MD, PhD, MAE, FMedSci, FRSB, FRCP, FRCPEd.

causation

The purpose of this review was to

  • identify and map the available evidence regarding the effectiveness and harms of spinal manipulation and mobilisation for infants, children and adolescents with a broad range of conditions;
  • identify and synthesise policies, regulations, position statements and practice guidelines informing their clinical use.

Two reviewers independently screened and selected the studies, extracted key findings and assessed the methodological quality of included papers. A descriptive synthesis of reported findings was undertaken using a level-of-evidence approach.

Eighty-seven articles were included. Their methodological quality varied. Spinal manipulation and mobilisation are being utilised clinically by a variety of health professionals to manage paediatric populations with

  • adolescent idiopathic scoliosis (AIS),
  • asthma,
  • attention deficit hyperactivity disorder (ADHD),
  • autism spectrum disorder (ASD),
  • back/neck pain,
  • breastfeeding difficulties,
  • cerebral palsy (CP),
  • dysfunctional voiding,
  • excessive crying,
  • headaches,
  • infantile colic,
  • kinetic imbalances due to suboccipital strain (KISS),
  • nocturnal enuresis,
  • otitis media,
  • torticollis,
  • plagiocephaly.

The descriptive synthesis revealed: no evidence to explicitly support the effectiveness of spinal manipulation or mobilisation for any condition in paediatric populations. Mild transient symptoms were commonly described in randomised controlled trials and on occasion, moderate-to-severe adverse events were reported in systematic reviews of randomised controlled trials and other lower-quality studies. There was strong to very strong evidence for ‘no significant effect’ of spinal manipulation for managing

  • asthma (pulmonary function),
  • headache,
  • nocturnal enuresis.

There was inconclusive or insufficient evidence for all other conditions explored. There is insufficient evidence to draw conclusions regarding spinal mobilisation to treat paediatric populations with any condition.

The authors concluded that, whilst some individual high-quality studies demonstrate positive results for some conditions, our descriptive synthesis of the collective findings does not provide support for spinal manipulation or mobilisation in paediatric populations for any condition. Increased reporting of adverse events is required to determine true risks. Randomised controlled trials examining effectiveness of spinal manipulation and mobilisation in paediatric populations are warranted.

Perhaps the most important findings of this review relate to safety. They confirm (yet again) that there is only limited reporting of adverse events in this body of research. Six reviews, eight RCTs and five other studies made no mention of adverse events or harms associated with spinal manipulation. This, in my view, amounts to scientific misconduct. Four systematic reviews focused specifically on adverse events and harms. They revealed that adverse events ranged from mild to severe and even death.

In terms of therapeutic benefit, the review confirms the findings from the previous research, e.g.:

  • Green et al (Green S, McDonald S, Murano M, Miyoung C, Brennan S. Systematic review of spinal manipulation in children: review prepared by Cochrane Australia for Safer Care Victoria. Melbourne, Victoria: Victorian Government 2019. p. 1–67.) explored the effectiveness and safety of spinal manipulation and showed that spinal manipulation should – due to a lack of evidence and potential risk of harm – be recommended as a treatment of headache, asthma, otitis media, cerebral palsy, hyperactivity disorders or torticollis.
  • Cote et al showed that evidence is lacking to support the use of spinal manipulation to treat non-musculoskeletal disorders.

In terms of risk/benefit balance, the conclusion could thus not be clearer: no matter whether chiropractors, osteopaths, physiotherapists, or any other healthcare professionals propose to manipulate the spine of your child, DON’T LET THEM DO IT!

Onion water seems to be all the rage these days. Advocates claim that it is a natural cold and flu remedy that can help the body heal faster and kick symptoms like coughing and congestion. And many consumers who feel threatened by flu, COVID, and various respiratory infections believe them.

But what on earth is onion water? It is precisely what it sounds like: onion immersed in water. Preparation starts with cutting up raw red or yellow onions, placing them into a bowl, and adding water. The fresh onion and water mixture should then soak for about 12 hours. After that, the onion water is ready for consumption.

Besides being a recipe for bad breath, can onion water actually relieve any symptoms, or help the body heal from infections?

A review of the evidence concluded that “effect of onion and its constituents on oxidative stress, inflammatory and immune system were shown indicating their therapeutic value in treatment of various diseases associated with oxidative stress, inflammation, and immune-dysregulation.”

This may sound encouraging but the review was based mostly on pre-clinical evidence, and the question, therefore, remains: are there any good trial data?

Another recent review included clinical trials (where available) and concluded that “possible bronchodilatory and preventive effects of onion and Qt on asthma and other obstructive respiratory diseases. The effects of the plant and its constituents on lung cancer, lung infections, and allergic disorders were also reported both in experimental and clinical studies. However, before preparing drugs based on A. cepa and its constituents for clinical practice, further standard clinical trials are needed to be performed.”

In other words, compelling trial evidence that preparations from onion are effective against viral infections does not exist.

And what about homeopathy?

Homeopaths frequently use potentised onion as a remedy for conditions that cause eyes to water (because ‘like cures like’). Is there any sound evidence that homeopathic onion remedies are better than a placebo? You probably guessed: the answer is NO!

So, no good evidence for onion, potentised onion, onion water, or any other preparations of onion. My advice, therefore, is to continue using your onions in the kitchen rather than in the medicine cabinet.

This double-blind, randomized study assessed the effectiveness of physiotherapy instrument mobilization (PIM) in patients with low back pain (LBP) and compared it with the effectiveness of manual mobilization.

Thirty-two participants with LBP were randomly assigned to one of two groups:

  • The PIM group received lumbar mobilization using an activator instrument, stabilization exercises, and education.
  • The manual group received lumbar mobilization using a pisiform grip, stabilization exercises, and education.

Both groups had 4 treatment sessions over 2-3 weeks. The following outcomes were measured before the intervention, and after the first and fourth sessions:

  • Numeric Pain Rating Scale (NPRS),
  • Oswestry Disability Index (ODI) scale,
  • Pressure pain threshold (PPT),
  • lumbar spine range of motion (ROM),
  • lumbar multifidus muscle activation.

There were no differences between the PIM and manual groups in any outcome measures. However, over the period of study, there were improvements in both groups in NPRS (PIM: 3.23, Manual: 3.64 points), ODI (PIM: 17.34%, Manual: 14.23%), PPT (PIM: ⩽ 1.25, Manual: ⩽ 0.85 kg.cm2), lumbar spine ROM (PIM: ⩽ 9.49∘, Manual: ⩽ 0.88∘), and/or lumbar multifidus muscle activation (percentage thickness change: PIM: ⩽ 4.71, Manual: ⩽ 4.74 cm; activation ratio: PIM: ⩽ 1.17, Manual: ⩽ 1.15 cm).

The authors concluded that both methods of lumbar spine mobilization demonstrated comparable improvements in pain and disability in patients with LBP, with neither method exhibiting superiority over the other.

If this conclusion is meant to tell us that both treatments were equally effective, I beg to differ. The improvements documented here are consistent with improvements caused by the natural history of the condition, regression towards the mean, and placebo effects. The data do not prove that they are due to the treatments. On the contrary, they seem to imply that patients get better no matter what therapy is used. Thus, I feel that the results are entirely in keeping with the hypothesis that spinal mobilization is a placebo treatment.

So, allow me to re-phrase the authors’ conclusion as follows:

Lumbar mobilizations do not seem to have specific therapeutic effects and might therefore be considered to be ineffective for LBP.

Acupuncture is emerging as a potential therapy for relieving pain, but the effectiveness of acupuncture for relieving low back and/or pelvic pain (LBPP) during pregnancy remains controversial. This meta-analysis aimed to investigate the effects of acupuncture on pain, functional status, and quality of life for women with LBPP pain during pregnancy.

The authors included all RCTs evaluating the effects of acupuncture on LBPP during pregnancy. Data extraction and study quality assessments were independently performed by three reviewers. The mean differences (MDs) with 95% CIs for pooled data were calculated. The primary outcomes were pain, functional status, and quality of life. The secondary outcomes were overall effects (a questionnaire at a post-treatment visit within a week after the last treatment to determine the number of people who received good or excellent help), analgesic consumption, Apgar scores >7 at 5 min, adverse events, gestational age at birth, induction of labor and mode of birth.

Ten studies, reporting on a total of 1040 women, were included. Overall, acupuncture

  • relieved pain during pregnancy (MD=1.70, 95% CI: (0.95 to 2.45), p<0.00001, I2=90%),
  • improved functional status (MD=12.44, 95% CI: (3.32 to 21.55), p=0.007, I2=94%),
  • improved quality of life (MD=−8.89, 95% CI: (−11.90 to –5.88), p<0.00001, I2 = 57%).

There was a significant difference in overall effects (OR=0.13, 95% CI: (0.07 to 0.23), p<0.00001, I2 = 7%). However, there was no significant difference in analgesic consumption during the study period (OR=2.49, 95% CI: (0.08 to 80.25), p=0.61, I2=61%) and Apgar scores of newborns (OR=1.02, 95% CI: (0.37 to 2.83), p=0.97, I2 = 0%). Preterm birth from acupuncture during the study period was reported in two studies. Although preterm contractions were reported in two studies, all infants were in good health at birth. In terms of gestational age at birth, induction of labor, and mode of birth, only one study reported the gestational age at birth (mean gestation 40 weeks).

The authors concluded that acupuncture significantly improved pain, functional status and quality of life in women with LBPP during the pregnancy. Additionally, acupuncture had no observable severe adverse influences on the newborns. More large-scale and well-designed RCTs are still needed to further confirm these results.

What should we make of this paper?

In case you are in a hurry: NOT A LOT!

In case you need more, here are a few points:

  • many trials were of poor quality;
  • there was evidence of publication bias;
  • there was considerable heterogeneity within the studies.

The most important issue is one studiously avoided in the paper: the treatment of the control groups. One has to dig deep into this paper to find that the control groups could be treated with “other treatments, no intervention, and placebo acupuncture”. Trials comparing acupuncture combined plus other treatments with other treatments were also considered to be eligible. In other words, the analyses included studies that compared acupuncture to no treatment at all as well as studies that followed the infamous ‘A+Bversus B’ design. Seven studies used no intervention or standard of care in the control group thus not controlling for placebo effects.

Nobody can thus be in the slightest surprised that the overall result of the meta-analysis was positive – false positive, that is! And the worst is that this glaring limitation was not discussed as a feature that prevents firm conclusions.

Dishonest researchers?

Biased reviewers?

Incompetent editors?

Truly unbelievable!!!

In consideration of these points, let me rephrase the conclusions:

The well-documented placebo (and other non-specific) effects of aacupuncture improved pain, functional status and quality of life in women with LBPP during the pregnancy. Unsurprisingly, acupuncture had no observable severe adverse influences on the newborns. More large-scale and well-designed RCTs are not needed to further confirm these results.

PS

I find it exasperating to see that more and more (formerly) reputable journals are misleading us with such rubbish!!!

The U.S. Food and Drug Administration issued warning letters to seven companies for illegally selling dietary supplements that claim to cure, treat, mitigate or prevent cardiovascular disease or related conditions, such as atherosclerosis, stroke or heart failure, in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FDA is urging consumers not to use these or similar products because they have not been evaluated by the FDA to be safe or effective for their intended use and may be harmful.

The warning letters were issued to:

“Given that cardiovascular disease is the leading cause of death in the U.S., it’s important that the FDA protect the public from products and companies that make unlawful claims to treat it. Dietary supplements that claim to cure, treat, mitigate or prevent cardiovascular disease and related conditions could potentially harm consumers who use these products instead of seeking safe and effective FDA-approved treatments from qualified health care providers,” said Cara Welch, Ph.D., director of the Office of Dietary Supplement Programs in the FDA’s Center for Food Safety and Applied Nutrition. “We encourage consumers to remain vigilant when shopping online or in stores to avoid purchasing products that could put their health at risk.”

Under the FD&C Act, products intended to diagnose, cure, treat, mitigate or prevent disease are drugs and are subject to the requirements that apply to drugs, even if they are labeled as dietary supplements. Unlike drugs approved by the FDA, the agency has not evaluated whether the unapproved products subject to the warning letters announced today are effective for their intended use, what the proper dosage might be, how they could interact with FDA-approved drugs or other substances, or whether they have dangerous side effects or other safety concerns.

The FDA advises consumers to talk to their doctor, pharmacist or other health care provider before deciding to purchase or use any dietary supplement or drug. Some supplements might interact with medicines or other supplements. Health care providers will work with patients to determine which treatment is the best option for their condition.

If a consumer thinks that a product might have caused a reaction or an illness, they should immediately stop using the product and contact their health care provider. The FDA encourages health care providers and consumers to report any adverse reactions associated with FDA-regulated products to the agency using MedWatch or the Safety Reporting Portal.

The FDA has requested responses from the companies within 15 working days stating how they will address the issues described in the warning letters or provide their reasoning and supporting information as to why they think the products are not in violation of the law. Failure to correct violations promptly may result in legal action, including product seizure and/or injunction.

The aim of this evaluator-blinded randomized clinical trial was to determine if manual therapy added to a therapeutic exercise program produced greater improvements than a sham manual therapy added to the same exercise program in patients with non-specific shoulder pain.

Forty-five subjects were randomly allocated into one of three groups:

  • manual therapy (glenohumeral mobilization technique and rib-cage technique);
  • thoracic sham manual therapy (glenohumeral mobilization technique and rib-cage sham technique);
  • sham manual therapy (sham glenohumeral mobilization technique and rib-cage sham technique).

All groups also received a therapeutic exercise program. Pain intensity, disability, and pain-free active shoulder range of motion were measured post-treatment and at 4-week and 12-week follow-ups. Mixed-model analyses of variance and post hoc pairwise comparisons with Bonferroni corrections were constructed for the analysis of the outcome measures.

All groups reported improved pain intensity, disability, and pain-free active shoulder range of motion. However, there were no between-group differences in these outcome measures.

The authors concluded that the addition of the manual therapy techniques applied in the present study to a therapeutic exercise protocol did not seem to add benefits to the management of subjects with non-specific shoulder pain.

What does that mean?

I think it means that the improvements observed in this study were due to 1) exercise and 2) a range of non-specific effects, and that they were not due to the manual techniques tested.

I cannot say that I find this enormously surprising. But I would also find it unsurprising if fans of these methods would claim that the results show that the physios applied the techniques not correctly.

In any case, I feel this is an interesting study, not least because of its use of sham therapy. But I somehow doubt that the patients were unable to distinguish sham from verum. If so, the study was not patient-blind which obviously is difficult to achieve with manual treatments.

Shiatsu is a Japanese form of so-called alternative medicine (SCAM) derived from Traditional Chinese Medicine using deep pressure on the paths of the postulated acupuncture meridians. Clinical observations on this topic are said to be encouraging, especially for the treatment of sleep and conduct disorders, but there is a lack of empirical data.

The objective of this study was to examine the possible therapeutic effects of shiatsu in a clinical population of children treated in child and adolescent psychiatry. It was designed as a qualitative descriptive and non-interventional study, conducted on children treated in day-care hospital units and outpatient clinical settings. Shiatsu was administered, at least during 3 sessions, to children with an autism spectrum disorder or other disorders according to ICD-11 criteria (such as conduct disorders with impulsivity or attention deficit).

The evaluation was performed by two independent researchers (a child psychiatrist and a psychologist who were not the caregivers) based on direct observation of children during the shiatsu sessions, combined with semi-structured non-inductive interviews with their parents, and data collected from focus groups conducted with the children’s caregivers. A phenomenological interpretive analysis (IPA) approach with Nvivo coding software was used to analyze the data.

Based on semi-structured interviews with 13 parents cross-referenced with data from 2 focus groups and direct observations of 7 children during 2 full shiatsu sessions for each observation, the results show that shiatsu has positive effects on

  • internal tension (a relief effect, notably on aggressive behaviors directed against others or self),
  • sleep (including improvement of sleep quality),
  • social interaction,
  • attention,
  • verbalization of affects and traumatic memories of early childhood,
  • perception of bodily limits.

As these children had several other treatments as well, it cannot be proved that the positive effects observed in this study are related specifically to shiatsu practice. Shiatsu may participate and facilitate the effects of other treatments. It is noteworthy that most of the children came willingly to the shiatsu sessions, ask their parents to repeat the shiatsu sessions at home, and indicate to the practitioner, from one session to the next, their elective body points where they wish to receive the application of shiatsu.

The authors concluded that the findings suggest therapeutic benefits of shiatsu, especially on externalize violence with a relief of aggressive behavior directed against others or self (knowing, moreover, that internal tension, sleep disorders and non-verbalization of affects or traumatic memories, all improved by shiatsu, are also all risk factors for externalize violence). These results highlight, therefore, the need to develop a daily practice of shiatsu in child and adolescent psychiatry. Further research is required to clarify the effects of shiatsu and ascertain better its underlying mechanisms based on this exploratory pilot study.

I do appreciate that, with a treatment that has not been submitted to many controlled clinical trials, researchers feel that they have to start from scratch, e.g. simple observations. However, they also must realize that their observations do not lend themselves to firm conclusions about the effects of the treatment. In the present case, the researchers do seem to be aware of this caveat but nevertheless make statements that go way beyond of what is warranted:

  • the results show that shiatsu has positive effects on …
  • Shiatsu may participate and facilitate the effects of other treatments
  • the findings suggest therapeutic benefits of shiatsu, especially on externalize violence
  • These results highlight, therefore, the need to develop a daily practice of shiatsu in child and adolescent psychiatry

I fear that these statements are not merely exaggerated but suspect they are also untrue. Testing them in properly controlled clinical trials would show whether my suspicion is correct. Meanwhile, I would like to remind

  • researchers,
  • reviewers,
  • and journal editors

of their duty to be truthful and not mislead the public.

 

This study aimed to evaluate the number of craniosacral therapy sessions that can be helpful to obtain a resolution of the symptoms of infantile colic and to observe if there are any differences in the evolution obtained by the groups that received a different number of Craniosacral Therapy sessions at 24 days of treatment, compared with the control group which did not received any treatment.

Fifty-eight infants with colic were randomized into two groups:

  • 29 babies in the control group received no treatment;
  • babies in the experimental group received 1-3 sessions of craniosacral therapy (CST) until symptoms were resolved.

Evaluations were performed until day 24 of the study. Crying hours served as the primary outcome measure. The secondary outcome measures were the hours of sleep and the severity, measured by an Infantile Colic Severity Questionnaire (ICSQ).

Statistically significant differences were observed in favor of the experimental group compared to the control group on day 24 in all outcome measures:

  • crying hours (mean difference = 2.94, at 95 %CI = 2.30-3.58; p < 0.001);
  • hours of sleep (mean difference = 2.80; at 95 %CI = – 3.85 to – 1.73; p < 0.001);
  • colic severity (mean difference = 17.24; at 95 %CI = 14.42-20.05; p < 0.001).

Also, the differences between the groups ≤ 2 CST sessions (n = 19), 3 CST sessions (n = 10), and control (n = 25) were statistically significant on day 24 of the treatment for crying, sleep and colic severity outcomes (p < 0.001).

The authors concluded that babies with infantile colic may obtain a complete resolution of symptoms on day 24 by receiving 2 or 3 CST sessions compared to the control group, which did not receive any treatment.

Why do SCAM researchers so often have no problem leaving the control group of patients in clinical trials without any treatment at all, while shying away from administering a placebo? Is it because they enjoy being the laughingstock of the science community? Probably not.

I suspect the reason might be that often they know that their treatments are placebos and that their trials would otherwise generate negative findings. Whatever the reasons, this new study demonstrates three things many of us already knew:

  1. Colic in babies always resolves on its own but can be helped by a placebo response (e.g. via the non-blinded parents), by holding the infant, and by paying attention to the child.
  2. Flawed trials lend themselves to drawing the wrong conclusions.
  3. Craniosacral therapy is not biologically plausible and most likely not effective beyond placebo.

Guest post by Norbert Aust and Viktor Weisshäupl

Readers of this blog may remember the recent study of Frass et al. about the adjunct homeopathic treatment of patients suffering from non-small cell lung cancer (here). It was published in 2020 by the ‘Oncologist’, a respectable journal, and came to stunning results about to the effectiveness of homeopathy.

In our analysis, however, we found strong indications for duplicity: important study parameters like exclusion criteria or observation time were modified post hoc, and data showed characteristics that occur when unwanted data sets get removed.

We, that is the German Informationsnetzwerk Homöopathie and the Austrian ‘Initiative für wissenschaftliche Medizin’, had informed the Medical University Vienna about our findings – and the research director then asked the Austrian Agency for Scientific Integrity (OeAWI) to review the paper. The analysis took some time and included not only the paper and publicly available information but also the original data. In the end, OeAWI corroborated our findings: The results are not based on sound research but on modified or falsified data.

Here is their conclusion in full:

The committee concludes that there are numerous breaches of scientific integrity in the Study, as reported in the Publication. Several of the results can only be explained by data manipulation or falsification. The Publication is not a fair representation of the Study. The committee cannot for all the findings attribute the wrongdoings and incorrect representation to a single individual. However following our experience it is highly unlikely that the principal investigator and lead author, but also the co-authors were unaware of the discrepancies between the protocols and the Publication, for which they bear responsibility. (original English wording)

Profil, the leading news magazine of Austria reported in its issue of October 24, 2022, pp 58-61 (in German). There the lead author, Prof. M. Frass, a member of Edzard’s alternative medicine hall of fame, was asked for his comments. Here is his concluding statement:

All the allegations are known to us and completely incomprehensible, we can refute all of them. Our work was performed observing all scientific standards. The allegation of breaching scientific integrity is completely unwarranted. To us, it is evident that not all documents were included in the analysis of our study. Therefore we requested insight into the records to learn about the basis for the final statement.

(Die Vorwürfe sind uns alle bekannt und absolut unverständlich, alle können wir entkräften. Unsere Arbeit wurde unter Einhaltung aller wissenschaftlichen Standards durchgeführt. Der Vorhalt von Verstößen gegen die wissenschaftliche Intergrität enbehrt jeder Grundlage. Für uns zeigt sich offenkundig, dass bei der Begutachtung unserer Studie nicht alle Unterlagen miteinbezogen wurden. Aus diesem Grunde haben wir um Akteneinsicht gebeten, um die Grundlagen für das Final Statment kennenzulernen.)

The OeAWI together with the Medical University Vienna asked the ‘Oncologist’ for a retraction of this paper – which has not occurred as yet.

Turmeric is a commonly used herbal product implicated in causing liver injury. The aim of this case series was to describe the clinical, histologic, and human leukocyte antigen (HLA) associations of turmeric-associated liver injury enrolled in the U.S. Drug Induced Liver Injury Network (DILIN).

All adjudicated cases enrolled in DILIN between 2004-2022 in which turmeric was an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing.

Ten cases of turmeric-associated liver injury were found, all enrolled since 2011 and six since 2017. Of the 10 cases, 8 were women, 9 were White and the median age was 56 years (range, 35-71). Liver injury was hepatocellular in 9 patients and mixed in one. Liver biopsies in 4 patients showed acute hepatitis or mixed cholestatic-hepatitic injury with eosinophils. Five patients were hospitalized, and one patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products tested; 3 also contained piperine (black pepper). HLA typing demonstrated that 7 patients carried HLA-B*35:01, 2 of whom were homozygous, yielding an allele frequency of 0.450 compared to population controls of 0.056-0.069.

The authors concluded that liver injury due to turmeric appears to be increasing in the United States, perhaps reflecting usage patterns or increased combination with black pepper. Turmeric causes potentially severe liver injury that is typically hepatocellular, with a latency of 1 to 4 months and strong linkage to HLA-B*35:01.

Turmeric or curcumin is said to cause multiple effects, such as inhibiting inflammation, oxidative stress, tumor cell proliferation, cell death, and infection. Yet, sound clinical trials to test whether these effects might translate into health benefits are rare. In addition, the bioavailability of oral turmeric supplements is known to be low.

Turmeric has been used in food for millennia and is thus generally considered to be safe. Known adverse effects include gastrointestinal problems such as nausea and diarrhea and allergic reactions. Clearly, the new case series casts considerable doubt on the safety of turmeric. Yet, one ought to point out that the number of cases is low (but, on the other hand under-reporting can be assumed to be high). Furthermore, we should take into account that the quality of commercially available products is often low. One must therefore ask whether the liver injuries were truly caused by turmeric itself or by contaminants.

My conclusion is that turmeric is unquestionably an interesting plant with considerable potential as a medicine. At present, there is much hype surrounding it. Yet, hype is almost always contra-productive. If we want to know the true value of turmeric, we need to solve the bioavailability problem and do much more research into its safety and efficacy for defined conditions.

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