adjusted for age, sex, comorbidities (diabetes and cardiovascular, respiratory, and psychiatric disease), number of healthcare contacts during 2019, socioeconomic factors, and dominant virus variant at time of infection.

Of 299 692 vaccinated individuals with covid-19, 1201 (0.4%) had a diagnosis of PCC during follow-up, compared with 4118 (1.4%) of 290 030 unvaccinated individuals. Covid-19 vaccination with any number of doses before infection was associated with a reduced risk of PCC (adjusted hazard ratio 0.42, 95% confidence interval 0.38 to 0.46), with a vaccine effectiveness of 58%. Of the vaccinated individuals, 21 111 received one dose only, 205 650 received two doses, and 72 931 received three or more doses. Vaccine effectiveness against PCC for one dose, two doses, and three or more doses was 21%, 59%, and 73%, respectively.

The authors concluded that the results of this study suggest a strong association between covid-19 vaccination before infection and reduced risk of receiving a diagnosis of PCC. The findings highlight the importance of primary vaccination against covid-19 to reduce the population burden of PCC.

This study should make the anti-vaxers re-consider their views. Sadly, I have little hope that they will. If they don’t, they provide rational thinkers with yet further evidence that they are cultists who are beyond learning from compelling data.

Omega-3 fatty acids (fish oil) supplementation reduces the occurrence of cardiovascular disease (CVD) and CVD-related mortality in patients at high-risk of CVD and in patients with elevated plasma triglyceride level. Yet, some studies have found an increased risk of atrial fibrillation (AF). AF is the most common sustained cardiac arrhythmia worldwide. It is associated with high morbidity and mortality rates and significant public health burden. Previous studies of the effect of omega-3 fatty acids on AF occurrence have reported contradictory results.

This review evaluated the effect of omega-3 fatty acids on the risk of AF. The results suggest that omega-3 fatty acids supplementation is associated with increased AF risk, particularly in trials that used high doses. Therefore, several factors should be considered before prescribing omega-3 fatty acids, including their dose, type, and formulation (fish, dietary fish oil supplements, and purified fatty acids), as well as patient-related factors and atrial mechanical milieu. Because the benefits of omega-3 fatty acids are dose-dependent, the associated AF risk should be balanced against the benefit for CVD. Patients who take omega-3 fatty acids, particularly at high doses, should be informed of the risk of AF and followed up for the possible development of this common and potentially hazardous arrhythmia.

Another recent review included 54,799 participants from 17 cohorts. A total of 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively.

The authors concluded that in vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

Faced with contradictory results based on non-RCT evidence, we clearly need an RCT. Luckily such a trial has recently been published. It was an ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017.

Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). The primary outcome was incident AF confirmed by medical record review.

Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39).

The authors concluded that among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF.

So, does the regular supplementation with omega-3 fatty acids increase the risk of atrial fibrillation? The evidence is not entirely clear but, on balance, I conclude that the risk is low or even non-existent.

Conspiracy beliefs (CBs) can have substantial consequences on health behaviours by influencing both conventional and non-conventional medicine uptake. They can target powerful groups (i.e. upward CBs) or powerless groups (i.e. downward CBs). Considering their repercussions in oncology, it appears useful to understand how CBs are related to the intentions to use conventional and so-called alternative medicines (SCAM), defined as “medical products and practices that are not part of standard medical care” including practices
such as mind–body therapies, botanicals, energy healing or naturopathic medicine.

This paper includes two pre-registered online correlational studies on a general French population (Study 1 N = 248, recruited on social media Mage = 40.07, SDage = 14.78; 205 women, 41 men and 2 non-binaries; Study 2 N = 313, recruited on social media and Prolific, Mage = 28.91, SDage = 9.60; 154 women, 149 men and 10 non-binaries). the researchers investigated the links between generic and chemotherapy-related CBs and intentions to use conventional or SCAMs. Study 2 consisted of a conceptual replication of Study 1, considering the orientation of CBs.

Generic CBs and chemotherapy-related CBs appear strongly and positively correlated, negatively correlated with intentions to take conventional medicine and positively with intentions to take SCAM. The link between generic CBs and medication intention is fully mediated by chemotherapy-related CBs. When distinguished, upward CBs are a stronger predictor of chemotherapy-related CBs than downward CBs.

The authors concluded that the findings suggest that intentions to use medicine are strongly associated with CBs. This has several important implications for further research and practice, notably on the presence and effects of CBs on medication behaviours in cancer patients.

Sadly, the influence of CBs is not confined to the field of oncology but applies across all diseases and conditions. We have seen and discussed these issues in several previous posts, e.g.:

The most impressive evidence, however, is regularly being provided by some of the people who post comments on this blog. Collectively, this evidence has prompted me to postulate that SCAM itself can be seen as a consiracy theory.

Although bullshit is common in everyday life and has attracted attention from philosophers, its reception (critical or ingenuous) has not, to our knowledge, been subject to empirical investigation. Pseudo-profound bullshit consists of seemingly impressive assertions that are presented as true and meaningful but are actually vacuous.

In this study, researchers presented participants with bullshit statements consisting of buzzwords randomly organized into statements with syntactic structure but no discernible meaning (e.g., “Wholeness quiets infinite phenomena”). Across multiple studies, the propensity to judge bullshit statements as profound was associated with a variety of conceptually relevant variables (e.g., intuitive cognitive style, supernatural belief). Parallel associations were less evident among profundity judgments for more conventionally profound (e.g., “A wet person does not fear the rain”) or mundane (e.g., “Newborn babies require constant attention”) statements.

The authors concluded that these results support the idea that some people are more receptive to this type of bullshit and that detecting it is not merely a matter of indiscriminate skepticism but rather a discernment of deceptive vagueness in otherwise impressive sounding claims. Our results also suggest that a bias toward accepting statements as true may be an important component of pseudo-profound bullshit receptivity.

Harry G Frankfurt published his delightful booklet ‘ON BULLSHIT‘ in 2005. Since then, the term ‘bullshit’ has become accepted terminology in philosophy and science. But what exactly is bullshit? Frankfurt explains that is something between a lie and a bluff, perhaps more like the latter than the former.

In another recent article, Fugelsang explains that the growing prevalence of misleading information (i.e., bullshit) in society carries with it an increased need to understand the processes underlying many people’s susceptibility to falling for it. He also reports two studies (N = 412) examining the associations between one’s ability to detect pseudo-profound bullshit, confidence in one’s bullshit detection abilities, and the metacognitive experience of evaluating potentially misleading information.

The results suggest that people with the lowest (highest) bullshit detection performance overestimate (underestimate) their detection abilities and overplace (underplace) those abilities when compared to others. Additionally, people reported using both intuitive and reflective thinking processes when evaluating misleading information. Taken together, these results show that both highly bullshit-receptive and highly bullshit-resistant people are largely unaware of the extent to which they can detect bullshit and that traditional miserly processing explanations of receptivity to misleading information may be insufficient to fully account for these effects.

I am sure that some of the discussions on this blog are excellent examples for people with low bullshit detection performance overestimating their detection abilities and overplacing those abilities.

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