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back pain

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These days, I live in France (some of my time) and I am often baffled by the number of osteopaths and the high level of acceptance of osteopathy in this country. The public seems to believe everything osteopaths claim and even most doctors have long given up to object to the idiocies they proclaim.

The website of the Institute of Osteopathy in Renne is but one of many examples. The Institute informed us as follows (my translation):

In addition to back pain, the osteopath can act on functional disorders of the digestive, neurological, cardiovascular systems or conditions related to ear, nose and throat. Osteopaths can promote recovery in athletes, relieve migraines, musculoskeletal disorders such as tendonitis, or treat sleep disorders. Less known for its preventive aspect, osteopathy also helps maintain good health. It can be effective even when everything is going well because it will prevent the appearance of pain. Osteopathy is, in fact, a manual medicine that allows the rebalancing of the major systems of the body, whatever the age of the patient and his problems. The osteopath looks for the root cause of your complaint in order to develop a curative and preventive treatment.

Who are osteopathic consultations for?

Osteopathic consultations at the Institute of Osteopathy of Rennes-Bretagne are intended for the following types of patients and pathologies

GERD (gastric reflux), plagiocephaly (cranial deformities), recurrent ENT disorders (sinusitis, ear infections…), digestive, sleep and behavioural disorders, motor delay, following a difficult birth…

Prevention, comfort treatment of osteoarthritis, musculoskeletal pain, functional abdominal pain, digestive disorders, headaches, dizziness, postural deficiency, facial pains…

Musculoskeletal pain (lumbago, back pain), digestive disorders, preparation for childbirth, post-partum check-up.

Prevention and treatment of MSDs (musculoskeletal disorders) linked to workstation ergonomics, stress, pain due to repetitive movements, poor posture at work, etc.

Scoliosis, prevention of certain pathologies linked to growth, fatigue, stress, follow-up of orthodontic treatment.

Musculoskeletal pain, tendonitis, osteopathic preparation for competition, osteopathic assessment according to the sport practised, repetitive injury.

In case you are not familiar with the evidence for osteopathy, let me tell you that as good as none of the many claims made in the above text is supported by anything that even resembles sound evidence.

So, how can we explain that, in France, osteopathy is allowed to thrive in a virtually evidence-free space?

In France, osteopathy started developing in the 1950s. In 2002, osteopathy received legislative recognition in France, and today, it is booming; between 2016 and 2018, 3589 osteopaths were trained in France. Osteopaths can be DO doctors, DO physiotherapists, DO nurses, DO midwives, DO chiropodists, or even DO dentists.

Thus, in 2018, and out of a total of 29,612 professionals practising osteopathy, there were 17,897 osteopaths DO and 11,715 DO health professionals. The number of professionals using the title of osteopath has roughly tripled in 8 years (11608 in 2010 for 29612 in 2018). There are currently around 30 osteopathic schools in France. About 3 out of 5 French people now consult osteopaths.

But this does not answer my question why, in France, osteopathy is allowed to thrive in a virtually evidence-free space! To be honest, I do not know its answer.

Perhaps someone else does?

If so, please enlighten me.

Myofascial release (also known as myofascial therapy or myofascial trigger point therapy) is a type of low-load stretch therapy that is said to release tightness and pain throughout the body caused by the myofascial pain syndrome, a chronic muscle pain that is worse in certain areas known as trigger points. Various types of health professionals provide myofascial release, e.g. osteopaths, chiropractors, physical or occupational therapists, massage therapists, or sports medicine/injury specialists. The treatment is usually applied repeatedly, but there is also a belief that a single session of myofascial release is effective. This study was a crossover clinical trial aimed to test whether a single session of a specific myofascial release technique reduces pain and disability in subjects with chronic low back pain (CLBP).

A total of 41 participants were randomly enrolled into 3 situations in a balanced and crossover manner:

  • experimental,
  • placebo,
  • control.

The subjects underwent a single session of myofascial release on thoracolumbar fascia and the results were compared with the control and placebo groups. A single trained and experienced therapist applied the technique.

For the control treatment, the subjects were instructed to remain in the supine position for 5 minutes. For the muscle release session, the subjects were in a sitting position with feet supported and the thoracolumbar region properly undressed. The trunk flexion goniometry of each participant was performed and the value of 30° was marked with a barrier to limit the necessary movement during the technique. The trained researcher positioned their hands on all participants without sliding over the skin or forcing the tissue, with the cranial hand close to the last rib and at the T12–L1 level on the right side of the individual’s body and the caudal hand on the ipsilateral side between the iliac crest and the sacrum. Then, the researcher caused slight traction in the tissues by moving their hands away from each other in a longitudinal direction. Then, the participant was instructed to perform five repetitions of active trunk flexion-extension (30°), while the researcher followed the movement with both hands simultaneously positioned, without losing the initial tissue traction and position. The same technique and the same number of repetitions of active trunk flexion-extension were repeated with the researcher’s hands positioned on the opposite sides. This technique lasted approximately five minutes.

For the placebo treatment, the subjects were not submitted to the technique of manual thoracolumbar fascia release, but they slowly performed ten repetitions of active trunk flexion-extension (30°) in the same position as the experimental situation. Due to the fact that touch can provide not only well-recognized discriminative input to the brain, but also an affective input, there was no touch from the researcher at this stage.

The outcomes, pain, and functionality, were evaluated using the numerical pain rating scale (NPRS), pressure pain threshold (PPT), and Oswestry Disability Index (ODI).

The results showed no effects between-tests, within-tests, nor for interaction of all the outcomes, i.e., NPRS (η 2 = 0.32, F = 0.48, p = 0.61), PPT (η2 = 0.73, F = 2.80, p = 0.06), ODI (η2 = 0.02, F = 0.02, p = 0.97).

The authors concluded that a single trial of a thoracolumbar myofascial release technique was not enough to reduce pain intensity and disability in subjects with CLBP.

I’m not!

Recently, I received this comment from a reader:

Edzard-‘I see you do not understand much of trial design’ is true BUT I wager that you are in the same boat when it comes to a design of a trial for LBP treatment: not only you but many other therapists. There are too many variables in the treatment relationship that would allow genuine , valid criticism of any design. If I have to pick one book of the several listed elsewhere I choose Gregory Grieve’s ‘Common Vertebral Joint Problems’. Get it, read it, think about it and with sufficient luck you may come to realize that your warranted prejudices against many unconventional ‘medical’ treatments should not be of the same strength when it comes to judging the physical therapy of some spinal problems as described in the book.

And a chiro added:

EE: I see that you do not understand much of trial design

Perhaps it’s Ernst who doesnt understand how to research back pain.

“The identification of patient subgroups that respond best to specific interventions has been set as a key priority in LBP research for the past 2 decades.2,7 In parallel, surveys of clinicians managing LBP show that there are strong views against generic treatment and an expectation that treatment should be individualized to the patient.6,22.”

Journal of Orthopaedic & Sports Physical Therapy
Published Online:January 31, 2017Volume47Issue2Pages44-48

Do I need to explain why the Grieve book (yes, I have it and yes, I read it) is not a substitute for evidence that an intervention or technique is effective? No, I didn’t think so. This needs to come from a decent clinical trial.

And how would one design a trial of LBP (low back pain) that would be a meaningful first step and account for the “many variables in the treatment relationship”?

How about proceeding as follows (the steps are not necessarily in that order):

  • Study the previously published literature.
  • Talk to other experts.
  • Recruit a research team that covers all the expertise you need (and don’t have yourself).
  • Formulate your research question. Mine would be IS THERAPY XY MORE EFFECTIVE THAN USUAL CARE FOR CHRONIC LBP? I know LBP is but a vague symptom. This does, however, not necessarily matter (see below).
  • Define primary and secondary outcome measures, e.g. pain, QoL, function, as well as the validated methods with which they will be quantified.
  • Clarify the method you employ for monitoring adverse effects.
  • Do a small pilot study.
  • Involve a statistician.
  • Calculate the required sample size of your study.
  • Consider going multi-center with your trial if you are short of patients.
  • Define chronic LBP as closely as you can. If there is evidence that a certain type of patient responds better to the therapy xy than others, that might be considered in the definition of the type of LBP.
  • List all inclusion and exclusion criteria.
  • Make sure you include randomization in the design.
  • Randomization should be to groups A and B. Group A receives treatment xy, while group B receives usual care.
  • Write down what A and B should and should not entail.
  • Make sure you include blinding of the outcome assessors and data evaluators.
  • Define how frequently the treatments should be administered and for how long.
  • Make sure all therapists employed in the study are of a high standard and define the criteria of this standard.
  • Train all therapists of both groups such that they provide treatments that are as uniform as possible.
  • Work out a reasonable statistical plan for evaluating the results.
  • Write all this down in a protocol.

Such a trial design does not need patient or therapist blinding nor does it require a placebo. The information it would provide is, of course, limited in several ways. Yet it would be a rigorous test of the research question.

If the results of the study are positive, one might consider thinking of an adequate sham treatment to match therapy xy and of other ways of firming up the evidence.

As LBP is not a disease but a symptom, the study does not aim to include patients that all are equal in all aspects of their condition. If some patients turn out to respond better than others, one can later check whether they have identifiable characteristics. Subsequently, one would need to do a trial to test whether the assumption is true.

Therapy xy is complex and needs to be tailored to the characteristics of each patient? That is not necessarily an unsolvable problem. Within limits, it is possible to allow each therapist the freedom to chose the approach he/she thinks is optimal. If the freedom needed is considerable, this might change the research question to something like ‘IS THAT TYPE OF THERAPIST MORE EFFECTIVE THAN THOSE EMPLOYING USUAL CARE FOR CHRONIC LBP?’

My trial would obviously not answer all the open questions. Yet it would be a reasonable start for evaluating a therapy that has not yet been submitted to clinical trials. Subsequent trials could build on its results.

I am sure that I have forgotten lots of details. If they come up in discussion, I can try to incorporate them into the study design.

This systematic review assessed the effects and reliability of sham procedures in manual therapy (MT) trials in the treatment of back pain (BP) in order to provide methodological guidance for clinical trial development.

Different databases were screened up to 20 August 2020. Randomized controlled trials involving adults affected by BP (cervical and lumbar), acute or chronic, were included. Hand contact sham treatment (ST) was compared with different MT (physiotherapy, chiropractic, osteopathy, massage, kinesiology, and reflexology) and to no treatment. Primary outcomes were BP improvement, the success of blinding, and adverse effects (AE). Secondary outcomes were the number of drop-outs. Dichotomous outcomes were analyzed using risk ratio (RR), continuous using mean difference (MD), 95% CIs. The minimal clinically important difference was 30 mm changes in pain score.

A total of 24 trials were included involving 2019 participants. Most of the trials were of chiropractic manipulation. Very low evidence quality suggests clinically insignificant pain improvement in favor of MT compared with ST (MD 3.86, 95% CI 3.29 to 4.43) and no differences between ST and no treatment (MD -5.84, 95% CI -20.46 to 8.78).ST reliability shows a high percentage of correct detection by participants (ranged from 46.7% to 83.5%), spinal manipulation is the most recognized technique. Low quality of evidence suggests that AE and drop-out rates were similar between ST and MT (RR AE=0.84, 95% CI 0.55 to 1.28, RR drop-outs=0.98, 95% CI 0.77 to 1.25). A similar drop-out rate was reported for no treatment (RR=0.82, 95% 0.43 to 1.55).

The authors concluded that MT does not seem to have clinically relevant effect compared with ST. Similar effects were found with no treatment. The heterogeneousness of sham MT studies and the very low quality of evidence render uncertain these review findings. Future trials should develop reliable kinds of ST, similar to active treatment, to ensure participant blinding and to guarantee a proper sample size for the reliable detection of clinically meaningful treatment effects.

The optimal therapy for back pain does not exist or has not yet been identified; there are dozens of different approaches but none has been found to be truly and dramatically effective. Manual therapies like chiropractic and osteopathy are often used, and some data suggest that they are as good (or as bad) as most other options. This review confirms what we have discussed many times previously (e.g. here), namely that the small positive effect of MT, or specifically spinal manipulation, is largely due to placebo.

Considering this information, what is the best treatment for back pain sufferers? The answer seems obvious: it is a therapy that is as (in)effective as all the others but causes the least harm or expense. In other words, it is not chiropractic nor osteopathy but exercise.

My conclusion:

avoid therapists who use spinal manipulation for back pain.

A new study evaluated the effects of yoga and eurythmy therapy compared to conventional physiotherapy exercises in patients with chronic low back pain.

In this three-armed, multicentre, randomized trial, patients with chronic low back pain were treated for 8 weeks in group sessions (75 minutes once per week). They received either:

  1. Yoga exercises
  2. Eurythmy
  3. Physiotherapy

The primary outcome was patients’ physical disability (measured by RMDQ) from baseline to week 8. Secondary outcome variables were pain intensity and pain-related bothersomeness (VAS), health-related quality of life (SF-12), and life satisfaction (BMLSS). Outcomes were assessed at baseline, after the intervention at 8 weeks, and at a 16-week follow-up. Data of 274 participants were used for statistical analyses.

The results showed no significant differences between the three groups for the primary and secondary outcomes. In all groups, RMDQ decreased comparably at 8 weeks but did not reach clinical meaningfulness. Pain intensity and pain-related bothersomeness decreased, while the quality of life increased in all 3 groups. In explorative general linear models for the SF-12’s mental health component, participants in the eurythmy arm benefitted significantly more compared to physiotherapy and yoga. Furthermore, within-group analyses showed improvements of SF-12 mental score for yoga and eurythmy therapy only. All interventions were safe.

Everyone knows what physiotherapy or yoga is, I suppose. But what is eurythmy?

It is an exercise therapy that is part of anthroposophic medicine. It consists of a set of specific movements that were developed by Rudolf Steiner (1861–1925), the inventor of anthroposophic medicine, in conjunction with Marie von Sievers (1867-1948), his second wife.

Steiner stated in 1923 that eurythmy has grown out of the soil of the Anthroposophical Movement, and the history of its origin makes it almost appear to be a gift of the forces of destiny. Steiner also wrote that it is the task of the Anthroposophical Movement to reveal to our present age that spiritual impulse that is suited to it. He claimed that, within the Anthroposophical Movement, there is a firm conviction that a spiritual impulse of this kind must enter once more into human evolution. And this spiritual impulse must perforce, among its other means of expression, embody itself in a new form of art. It will increasingly be realized that this particular form of art has been given to the world in Eurythmy.

Consumers learning eurythmy are taught exercises that allegedly integrate cognitive, emotional, and volitional elements. Eurythmy exercises are based on speech and direct the patient’s attention to their own perceived intentionality. Proponents of Eurythmy believe that, through this treatment, a connection between internal and external activity can be experienced. They also make many diffuse health claims for this therapy ranging from stress management to pain control.

There is hardly any reliable evidence for eurythmy, and therefore the present study is exceptional and noteworthy. One review concluded that “eurythmy seems to be a beneficial add-on in a therapeutic context that can improve the health conditions of affected persons. More methodologically sound studies are needed to substantiate this positive impression.” This positive conclusion is, however, of doubtful validity. The authors of the review are from an anthroposophical university in Germany. They included studies in their review that were methodologically too weak to allow any conclusions.

So, does the new study provide the reliable evidence that was so far missing? I am afraid not!

The study compared three different exercise therapies. Its results imply that all three were roughly equal. Yet, we cannot tell whether they were equally effective or equally ineffective. The trial was essentially an equivalence study, and I suspect that much larger sample sizes would have been required in order to identify any true differences if they at all exist. Lastly, the study (like the above-mentioned review) was conducted by proponents of anthroposophical medicine affiliated with institutions of anthroposophical medicine. I fear that more independent research would be needed to convince me of the value of eurythmy.

The purpose of this study was to describe changes in opioid-therapy prescription rates after a family medicine practice included on-site chiropractic services. It was designed as a retrospective analysis of opioid prescription data. The database included opioid prescriptions written for patients seeking care at the family medicine practice from April 2015 to September 2018. In June 2016, the practice reviewed and changed its opioid medication practices. In April 2017, the practice included on-site chiropractic services. Opiod-therapy use was defined as the average rate of opioid prescriptions overall medical providers at the practice.

There was a significant decrease of 22% in the average monthly rate of opioid prescriptions after the inclusion of chiropractic services (F1,40 = 10.69; P < .05). There was a significant decrease of 32% in the prescribing rate of schedule II opioids after the inclusion of chiropractic services (F2,80 = 6.07 for the Group × Schedule interaction; P < .05). The likelihood of writing schedule II opioid prescriptions decreased by 27% after the inclusion of chiropractic services (odds ratio, 0.73; 95% confidence interval, 0.59-0.90). Changes in opioid medication practices by the medical providers included prescribing a schedule III or IV opioid rather than a schedule II opioid (F6,76 = 29.81; P < .05) and a 30% decrease in the daily doses of opioid prescriptions (odds ratio, 0.70; 95% confidence interval, 0.50-0.98).

The authors concluded that this study demonstrates that there were decreases in opioid-therapy prescribing rates after a family medicine practice included on-site chiropractic services. This suggests that inclusion of chiropractic services may have had a positive effect on prescribing behaviors of medical physicians, as they may have been able to offer their patients additional nonpharmaceutical options for pain management.

The authors are correct in concluding the inclusion of chiropractic services MAY have had a positive effect. And then again, it may not!

Cause and effect cannot be established by correlation alone.

And even if the inclusion of chiropractic services caused the positive effect, it would not prove that chiropractic is effective in the management of pain. It would only mean that the physicians had an option that helped them to write fewer opioid prescriptions. Had they hired a crystal healer or a homeopath or a faith healer or any other practitioner of an ineffective therapy, the findings might have been very similar.

The long and short of it is this: if we want to use fewer opioids, there is only one way to achieve it: we must prescribe less.

The objective of this systematic review was to examine whether back pain is associated with increased mortality risk and, if so, whether this association varies by age, sex, and back pain severity.

A systematic search of published literature was conducted and English-language prospective cohort studies evaluating the association of back pain with all-cause mortality with follow-up periods >5 years were included. Three reviewers independently screened studies, abstracted data, and appraised risk of bias using the Quality in Prognosis Studies (QUIPS) tool. A random-effects meta-analysis estimated combined odds ratios (OR) and 95% confidence intervals (CI), using the most adjusted model from each study. Potential effect modification by a priori hypothesized factors (age, sex, and back pain severity) was evaluated with meta-regression and stratified estimates.

Eleven studies with a total of 81,337 participants were included. Follow-up periods ranged from 5 to 23 years. The presence of any back pain, compared to none, was not associated with an increase in mortality (OR, 1.06; 95% CI, 0.97 to 1.16). However, back pain was associated with mortality in studies of women (OR, 1.22; 95% CI, 1.02 to 1.46) and among adults with more severe back pain (OR, 1.26; 95% CI, 1.14 to 1.40).

The authors concluded that back pain was associated with a modest increase in all-cause mortality among women and those with more severe back pain.

I bet that back pain is associated with hundreds of things. The question is whether there might be a causal association; could it be that people die earlier BECAUSE of back pain?

Unless someone’s back pain is so unbearable that she commits suicide, I cannot see how the two can be directly linked in a cause/effect relationship. But there could be indirect causal links. For instance, certain cancers can cause both back pain and death. Or someone’s back pain might make him take treatment against a life-threatening condition less seriously and thus hasten his death.

It has also occurred to me that chiropractors might jump on the bandwagon and use the association between back pain and mortality for boosting their business. Something like this:

Back pain is a risk factor for premature death.

Come to us, and we treat your back pain.

This will make you live longer.

Chiropractic prolongs life!

That would, of course, be daft. Firstly, chiropractic is not all that effective for back pain (or anything else). Secondly, getting rid of back pain is unlikely to prolong your life.

Correlation is not causation!

The objective of this study was to assess a new treatment, Medi-Taping, which aims at reducing complaints by treating pelvic obliquity with a combination of manual treatment of trigger points and kinesio taping in a pragmatic RCT with pilot character.

One hundred ten patients were randomized at two study centers either to Medi-Taping or to a standard treatment consisting of patient education and physiotherapy as control. Treatment duration was 3 weeks. Measures were taken at baseline, end of treatment and at follow-up after 2 months. Main outcome criteria were low back pain measured with VAS, the Chronic Pain Grade Scale (CPGS) and the Oswestry Low Back Pain Disability Questionnaire (ODQ).

Patients of both groups benefited from the treatment by medium to large effect sizes. All effects were pointing towards the intended direction. While Medi-Taping showed slightly better improvement rates, there were no significant differences for the primary endpoints between groups at the end of treatment (VAS: mean difference in change 0.38, 95-CI [- 0.45; 1.21] p = 0.10; ODQ 2.35 [- 0.77; 5.48] p = 0.14; CPGS – 0.19 [- 0.46; 0.08] p = 0.64) and at follow-up. Health-related quality of life was significantly higher (p = .004) in patients receiving Medi-Taping compared to controls.

The authors concluded that Medi-Taping, a purported way of correcting pelvic obliquity and chronic tension resulting from it, is a treatment modality similar in effectiveness to complex physiotherapy and patient education.

This conclusion is obviously nonsense! The authors stated that their trial has ‘pilot character’. The study was not designed as an equivalence trial. Thus it is improper to draw conclusions about the comparative effectiveness of Medi-Taping.

Having clarified this crucial point, we might ask, what is this new therapy called Medi-Taping? This is how the authors of the above paper describe the technique:

…sessions started with an assessment of leg length difference. Patients were asked to lie on their back and the legs were slightly stretched by a soft pull at the ankles. Next, a continuous horizontal line was drawn on the inside of both calves indicating the position of the calves relative to each other. Then the patient was asked to sit up with the legs remaining outstretched. This procedure results in a shift of the line between the two calves for most people. This shift was measured in millimeters as leg length difference.

The patient was then asked to stretch out, lying supine, and the therapist palpated any myogeloses (areas of abnormal hardening in a muscle) and tense muscles areas that could be found next to the cervical spine between the base of the skull and seventh cervical vertebra on both sides. After this treatment the leg length difference assessment was repeated. If there was still a substantial difference. The same treatment was also performed on the thoracic and lumbar spine. Also, the mandibular joint was assessed for tense muscles and, if necessary, treated by palpation.

Next, the leg length difference was assessed again and several tapes were applied as follows: First, two parallel tapes were fixed on both sides of the spine above the erector spinae muscles ranging from the base of the skull to the sacrum. For the application patients were asked to bend forward and to lean on a bench. This position stretches the back and its anatomical structure before applying the tape and thus provides the tape with tension before fixing it. Next a star-shaped pattern of tape (three stripes meeting in one point) was placed on the lower back while the patient was still in the same bent position. Thus, the star tape covered the area of the patient’s maximum pain and additionally stabilized the sacroiliac joint. This tape was placed with maximum tension in the middle section by stretching the tape before application, with the ends (approx. 5 cm) applied without tension. If after this procedure there was still residual pain, a third tape was placed at the gluteus maximus muscle. This tape was first fixed distally from the greater trochanter then stretched up to approx. 80% of the possible tension before the other end was placed on the sacrum. On average six tapes were applied for the gluteus tape.

Patients were instructed to keep the tapes on as long as they stuck to the skin. If the patients had recurring low back pain (LBP) within the same week, they were asked to see the therapist again immediately. Otherwise, the second and the third treatment were scheduled once a week for the following 2 weeks, respectively.

(Elsewhere MEDI-Taping is described differently as a technique using an elastic tape. The tape comes in different colors that are used depending on the patient’s need. The fabric and adhesive are made from cotton and other all natural materials. The tape can be ‘stretched’ in order to better support a given joint or muscle. Through the stretch, the underlying areas are relieved of tension, circulation is improved, and as a result injuries are healing faster. While it is applied to the skin, the tape gently massages the affected area as the body is moving. As the tape is applied, an improvement in motor function and pain relief should be felt immediately.)

Considering the above, I think that the most likely explanation of the outcome of this study (if it ever got confirmed in a properly designed equivalence trial) is that Medi-Taping itself is fairly useless. The fact that it did as well as (more precisely perhaps not worse than) standard physiotherapy is due to its exotic and novel flair which raised expectations and thus contributed to a large placebo response.

Whether my speculation is true or not, I don’t feel that Medi-Taping is the solution to back or any other problems.

The senior author of this study is Harad Walach who has been a regular feature on this blog, and I could not help but notice that he now has 4 affiliations:

Low back pain must be one of the most frequent reasons for patients to seek out some so-called alternative medicine (SCAM). It would therefore be important that the information they get is sound. But is it?

The present study sought to assess the quality of web-based consumer health information available at the intersection of LBP and CAM. The investigators searched Google using six unique search terms across four English-speaking countries. Eligible websites contained consumer health information in the context of CAM for LBP. They used the DISCERN instrument, which consists of a standardized scoring system with a Likert scale from one to five across 16 questions, to conduct a quality assessment of websites.

Across 480 websites identified, 32 were deemed eligible and assessed using the DISCERN instrument. The mean overall rating across all websites 3.47 (SD = 0.70); Summed DISCERN scores across all websites ranged from 25.5-68.0, with a mean of 53.25 (SD = 10.41); the mean overall rating across all websites 3.47 (SD = 0.70). Most websites reported the benefits of numerous CAM treatment options and provided relevant information for the target audience clearly, but did not adequately report the risks or adverse side-effects adequately.

The authors concluded that despite some high-quality resources identified, our findings highlight the varying quality of consumer health information available online at the intersection of LBP and CAM. Healthcare providers should be involved in the guidance of patients’ online information-seeking.

In the past, I have conducted several similar surveys, for instance, this one:

Background: Low back pain (LBP) is expected to globally affect up to 80% of individuals at some point during their lifetime. While conventional LBP therapies are effective, they may result in adverse side-effects. It is thus common for patients to seek information about complementary and alternative medicine (CAM) online to either supplement or even replace their conventional LBP care. The present study sought to assess the quality of web-based consumer health information available at the intersection of LBP and CAM.

Methods: We searched Google using six unique search terms across four English-speaking countries. Eligible websites contained consumer health information in the context of CAM for LBP. We used the DISCERN instrument, which consists of a standardized scoring system with a Likert scale from one to five across 16 questions, to conduct a quality assessment of websites.

Results: Across 480 websites identified, 32 were deemed eligible and assessed using the DISCERN instrument. The mean overall rating across all websites 3.47 (SD = 0.70); Summed DISCERN scores across all websites ranged from 25.5-68.0, with a mean of 53.25 (SD = 10.41); the mean overall rating across all websites 3.47 (SD = 0.70). Most websites reported the benefits of numerous CAM treatment options and provided relevant information for the target audience clearly, but did not adequately report the risks or adverse side-effects adequately.

Conclusion: Despite some high-quality resources identified, our findings highlight the varying quality of consumer health information available online at the intersection of LBP and CAM. Healthcare providers should be involved in the guidance of patients’ online information-seeking.

Or this one:

Background: Some chiropractors and their associations claim that chiropractic is effective for conditions that lack sound supporting evidence or scientific rationale. This study therefore sought to determine the frequency of World Wide Web claims of chiropractors and their associations to treat, asthma, headache/migraine, infant colic, colic, ear infection/earache/otitis media, neck pain, whiplash (not supported by sound evidence), and lower back pain (supported by some evidence).

Methods: A review of 200 chiropractor websites and 9 chiropractic associations’ World Wide Web claims in Australia, Canada, New Zealand, the United Kingdom, and the United States was conducted between 1 October 2008 and 26 November 2008. The outcome measure was claims (either direct or indirect) regarding the eight reviewed conditions, made in the context of chiropractic treatment.

Results: We found evidence that 190 (95%) chiropractor websites made unsubstantiated claims regarding at least one of the conditions. When colic and infant colic data were collapsed into one heading, there was evidence that 76 (38%) chiropractor websites made unsubstantiated claims about all the conditions not supported by sound evidence. Fifty-six (28%) websites and 4 of the 9 (44%) associations made claims about lower back pain, whereas 179 (90%) websites and all 9 associations made unsubstantiated claims about headache/migraine. Unsubstantiated claims were made about asthma, ear infection/earache/otitis media, neck pain,

Conclusions: The majority of chiropractors and their associations in the English-speaking world seem to make therapeutic claims that are not supported by sound evidence, whilst only 28% of chiropractor websites promote lower back pain, which is supported by some evidence. We suggest the ubiquity of the unsubstantiated claims constitutes an ethical and public health issue.

The findings were invariably disappointing and confirmed those of the above paper. As it is nearly impossible to do much about this lamentable situation, I can only think of two strategies for creating progress:

  1. Advise patients not to rely on Internet information about SCAM.
  2. Provide reliable information for the public.

Both describe the raison d’etre of my blog pretty well.

Osteopathic manipulative treatment (OMT) is popular, but does it work? On this blog, we have often discussed that there are good reasons to doubt it.

This study compared the efficacy of standard OMT vs sham OMT for reducing low back pain (LBP)-specific activity limitations at 3 months in persons with nonspecific subacute or chronic LBP. It was designed as a prospective, parallel-group, single-blind, single-center, sham-controlled randomized clinical trial. 400 patients with nonspecific subacute or chronic LBP were recruited from a tertiary care center in France starting and randomly allocated to interventions in a 1:1 ratio.

Six sessions (1 every 2 weeks) of standard OMT or sham OMT delivered by osteopathic practitioners. For both
experimental and control groups, each session lasted 45 minutes and consisted of 3 periods: (1) interview focusing on pain location, (2) full osteopathic examination, and (3) intervention consisting of standard or sham OMT. In both groups, practitioners assessed 7 anatomical regions for dysfunction (lumbar spine, root of mesentery, diaphragm, and atlantooccipital, sacroiliac, temporomandibular, and talocrural joints) and applied sham OMT to all areas or standard OMT to those that were considered dysfunctional.

The primary endpoint was the mean reduction in LBP-specific activity limitations at 3 months as measured by the self-administered Quebec Back Pain Disability Index. Secondary outcomes were the mean reduction in LBP-specific activity limitations; mean changes in pain and health-related quality of life; number and duration of sick leave, as well as the number of LBP episodes at 12 months, and the consumption of analgesics and nonsteroidal anti-inflammatory drugs at 3 and 12 months. Adverse events were self-reported at 3, 6, and 12 months.

A total of 200 participants were randomly allocated to standard OMT and 200 to sham OMT, with 197 analyzed in each group; the median (range) age at inclusion was 49.8 (40.7-55.8) years, 235 of 394 (59.6%) participants were women, and 359 of 393 (91.3%) were currently working. The mean (SD) duration of the current LBP episode had been 7.5 (14.2) months. Overall, 164 (83.2%) patients in the standard OMT group and 159 (80.7%) patients in the sham OMT group had the primary outcome data available at 3 months.

The mean (SD) Quebec Back Pain Disability Index scores were:

  • 31.5 (14.1) at baseline and 25.3 (15.3) at 3 months in the OMT-group,
  • 27.2 (14.8) at baseline and 26.1 (15.1) at 3 months in the sham group.

The mean reduction in LBP-specific activity limitations at 3 months was -4.7 (95% CI, -6.6 to -2.8) and -1.3 (95% CI, -3.3 to 0.6) for the standard OMT and sham OMT groups, respectively (mean difference, -3.4; 95% CI, -6.0 to -0.7; P = .01). At 12 months, the mean difference in mean reduction in LBP-specific activity limitations was -4.3 (95% CI, -7.6 to -1.0; P = .01), and at 3 and 12 months, the mean difference in mean reduction in pain was -1.0 (95% CI, -5.5 to 3.5; P = .66) and -2.0 (95% CI, -7.2 to 3.3; P = .47), respectively. There were no statistically significant differences in other secondary outcomes. Four and 8 serious adverse events were self-reported in the standard OMT and sham OMT groups, respectively, though none was considered related to OMT.

The authors concluded that standard OMT had a small effect on LBP-specific activity limitations vs sham OMT. However, the clinical relevance of this effect is questionable.

This study was funded the French Ministry of Health and sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique-Hôpitaux de Paris. It is of exceptionally good quality. Its findings are important, particularly in France, where osteopaths have become as numerous as their therapeutic claims irresponsible.

In view of what we have been repeatedly discussing on this blog, the findings of the new trial are unsurprising. Osteopathy is far less well supported by sound evidence than osteopaths want us to believe. This is true, of course, for the plethora of non-spinal claims, but also for LBP. The French authors cite previously published evidence that is in line with their findings: In a systematic review, Rubinstein and colleagues compared the efficacy of manipulative treatment to sham manipulative treatment on LBP-specific activity limitations and did not find evidence of differences at 3 and 12 months (3 RCTs with 573 total participants and 1 RCT with 63 total participants). Evidence was considered low to very low quality. When merging the present results with these findings, we found similar standardized mean difference values at 3months (−0.11 [95% CI, −0.24 to 0.02]) and 12 months (−0.11 [95% CI, −0.33 to 0.11]) (4 RCTs with 896 total participants and 2 RCTs with 320 total participants).

So, what should LBP patients do?

The answer is, as I have often mentioned, simple: exercise!

And what will the osteopaths do?

The answer to this question is even simpler: they will find/invent reasons why the evidence is not valid, ignore the science, and carry on making unsupported therapeutic claims about OMT.

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Andaman & Nicobar Is. to W. Pacific as per WCSP;
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Ornamental Plant For ID : Nasik : 230314 : AK-32 : 4 posts by 2 authors. Attachments (1).

A cultivated, potted plant seen at a plant nursery in Nasik during Nov, 2011.

Id please.

I think this is Pandanus dubius

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Is the id correct as Pandanus dubius Spreng. ?

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Hebrew text to speech for how to help your depression

Hebrew text to speech

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Pregnancy & Fertility

There is hope!

Eggschain Team 0

  1. There is always hope in everything! It can be disappointing when an IVF treatment did not work. However, studies have found that many (up to close to one third of couples) conceive naturally after failed IVF cycles.
  2. IVF treatment can be expensive. But what if a successful or unsuccessful IVF treatment can lead to conceiving naturally soon after?
  3. At times, physicians do find health issues that completely prevent pregnancy, but using adopted eggs/sperm/embryos is an option. Adoption of a child is another option!

  1. Research found that up to 1/3 of women undergo IVF treatment can conceive naturally within 2 years
  2. Sometimes, they can conceive as soon as a few months after a failed IVF treatment

Why is this important?

This is important because IVF treatment can be expensive, and many cannot afford a second IVF treatment for additional family building. This finding is good for our mental health and gives all of us hope that perhaps with carefully calibrated treatment, good diet, and positive lifestyle choices, we can potentially evoke our bodies’ natural abilities to reproduce, after IVF treatments.

Why is it that, sometimes, we can conceive naturally after IVF treatment?

  • One of the reasons is that, as part of IVF treatment, our doctors can discover previously unknown issues that prevent pregnancy. For example, fibroids.

Fibroids is growth in a woman’ body that could potentially prevent pregnancy. If IVF treatment successfully discovered the presence of fibroids and the doctor/surgeon subsequently removed the growth, then the women can improve her chance of potentially conceiving naturally because that particular obstacle to conception is removed.

  • Also, during the IVF treatment, women are advised to be watchful of her diet, avoid pesticide and harmful environmental elements. One could argue that she may continue following those guidelines after the IVF treatment is completed, if possible.
  • Additionally, the IVF treatment often serves as an educational process that teaches all of us (women, men, and couples) the factors that could potentially cause infertility, such as cigarettes-smoking. We could potentially discontinue those habits and lead a healthier lifestyle after IVF treatments, and hence, increase the chances of conceiving naturally.
  • The IVF treatment teaches us about ovulation, menstruation cycles and knowledge about our specific body that we did not know before. Every woman’s ovulation dates and situation are different. The IVF process is a tailor-made process that teaches us about our own body.

Key takeaway:

  1. There is still hope if one’s first IVF treatment did not work. One may still potentially conceive naturally afterwards.
  2. Be prepared that you could be pregnant naturally after your IVF treatments. There could surprises. 😊
  3. If there are serious health issues that completely prevent pregnancy, talk to your doctor about adoption of a sperm/egg/embryo or adopting a child.

This does not constitute medical advice. Please consult your doctor for your specific situation. Lifestyle choices are individuals’ choices.

It is written by Eggschain editors and medically reviewed by Hugh Taylor, MD, the Anita O’Keeffe Young Professor and Chair, Department of Obstetrics Gynecology and Reproductive Sciences at Yale School of Medicine and Chief of Obstetrics and Gynecology at Yale-New Haven Hospital. He is also Professor of Molecular, Cellular and Developmental biology at Yale University.

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Categories: Pregnancy & Fertility

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The Royal Carriages Museum

The Royal Carriages Museum

The Royal carriages Museum in Boulaq is one of the earliest of its kind worldwide, both from the prospect of the authenticity of its building and the originality of its displays. The building was particularly adapted to preserve the cultural heritage of the royal carriages and all related material dating back to the era of Mohammed Ali Dynasty.

The idea of establishing the museum building dates back to the reign of khedive Ismail (r. 1863- 1879), who thought of founding a special structure for housing the horses and the khedivial carriages. Initially, the establishment was called the “Khedivial Carriages Service”, then its name was changed in 1922 to “Royal Stables Department (Royal Mews)” under the reign of king Fouad  (r. 1917- 1936).

Being the focus of royal attention, this establishment was provided with all specialized experts and skilled workers. The building was converted into a museum after the revolution of 1952.

The Museum houses a unique collection, of which the most notable are various sizes and types of royal carriages, one of the most distinguished objects in the Museum is the grand Alay Carriage, which is characterized by its finest workmanship and elaborate decoration. It was the gift of Emperor Napoleon III and his wife Empress Eugenie to Khedive Ismail on the occasion of the Suez Canal inauguration in 1869. King Faruk ordered its restoration and used it on the inauguration of the Parliament in 1942, also its contain horse riding equipments, uniforms of the Carriages Service employees, as well as oil paintings dating to the same era.

Worthy of note is that few museums all over the world are specialized in exhibiting this kind of displays, for examples museums in Austria, France, Russia, and England.

09:00 AM

01:00 PM

Opening Hours

FOREIGNER: Adult: EGP 100\ Student: EGP 50 EGYPTIAN\ ARABS: Adult: EGP 20\ Student: EGP 10

Our Insider Tips

Visit Hours

Museum Hours every day: 9:00 am – 1:00 pm (ticket window closes at 12:15 pm) Evening Hours: 5:00 pm – 9:00 pm (ticket window closes at 8:15 pm)

Free tickets

1. Seniors aged 60 and over 2- special needs 3- Orphaned children 4- Public schools trips primary and preparatory school

General Policies

- Please do not touch any exhibits or showcases. - Food and drinks are not allowed within the galleries, except for small water bottles. - Smoking is prohibited throughout the museum. - Please refrain from disorderly, disruptive, and offensive language or actions. - Please be mindful of others, and be quiet when using your cell phone. - Audio players are not permitted throughout the museum. - For the safety of the exhibits, please do not use flashlights or laser pointers inside the museum. - Appropriate attire is requested. - Please do not lay down on seats or on the floor, and do not remove your shoes. - Please follow all posted signs and visitor instructions.

- Private photography is permitted inside the museum after paying ticketfees. - Please refrain from taking photographs of other visitors or staff as it may violate their personal rights. - Please refrain from taking video recordings (cell phone, cameras) in the galleries unless you have paid the appropriate ticket fees. - Taking photographs and video recordings for commercial use (TV, cinema, programmes, advertising, documentary clips, et) are permitted only after obtaining permissionfrom the concerned authority and paying the daily rate. - Please refrain from using flash photography. - Please refrain from using tripods or monopods except for permitted commercial use

With regards to the students of Art Faculties, please conduct yourself respectively in regards to the following:  The use of pens and pen markersare prohibited in all galleries: only pencils may be used in taking notes or sketching.  Sketchbooksexceeding 18 x 24 inches are not permitted.  Please do not hinder visitor traffic flow in the galleries by blocking visitors or walking paths.

 In times of emergency such as an earthquake or fire, please follow the instructions of museum staff.  In the event of an earthquake, please move away from large sculptures, displaycases, and other objects that may fall down.


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Dose–response evaluation of urinary cadmium and kidney injury biomarkers in Chinese residents and dietary limit standards

Cadmium (Cd) is a common heavy metal that mainly causes renal damage. There is a lack of research on the large-scale and systematic evaluation of the association between urinary Cd (U-Cd) and various effect biomarkers among Chinese residents.

Based on the establishment process of dietary Cd limit standards by European Food Safety Authority (EFSA), the dose–response relationships between U-Cd and four biomarkers, β2-microglobulin (β2-MG), N-acetyl-β-glucosidase (NAG), microalbumin (mALB), and retinol binding Protein (RBP) were explored, respectively. Toxicokinetic model was used to derive the dietary Cd exposure limit for Chinese residents after critical U-Cd concentration was calculated.

As the sensitive biomarkers of renal injury, β2-MG and NAG were selected to estimate the 95% confidence interval lower limit of the U-Cd benchmark dose (BMDL5) to be 3.07 and 2.98 μg/g Cr, respectively. Dietary Cd exposure limit was calculated to be 0.28 μg/kg bw/day (16.8 μg/day, based on the body weight of 60 kg), which was lower than the average Chinese Cd exposure (30.6 μg/day) by the China National Nutrient and Health Survey.

This study established an overall association between U-Cd and renal injury biomarkers, and explored the Chinese dietary Cd exposure limits, which helps improve Chinese Cd exposure risk assessment and provides a reference basis for formulating reasonable exposure standards.

Peer Review reports

Cadmium (Cd) is a toxic heavy metal commonly found in the environment, with an average concentration in the earth's crust of about 0.2 mg/kg [1]. With the development of social industry, human activities, such as mineral development, metal smelting, industrial emissions, fossil fuels, and waste incineration, have caused Cd to enter soil and water through farmland irrigation, atmospheric dust reduction and urban compost [2, 3] and lead to long-term and wide presence of Cd in the environment. Kidney is the main target organ of Cd exposure [4, 5]. Adverse outcomes such as tubular injury, decreased glomerular reabsorption rate have been shown to be closely related to Cd exposure [6].

Considering the potential hazards of Cd exposure to human health, the European Food Safety Authority (EFSA) proposed a tolerable weakly intake (TWI) of 2.5 μg/kg bw/week for dietary Cd intake in 2009 [7]. The committee used a meta-analysis to determine the dose–response relationship between urinary Cd (U-Cd) and the renal injury biomarker β2-microglobulin (β2-MG). Benchmark dose lower-bound confidence limit (BMDL) of U-Cd, which was derived by Hill model, was used as the safety threshold dose. Based on the critical U-Cd concentration, corresponding external exposure limit was calculated by toxicokinetic (TK) model. The TK model is an in vitro mathematical model based on physiology, biochemistry, dissection and pharmacokinetics, which could simulate the internal exposure dose in specific organs based on the external exposure of pollutants, and provide reliable information for quantitative assessment of the metabolic concentrations of toxic chemicals [8]. At present, it has been widely used in the risk assessment of pollutants such as heavy metals, persistent organic pollutants, and organic pesticides [9,10,11].

By integrating and reanalyzing the published data, a comprehensive meta-analysis can reduce the uncertainty in a single study and improve the representativeness of the analysis results [12]. This is also a commonly used method for establishing pollutant limit standards and safety thresholds and risk assessments internationally [7, 10]. However, China has not established dietary Cd exposure limits based on the exposure characteristics of Chinese. In previous risk assessment studies, international standards such as EFSA or the Joint FAO/WHO Expert Committee on Food Additives (JECFA) standards were often used to evaluate the risk of the Chinese residents. The Cd pollution status and dietary patterns of the main data sources of the above standards, such as Europe and Japan, are quite different from those of China, inevitably affecting the accuracy of Cd exposure risk assessment in China. Therefore, it is essential to investigate the sensitive effect biomarker of Cd exposure and reference dietary Cd intake in Chinese population.

This study is based on the epidemiological studies of U-Cd and renal injury in China, aiming to evaluate the effects of Cd exposure on renal biomarkers in Chinese. In particular, this study attempts to (1) establish a dose–response relationship between U-Cd and renal biomarkers; (2) calculate the critical threshold dose of U-Cd in Chinese population based on continuous data; (3) use the TK model to calculate the dietary Cd exposure limit applicable to the Chinese population. As far as we know, this is the first study to conduct a large-scale systematic analysis of U-Cd and multiple effect biomarkers and estimate the tolerable dietary intake (TDI) limit of Cd in China. The results will provide reliable information for the establishment of dietary Cd limits and improve the risk assessment of Cd exposure among Chinese.

Materials and methods

Data collection

In this study, renal injury effects were used as the endpoints of Cd exposure. Systematic screening was performed in four common databases (Web of Science, PubMed, China National Knowledge Infrastructure (CNKI) and WANFANG Database). The U-Cd with renal injury biomarkers in Chinese were used as the research object to establish a comprehensive database.

Based on previous researches, four renal injury biomarkers were selected: β2-MG, N-acetyl-β-glucosidase (NAG), microalbumin (mALB), and retinol binding Protein (RBP). Taking the β2-MG as an example, the following search formulas were used to search in the databases: PubMed: Cadmium AND β2-Microglobulin AND (China OR Hongkong OR Taiwan); Web of science: TS = (Cadmium AND β2-Microglobulin) AND TS = (China OR Hongkong OR Taiwan); CNKI Database: SU = Cadmium AND SU = β2-Microglobulin; WANFANG Database: Subject: (Cadmium)*Subject: (β2-Microglobulin). (Published time: 1980.1–2021.3).

Literatures were included in a consolidated database by detailed screening based on the following criteria: 1. The study measured U-Cd (in μg/g creatinine or other units that could be converted) as biomarker of internal dose together with at least one biomarker of renal injury both as continuous variables; 2. If the research data are used in more than one study, the study providing the most complete and detailed information was chosen (e.g., the study which provides the most dose sub-groups); 3. In order to reduce the heterogeneities, the outliers and sample size below 15 were excluded.

Data processing

In order to harmonize and validate the database, some further checks and transformations were performed. Abnormal values or data from the same population were double-checked. The units of U-Cd were adjusted in consistent. U-Cd values reported in nmol/mmol Cr were transformed into μg/g Cr by applying the factor of 0.99375 (= Molar Mass (Cd)/ Molar Mass (creatinine)) [13]. In addition, geometric mean (GM) and geometric standard deviation (GSD) were used to record the included data. If the study only provided the arithmetic mean (AM) and arithmetic standard deviation (SD), the following data transformations were made [14, 15]:

If only the median and range (min, max) were provided, GM and GSD were converted according to the following formula [16]:

$$GM = Median$$
$$GSD={e }^{max(\mathit{log}\left(GM/min\right), log(max/GM)/{}^{-1}(1-1/2n)}$$

where Φ represents the cumulative density function of the standardized Gaussian distribution and n represents the sample size.

Calculation of U-Cd safety threshold

After the databases compilation, the benchmark dose software (BMDS) was used to calculate the BMD and BMDL. The Hill model (based on the EFSA, as preferred) and exponential model (as complementary) were used to evaluate the dose–response relationship between the mean dose of each population subgroup to the mean response. Akaike's information criterion was performed for model selection, and the model with the lowest Akaike's information criterion value was preferred. Goodness of fit test was conducted with the criteria of P > 0.05. The benchmark response factor (BMRF) is set at 5%. The risk type of BMR is extra for Hill model, indicating that the response associated with the BMR is the background estimate plus the product of the BMRF times the difference between the background estimate and the model estimates of the maximum response. The BMR type for exponential model is standard deviation (Std. Dev.), indicating the response associated with the BMR is the background estimate plus the product of the BMRF times the standard deviation for the control group data [17]. Among 4 biomarker databases, the BMD and BMDL of U-Cd were calculated and compared, and the lowest dose was selected as the safety threshold.

The dose–effect relationship described by Hill model is an S-shape with 4 parameters. The model equation is given by:

$$Effect\left(d\right)=background+amplitude\times {(d}^{\mathrm{\eta }}/({d}^{\mathrm{\eta }}+{ed}_{50}^{\mathrm{\eta }}))$$

where d stands for the dose (U-Cd), ‘amplitude’ corresponds to the difference between the 2 plateaux of the S-shape, ed50 corresponds to the dose where 50% of the maximal effect is achieved, and eta (η) corresponds to the shape parameter defining the steepness of the S curve. The exponential model, as a complementary model, is also used to fit the dose–effect relationship when the hill model does not fit well.

Derivation of dietary Cd expose TDI

Based on the U-Cd safety threshold, the TK model was used to estimate the TDI limits of the dietary Cd exposure. The formula of the TK model is as follows [18]:

$${Cd}_{urine}\left(age\right)=\frac{{f}_{u}\times {f}_{k}}{\mathrm{l}\mathrm{o}\mathrm{g}(2)}\times d\times {t}_{1/2}\frac{[1-\mathrm{e}\mathrm{x}\mathrm{p}(-\frac{\mathrm{log}\left(2\right)\times age}{{t}_{1/2}})]}{[1-\mathrm{e}\mathrm{x}\mathrm{p}(-\frac{\mathrm{log}\left(2\right)}{{t}_{1/2}})]}$$

where Cdurine (age) represents the U-Cd (μg/g Cr) at specific age; d is daily dietary Cd exposure (μg/kg/day); t1/2 is the half-life of Cd in the renal; fu*fk represents the comprehensive constant related to absorption. Parameters of the model referred to EFSA which were as follows [7, 18]: the half-life was drawn from a lognormal distribution (Mean: 11.6, SD: 3.0) to consider the variability among populations; age was set to be 50 years old; the absorption rate (fu*fk) is fixed at 0.0063. In addition, considering the differences between the studies, adjustment factor (AF(95) = 3.9) was introduced to account for the lack of individual data and avoid overestimation of the TDI limit [7]. A total of 100,000 Monte Carlo sampling iterations was conducted to estimate the relative frequency distribution of dietary Cd exposure in the Chinese corresponding to the U-Cd at threshold dose using @Risk. To ensure that 95% of the residents' U-Cd are below the safety threshold, the dietary Cd exposure corresponding to 5th percentiles of the population reaching this threshold was selected as the TDI limit.

Statistical analysis

The BMD/BMDL was calculated by BMDS (Version 2.7.0, Environmental Protection Agency, USA; @Risk 7.6 (Palisade software, USA) was used to conduct Monte Carlo sampling. Origin 2018 (OriginLab, Northampton, Massachusetts, USA) was used for drawing. SPSS 16.0 (SPSS Inc., Chicago, IL, USA) was used to perform other statistical analysis. Spearman correlation was used to determine the association between U-Cd and renal effect biomarkers. Mann–Whitney U test was used to compare the U-Cd or biomarkers among different subgroups. P < 0.05 was considered as statistically significant.

Included studies

After searching from 4 databases, a total of 158 studies were included in this study. The process of inclusion and exclusion of the study is shown in Fig. 1. Of all the included studies, 332 matched pairs of U-Cd and β2-MG levels can be gathered from 85 studies, followed by NAG (N = 29 with 143 data), mALB (N = 23 with 87 data), and RBP (N = 21 with 74 data). All included publications are listed in the supplementary material (Table S3-6). The composition of gender and occupational status in the database of different effect biomarkers is detailed in the supplementary material (Table S1). The gender composition of each dataset is uniform, and the sample size of the non-occupational is higher than that of the occupational population.

Fig. 1

Retrieval and exclusion flow chart of U-Cd and renal injury biomarkers

Characteristics of U-Cd and four effect biomarkers

The characteristics of U-Cd and four corresponding biomarkers (β2-MG, NAG, mALB, and RBP) in each dataset are listed in Table 1. In the database of β2-MG, the mean values of U-Cd and β2-MG are 4.89 and 384.6 μg/g Cr. In the NAG database, the mean values of U-Cd and NAG are 4.43 μg/g Cr and 8.18 U/g Cr. In the mALB databases, the mean values of U-Cd and mALB are 4.23 μg/g Cr and 7.66 mg/g Cr. In the database of RBP, the mean values of U-Cd and RBP are 6.12 and 215.62 μg/g Cr, respectively. Spearman coefficients show that β2-MG and NAG have significant positive correlations with U-Cd. The distribution characteristics of age, gender, and occupational exposure subgroups are listed in the supplementary material (Table S2). Figure 2 depicts the scatter plot of the U-Cd and four effect biomarkers on the log–log scale. Four biomarkers all show an increasing trend with U-Cd and the trend is more pronounced in high concentrations range.

Table 1 Dataset characteristics and Spearman coefficients of U-Cd and different effect biomarkers
Fig. 2

The scatter plot for the U-Cd and renal effect biomarkers (Color represents gender: red (female); blue (male), black (gender information is not clear); shape represents occupational: round (non-occupational), triangle (occupational); dot size represents sample size: size = sqrt (sample size)/158)

Urinary Cd safety threshold

The dose–response relationship fit by Hill or exponential model of U-Cd and the four effect biomarkers are shown in Fig. 3. Except for mALB, which uses the exponential model for fitting, the other three effect biomarkers are all fitted by Hill model. For the four effect biomarkers of β2-MG, NAG, mALB and RBP, the calculated BMD5 is 4.05, 3.43, 7.12 and 7.22 μg/g Cr, respectively, and the BMDL5 is 3.07, 2.98, 4.17 and 5.46 μg/g Cr, respectively. The corresponding U-Cd safety thresholds are listed in Table 2. The threshold dose of U-Cd derived by β2-MG and NAG are lower than the results of the mALB and RBP. EFSA chose β2-MG as the key biomarker, while NAG is the most sensitive biomarker in this study. Therefore, β2-MG and NAG were both selected as sensitive biomarkers for comparison. The corresponding BMDL52-MG: 3.07 μg/g Cr; NAG: 2.98 μg/g Cr) were used as U-Cd safety thresholds to derive the tolerable dietary Cd intake limits, respectively.

Fig. 3

Dose–response relationship between U-Cd and effect biomarkers. (The red solid curve is a fitted dose–response model (Hill or Exponential model). The horizontal line corresponds to a 5% change of the range of the response in the background (BMR = 0.05). The intersections of the horizontal line and the curve is the BMD. The BMDL is illustrated by the dashed-dotted line and represents the lower limit of the 95% confidence interval for BMD.)

Table 2 The BMD5/BMDL5 of the U-Cd for renal injury biomarkers

Tolerable dietary intake for Cd exposure

The cumulative probability distribution of dietary Cd exposure in Chinese population derived from the BMDL5 of U-Cd of NAG and β2-MG is shown in Fig. 4. In order to protect most people from kidney injury caused by Cd exposure, the dietary intake corresponding to the 5% quantile is selected as the TDI value, which are 0.28 μg/kg bw/day for NAG and 0.29 μg/kg bw/day for β2-MG, respectively. The more stringent value (0.28 μg/kg bw/day) was decided as the final TDI limit (16.8 μg/day, based on body weight of 60 kg). Within this TDI, at least 95% of the population have U-Cd concentrations below the safe threshold.

Fig. 4

Cumulative population frequency distribution of daily dietary Cd expose considering NAG and β2-MG as biomarkers to calculate U-Cd threshold

This study focused on the U-Cd and renal injury biomarkers among Chinese and conducted a comprehensive search for related studies. The dose–response relationships between U-Cd and four renal injury biomarkers were established using Hill or exponential model. β2-MG and NAG were used as the sensitive biomarkers to determine the BMDL5 of U-Cd safe thresholds (β2-MG: 3.07 μg/g Cr; NAG: 2.98 μg/g Cr). The TDI limit derived by TK model was determined to be 0.28 μg/kg bw/day. Within this limit, U-Cd concentrations of 95% of the residents in China would be below the safety threshold, effectively avoiding the risk of renal damage caused by dietary Cd exposure. This study provides reference for formulating of China's Cd exposure standards, which is conducive to objectively and accurately assessing the Cd exposure health risk of Chinese residents.

The dose–response relationship is the basis for risk assessment of pollutant exposure. In the past, the “No-observed-adverse-effect-level” (NOAEL), usually obtained by animal experiments, was commonly served as the potential key dose endpoint related to human health [19]. However, the dose setting, the sensitivity of the detection method and the sample size in the experimental design will have a great impact on the NOAEL results in practice. The BMD method, which was first proposed by Crump in 1984 [20], has been widely adopted in health risk assessment. The BMD is defined as the exposure level corresponding to a predetermined increase in the probability of an adverse response (e.g., 1%–10%) above the background level [21]. Because BMD can make full use of dose–response data and has lower dependence on experimental dose, which increases the reliability and accuracy of the results, it has been widely used in risk assessment [22].

U-Cd is the main indicator reflecting the degree of Cd accumulation in the body under long-term exposure, while blood Cd represents the Cd that enters the body more recently [23]. Choosing U-Cd as the internal exposure marker can well reflect the effect of long-term Cd exposure on the renal injury biomarkers. Renal injury is the main toxic effect caused by chronic low-dose Cd exposure [24]. β2-MG, RBP and NAG are biomarkers of renal tubular injury, and mALB is a biomarker of renal glomerular insufficiency [25]. This study showed that β2-MG and NAG were more sensitive to the changes in U-Cd. This suggested that tubular biomarkers were more sensitive to environmental Cd exposure than glomerular biomarkers, which was consistent with previous research [25]. However, the correlation between U-Cd and biomarkers of kidney function will be affected by many aspects such as normal variation in renal function (including changes in urinary flow) and concentration adjustment methods (creatinine, specific gravity, etc.). Low-level urinary Cd corrected with creatinine may cause a false association between Cd exposure and protein excretion [26]. Moreover, it is still inconclusive whether β2-MG or NAG can better reflect the degree of kidney injury. An 8-year follow-up study conducted in China's Cd-contaminated area showed that monitoring β2-MG can provide more comprehensive information on renal tubular function changes than NAG [27]. However, Moriguchi J et al. found that the correlation coefficient between U-Cd and NAG was higher than β2-MG, and NAG could be used as the most sensitive biomarker for monitoring renal tubular dysfunction for residents in non-polluted areas [28].

The safety threshold of U-Cd in Chinese (2.98 μg/g Cr) obtained in this study is lower than the EFSA result (4 μg/g Cr) [14], which was based on the U-Cd and β2-MG data in populations around the world. This could be caused by the fact that the data of EFSA contained extremely high values (β2-MG > 100,000 μg/g Cr) and affected the overall distribution of the model, resulting in higher BMDL. Other studies also supported a relative lower threshold of U-Cd. A recent evaluation by the International Union on Pure and Applied Chemistry (IUPAC) estimated a LOAEL for renal dysfunction of 2 nmol/mmol Cr (2 μg/g Cr) [29]. A study in China explored U-Cd limits in a polluted area in southwest China and determined BMDL5 to be 3.48 μg/g Cr [30]. The BMDL5 of U-Cd based on β2-MG in non-polluted areas in Zhejiang, China, was calculated to be 0.62–0.64 μg/g Cr [31]. Another study of residents in five different regions of China calculated the BMDL10 of U-Cd based on β2-MG to be 1.69–2.00 μg/g Cr [32]. Different characteristics of Cd exposure, pollution levels, and BMD analysis methods could lead to different BMDL results. The data of this study comes from a systematic analysis of nationwide researches, which includes not only ordinary residents, but also some polluted areas and occupationally exposed people. The obtained U-Cd safety threshold could cover most areas of China and represent the average level of Chinese population.

The TDI value of Cd in this study (16.8 μg/day for a 60 kg BW of adults) was lower than that of EFSA (21.6 μg/day) [7] and JECFA (50 μg/day) [33]. However, some cohort studies suggested that even if the dietary Cd intake was below the EFSA or JECFA standards, it might still increase the risk of death from cancer, cardiovascular disease, and Alzheimer's disease [34, 35]. A Swedish cohort study showed that a 32% increased risk of osteoporosis and 31% increased risk of fracture were observed when dietary Cd exposure was above 13 μg/day [36]. The impairment caused by long-term and low-level dietary Cd intake in population has now been implicated in more serious health outcomes than previously perceived [37]. This study referred to the EFSA standard establishment process and used BMDL5 and 5% population risk, which was a very conservative standard.

According to China National Nutrient and Health Survey, the mean Cd exposure of the general population was 15.3 μg/kg bw/month (approximately 30.6 μg/day), which was higher than the TDI in this study. Rice (contribution rate of over 55.8%), leafy vegetables (11.8%) and wheat flour (10.5%) were the three most important contributors to dietary Cd exposure. For the high exposure sub-population with Cd exposure above the 95th percentile, rice was still the main contributor (58.6%), followed by shellfish (13.2%) and leafy vegetables (9.2%) [38]. Another study in non-polluted areas of China pointed out that the median lifetime cumulative Cd intakes was 0.5 g [39], higher than the result from this study (0.37 g, calculated based on age 60). Due to the persistent of Cd in the environment and its high transfer rate from soil to plant [40], maintenance of low Cd in crops and leafy is pivotal. The more stringent TDI value of Cd put forth in this study suggested the need for a revision of dietary standards of Cd and public measures to minimize the food-chain contamination in China.

This study is the first to explore dietary limits for Chinese population based on a systematic analysis of four effect biomarkers of Cd exposure, but it is still subject to following limitations. First, the included research data were from different laboratories. The detection methods of U-Cd and effect biomarkers were inconsistent, which might cause systematic errors. Second, due to the low number of studies on other effect biomarkers (α1-microglobulin, bone density, serum calcium, etc.), only four renal injury biomarkers were analyzed. More high-quality and large-scale epidemiological studies in the future are warranted to provide reliable data for sensitive effect biomarkers and health risk assessment. Third, the TK model used to derive the TDI is established based on a Swedish female cohort. Due to the regional and ethnic differences in the absorption and metabolism characteristics of Cd in Chinese and European, the uncertainty of the results obtained by this model increased [41]. Last, potential kidney function damage and adjustment approach of biomarker concentrations in urine samples may affect the association between U-Cd and biomarkers of kidney function [42]. As there are few related prospective studies, it has become an inevitable obstacle to assess the causal relationship between pollutants and adverse outcomes in environmental epidemiological research.

This study comprehensively analyzed the dose–response relationship between U-Cd and renal injury biomarkers in Chinese residents. The BMDL5 of U-Cd using β2-MG and NAG as sensitive biomarkers was taken as the critical threshold of Cd exposure. Based on the TK model, a preliminary discussion on the limit standards of dietary Cd exposure for residents in China was conducted. This study provides a reference for formulating Chinese dietary Cd exposure limit standards.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Urinary Cd

Retinol binding Protein

Tolerable weakly intake

Tolerable dietary intake

Benchmark dose

Lower confidence bounds of benchmark dose

Benchmark response

Low-observed-adverse-effect level

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This work was supported by the National Key R&D Program of China of Ministry of Science and Technology of the People's Republic of China (No. 2017YFC1600500, 2017YFC1600200), and the Shanghai Sailing Program (No. 21YF1418500).

Author information

All authors have contributed substantially to this work. Ying Qing: Conceptualization, Methodology, Data curation, Writing-original draft. Writing-review & editing. Jiaqi Yang: Methodology, Software, Writing-review & editing. Yuanshen Zhu: Data curation. Yongzhen Li: Data curation. Weiwei Zheng: Writing-review & editing. Min Wu: Resources. Gengsheng He: Project administration, Validation, Supervision, Funding acquisition. The author(s) read and approved the final manuscript.

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Correspondence to Gengsheng He.

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Supplementary Information

Additional file 1: Table S1

. Composition of gender and occupation sample size (absolute values and percentage) for different kidney injury indicators. Table S2. Data distribution characteristics of age, gender, and occupational exposure subgroups of U-Cd and responder in different data sets. Table S3. Study-ID and corresponding references for urinary cadmium (U-Cd) and β2-microglobulin (β2-MG). Table S4. Study-ID and corresponding references for urinary cadmium (U-Cd) and N-acetyl-β-glucosidase (NAG).Table S5. Study-ID and corresponding references for urinary cadmium (U-Cd) and microalbumin (mALB). Table S6. Study-ID and corresponding references for urinary cadmium (U-Cd) and retinol binding Protein (RBP).

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Qing, Y., Yang, J., Zhu, Y. et al. Dose–response evaluation of urinary cadmium and kidney injury biomarkers in Chinese residents and dietary limit standards. Environ Health 20, 75 (2021).

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  • Cadmium
  • Toxicokinetic model
  • Effect biomarkers
  • Benchmark dose
  • Tolerable daily intake