Complementary and Alternative Medicine Use Among Women with Symptomatic Uterine Fibroids.

Objective: The aim of this study is to examine complementary and alternative medicine (CAM) use among women with symptomatic uterine fibroids in the United States. Materials and Methods: In this cross-sectional analysis of baseline data from a multicenter, prospective cohort study of premenopausal women undergoing surgery for symptomatic fibroids and who enrolled in the Uterine Leiomyoma Treatment with Radiofrequency Ablation study from 2017 to 2019, we contrast women indicating use of at least one CAM modality specifically for fibroid symptoms against women using CAM for other reasons and CAM nonusers. Multivariable logistic regression models were performed to identify participant characteristics independently associated with CAM use for fibroids. Results: Among 204 women, 55% were Black/African American and the mean age was 42 (standard deviation 6.6) years. CAM use was common (67%), with 42% (95% confidence interval [CI]: 35%-49%) reporting use of CAM specifically to treat fibroid symptoms. Most commonly, CAM treatments used for fibroids were diet (62%) and herbs (52%), while CAM treatments for other reasons were exercise (80%) and massage (43%). On average, each participant who reported CAM use utilized three different types of CAM modalities. In a multivariable model, participants were more likely to use CAM for fibroids if they had pelvic pressure (odds ratio [OR] 2.50, 95% CI: 1.07-5.87, p = 0.04), a body-mass index lower than average (OR 0.76, 95% CI: 0.60-0.97, p = 0.03), and a lower health-related quality of life score (OR 0.61, 95% CI: 0.46-0.81, p = 0.001). Conclusions: In this diverse sample of women with symptomatic fibroids, CAM use was highly prevalent. Our findings highlight the need for providers to query patients about CAM use and understand the role of CAM in fibroid management. ClinicalTrials.gov Identifier: NCT02100904.

Association of Social and Behavioral Risk Factors With Mortality Among US Veterans With COVID-19.

Importance: The US Department of Veterans Affairs (VA) offers programs that reduce barriers to care for veterans and those with housing instability, poverty, and substance use disorder. In this setting, however, the role that social and behavioral risk factors play in COVID-19 outcomes is unclear. Objective: To examine whether social and behavioral risk factors were associated with mortality among US veterans with COVID-19 and whether this association might be modified by race/ethnicity. Design, Setting, and Participants: This cohort study obtained data from the VA Corporate Data Warehouse to form a cohort of veterans who received a positive COVID-19 test result between March 2 and September 30, 2020, in a VA health care facility. All veterans who met the inclusion criteria were eligible to participate in the study, and participants were followed up for 30 days after the first SARS-CoV-2 or COVID-19 diagnosis. The final follow-up date was October 31, 2020. Exposures: Social risk factors included housing problems and financial hardship. Behavioral risk factors included current tobacco use, alcohol use, and substance use. Main Outcomes and Measures: The primary outcome was all-cause mortality in the 30-day period after the SARS-CoV-2 or COVID-19 diagnosis date. Multivariable logistic regression was used to estimate odds ratios, clustering for health care facilities and adjusting for age, sex, race, ethnicity, marital status, clinical factors, and month of COVID-19 diagnosis. Results: Among 27 640 veterans with COVID-19 who were included in the analysis, 24 496 were men (88.6%) and the mean (SD) age was 57.2 (16.6) years. A total of 3090 veterans (11.2%) had housing problems, 4450 (16.1%) had financial hardship, 5358 (19.4%) used alcohol, and 3569 (12.9%) reported substance use. Hospitalization occurred in 7663 veterans (27.7%), and 1230 veterans (4.5%) died. Housing problems (adjusted odds ratio [AOR], 0.96; 95% CI, 0.77-1.19; P = .70), financial hardship (AOR, 1.13; 95% CI, 0.97-1.31; P = .11), alcohol use (AOR, 0.82; 95% CI, 0.68-1.01; P = .06), current tobacco use (AOR, 0.85; 95% CI, 0.68-1.06; P = .14), and substance use (AOR, 0.90; 95% CI, 0.71-1.15; P = .41) were not associated with higher mortality. Interaction analyses by race/ethnicity did not find associations between mortality and social and behavioral risk factors. Conclusions and Relevance: Results of this study showed that, in an integrated health system such as the VA, social and behavioral risk factors were not associated with mortality from COVID-19. Further research is needed to substantiate the potential of an integrated health system to be a model of support services for households with COVID-19 and populations who are at risk for the disease.

Examining Clinics for Children with Autism: The Autism Translating To Treatment Study.

OBJECTIVES: Certain clinical providers specialize in providing complementary and integrative medicine (CIM) therapies for children with autism spectrum disorder (ASD). Because many of these providers and their patients/families have reported substantial improvement, the authors developed an online platform to carefully examine these clinical practices. The initial goal was to examine the feasibility of prospective data collection in this setting. The larger goals were to characterize the tests and treatments used in these clinics; examine associations between specific treatments, biomarkers, and improved outcomes; and identify promising treatments for future study. DESIGN: Prospective cohort study. SETTING: Four CIM clinics specializing in treating children with ASD. PATIENTS: Children with ASD age 2-8 years. INTERVENTIONS: The study protocol provided no interventions, but all interventions provided by the CIM clinical providers were recorded. OUTCOME MEASURES: Aberrant Behavior Checklist (ABC); Social Responsiveness Scale (SRS); and instruments that assessed sensory sensitivity, language, gastrointestinal (GI) symptoms, pediatric quality of life, and caregiver strain. RESULTS: Fourteen children were enrolled (mean age, 4.4 years). Over 3 months, the total behavior score (ABC) decreased (improved) from 110.8 to 103.8 (change, -7.0; 95% confidence interval [CI], -27.9 to 13.9), and the total social responsiveness score (SRS) decreased (improved) from 133.8 to 127.2 (change, -6.6; 95% CI, -30.5 to 17.3), but these changes were not statistically significant. Similarly, caregiver strain and pediatric quality of life decreased (improved) but by a nonsignificant amount. More severe GI symptoms and more severe ASD symptoms were associated with lower quality of life (p < 0.001). CONCLUSIONS: Barriers to successful data collection were identified. Despite these challenges, this study could confirm interesting associations between data elements, highlighting the future value of similar systems for improving evidence-based care in this population.

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism.

OBJECTIVE: Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. METHODS: A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 µg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. RESULTS: A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure - the clinician rated CGI-I score - was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine (p = 0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p = 0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. CONCLUSIONS: Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 ( clinicaltrials.gov1 ).

Prevalence and Predictors of Complementary and Alternative Medicine Use in a Large Insured Sample of Children with Autism Spectrum Disorders.

PURPOSE: The purpose of the present study was to examine the prevalence and predictors of complementary and alternative medicine (CAM) use as well as parental perceptions of CAM efficacy in a large, geographically diverse sample of children with Autism Spectrum Disorders (ASD). METHODOLOGY: Data were obtained from a web-based survey administered to parents of children with ASD at four sites participating in the Mental Health Research Network (MHRN). The web survey obtained information about services and treatments received by children with ASD as well as the caregivers' experiences with having a child with ASD. RESULTS: Approximately 88% of the sample had either used CAM in the past or had recently used some type of CAM. The following characteristics were associated with CAM use: greater parental education, younger child age, a mix of regular and special classroom settings and prescription drug use in the past three months. CONCLUSIONS: The use of CAM was very prevalent in this large, geographically diverse sample of children with ASD. It is critical that providers be prepared to discuss the advantages and potential side effects with families to help them make well-informed health care decisions and prevent possible CAM-drug interactions.

Inducible and reversible lentiviral and Recombination Mediated Cassette Exchange (RMCE) systems for controlling gene expression.

Manipulation of gene expression to invoke loss of function (LoF) or gain of function (GoF) phenotypes is important for interrogating complex biological questions both in vitro and in vivo. Doxycycline (Dox)-inducible gene expression systems are commonly used although success is often limited by high background and insufficient sensitivity to Dox. Here we develop broadly applicable platforms for reliable, tightly controlled and reversible Dox-inducible systems for lentiviral mediated generation of cell lines or FLP Recombination-Mediated Cassette Exchange (RMCE) into the Collagen 1a1 (Col1a1) locus (FLP-In Col1a1) in mouse embryonic stem cells. We significantly improve the flexibility, usefulness and robustness of the Dox-inducible system by using Tetracycline (Tet) activator (Tet-On) variants which are more sensitive to Dox, have no background activity and are expressed from single Gateway-compatible constructs. We demonstrate the usefulness of these platforms in ectopic gene expression or gene knockdown in multiple cell lines, primary neurons and in FLP-In Col1a1 mouse embryonic stem cells. We also improve the flexibility of RMCE Dox-inducible systems by generating constructs that allow for tissue or cell type-specific Dox-inducible expression and generate a shRNA selection algorithm that can effectively predict potent shRNA sequences able to knockdown gene expression from single integrant constructs. These platforms provide flexible, reliable and broadly applicable inducible expression systems for studying gene function.

Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism.

OBJECTIVE: Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with autism spectrum disorder (ASD). We sought to examine the feasibility of a novel, Internet-based clinical trial design to evaluate the efficacy of this supplement. METHOD: E-mail invitations were sent to parents of children aged 5 to 8 years enrolled in the Interactive Autism Network. All study procedures, including screening, informed consent, and collection of outcome measures took place over the Internet. The primary outcome measures were parent- and teacher-rated changes in hyperactivity on the Aberrant Behavior Checklist (ABC-H). RESULTS: During the 6-week recruitment period, 57 children from 28 states satisfied all eligibility criteria and were randomly assigned to 1.3 grams of omega-3 fatty acids or an identical placebo daily for 6 weeks. Outcome assessments were obtained from all 57 participants and 57 teachers, and the study was completed in 3 months. Children in the omega-3 fatty acid group had a greater reduction in hyperactivity (-5.3 points) compared to the placebo group (-2.6 points), but the difference was not statistically significant (1.9-point greater improvement in the omega-3 group, 95% CI = -2.2 to 5.2). Adverse events were rare and not associated with omega-3 fatty acids. Participant feedback was positive. CONCLUSION: Internet-based, randomized controlled trials of therapies in children with ASD are feasible and may lead to marked reductions in the time and cost of completing trials. A larger sample size is required to definitively determine the efficacy of omega-3 fatty acids. Clinical trial registration information-Omega-3 Fatty Acids for Hyperactivity Treatment in Autism Spectrum Disorder; http://clinicaltrials.gov; NCT01694667.

Brief report: Hyperbaric oxygen therapy (HBOT) in children with autism spectrum disorder: a clinical trial.

We sought to determine whether HBOT leads to parental reported behavioral changes and alterations in cytokines in children with ASD. Ten children completed 80 sessions of HBOT and all improved by 2 points on the clinician-rated CGI-I scale (much improved) as well as several parent-completed measures of behavior. The lack of a control group limits the ability to determine if improvements were related to HBOT. Enrolled children did not exhibit abnormal cytokine levels at baseline and no significant changes in mean cytokine levels were observed. Although this study was limited by the small sample size and by the variable nature of cytokines, we found no evidence that HBOT affects cytokine levels or that cytokine levels were associated with behavioral changes.

What do I tell patients about saw palmetto for benign prostatic hyperplasia?

Saw palmetto is widely used to treat lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Although there is passionate support for herbal and complementary therapies for LUTS, clinical evidence is mixed. Because there is a well-recognized, profound placebo effect in tests of efficacy for agents treating LUTS, it is imperative that all therapies be tested in placebo-controlled trials. This article reviews evidence of the efficacy and safety of saw palmetto for men with LUTS caused by BPH, with particular emphasis on published randomized clinical trials and the upcoming Complementary and Alternative Medicine for Urologic Symptoms (CAMUS) trial.

A pilot randomized controlled trial of omega-3 fatty acids for autism spectrum disorder.

We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3 g/day) for the treatment of hyperactivity in 27 children ages 3-8 with autism spectrum disorder (ASD). After 12 weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (± 4.8) points in the omega-3 group compared to 0.3 (± 7.2) points in the placebo group (p = 0.40; effect size = 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects.

Improving the prediction of response to therapy in autism.

Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.

Omega-3 fatty acids for autistic spectrum disorder: a systematic review.

We conducted a systematic review to determine the safety and efficacy of omega-3 fatty acids for autistic spectrum disorder (ASD). Articles were identified by a search of MEDLINE, EMBASE, and the Cochrane Database using the terms autism or autistic and omega-3 fatty acids. The search identified 143 potential articles and six satisfied all inclusion criteria. One small randomized controlled trial (n = 13) noted non-significant improvements in hyperactivity and stereotypy. The remaining five studies were small (n = 30, 22, 19, 9, and 1) with four reporting improvements in a wide range of outcomes including language and learning skills, parental observations of general health and behavior, a clinician-administered symptom scale, and clinical observations of anxiety. Due to the limitations of evidence from uncontrolled studies and the presence of only one small randomized controlled trial, there is currently insufficient scientific evidence to determine if omega-3 fatty acids are safe or effective for ASD.

Dietary supplement adverse events: report of a one-year poison center surveillance project.

BACKGROUND: The safety and efficacy of dietary supplements is of growing concern to regulators, health-care providers and consumers. Few scientific data exist on clinical effects and potential toxicities of marketed products. Harmful supplements may not be identified for months or years with existing adverse event monitoring mechanisms. Retrospective review of poison center statistics to capture supplement-associated toxicity also has limitations. METHODS: We collaborated with the FDA Center for Food Safety and Nutrition (CFSAN) to conduct a 1-year prospective surveillance study of dietary supplement-related poison control center calls in 2006. Prompt follow-up of symptomatic cases, laboratory analysis of implicated dietary supplements, and causality assessment by a case review expert panel were performed. RESULTS: Of 275 dietary supplements calls, 41% involved symptomatic exposures; and two-thirds were rated as probably or possibly related to supplement use. Eight adverse events required hospital admission. Sympathomimetic toxicity was most common, with caffeine products accounting for 47%, and yohimbe products accounting for 18% of supplement-related symptomatic cases. Suspected drug-herb interactions occurred in 6 cases, including yohimbe co-ingested with buproprion (1) and methamphetamine (3), and additive anticoagulant/antiplatelet effects of NSAIDs taken with fish oils (1) and ginkgo (1). Laboratory analysis identified a pharmacologically active substance in 4 cases; supplement toxicity was ruled unlikely when analytical testing was negative in 5 cases. CONCLUSION: Most supplement-related adverse events were minor. Clinically significant toxic effects were most frequently reported with caffeine and yohimbe-containing products. Active surveillance of poison control center reports of dietary supplement adverse events enables rapid detection of potentially harmful products, which may facilitate regulatory oversight.

A detailed safety assessment of a saw palmetto extract.

BACKGROUND: Saw palmetto is commonly used by men for lower-urinary tract symptoms. Despite its widespread use, very little is known about the potential toxicity of this dietary supplement. METHODS: The Saw palmetto for Treatment of Enlarged Prostates (STEP) study was a randomized clinical trial performed among 225 men with moderate-to-severe symptoms of benign prostatic hyperplasia, comparing a standardized extract of the saw palmetto berry (160 mg twice daily) with a placebo over a 1-year period. As part of this study, detailed data were collected on serious and non-serious adverse events, sexual functioning, and laboratory tests of blood and urine. Between-group differences were assessed with mixed-effects regression models. RESULTS: There were no significant differences observed between the saw palmetto and placebo-allocated participants in the risk of suffering at least one serious adverse event (5.4% vs. 9.7%, respectively; p=0.31) or non-serious symptomatic adverse event (34.8% vs. 30.1%, p=0.48). There were few significant between-group differences in sexual functioning or for most laboratory analyses, with only small differences observed in changes over time in total bilirubin (p=0.001), potassium (p=0.03), and the incidence of glycosuria (0% in the saw palmetto group vs. 3.7% in the placebo group, p=0.05). CONCLUSIONS: Despite careful assessment, no evidence for serious toxicity of saw palmetto was observed in this clinical trial. Given the sample size and length of this study, however, these data do not rule out potential rare adverse effects associated with the use of saw palmetto.

Herbal medicine in the United States: review of efficacy, safety, and regulation: grand rounds at University of California, San Francisco Medical Center.

INTRODUCTION: Herbal products have gained increasing popularity in the last decade, and are now used by approximately 20% of the population. Herbal products are complex mixtures of organic chemicals that may come from any raw or processed part of a plant, including leaves, stems, flowers, roots, and seeds. Under the current law, herbs are defined as dietary supplements, and manufacturers can therefore produce, sell, and market herbs without first demonstrating safety and efficacy, as is required for pharmaceutical drugs. Although herbs are often perceived as "natural" and therefore safe, many different side effects have been reported owing to active ingredients, contaminants, or interactions with drugs. RESULTS: Unfortunately, there is limited scientific evidence to establish the safety and efficacy of most herbal products. Of the top 10 herbs, 5 (ginkgo, garlic, St. John's wort, soy, and kava) have scientific evidence suggesting efficacy, but concerns over safety and a consideration of other medical therapies may temper the decision to use these products. CONCLUSIONS: Herbal products are not likely to become an important alternative to standard medical therapies unless there are changes to the regulation, standardization, and funding for research of these products.

Valerian for sleep: a systematic review and meta-analysis.

Insomnia affects approximately one-third of the adult population and contributes to increased rates of absenteeism, health care use, and social disability. Extracts of the roots of valerian (Valeriana officinalis) are widely used for inducing sleep and improving sleep quality. A systematic review of randomized, placebo-controlled trials of valerian for improving sleep quality is presented. An extensive literature search identified 16 eligible studies examining a total of 1093 patients. Most studies had significant methodologic problems, and the valerian doses, preparations, and length of treatment varied considerably. A dichotomous outcome of sleep quality (improved or not) was reported by 6 studies and showed a statistically significant benefit (relative risk of improved sleep = 1.8, 95% confidence interval, 1.2-2.9), but there was evidence of publication bias in this summary measure. The available evidence suggests that valerian might improve sleep quality without producing side effects. Future studies should assess a range of doses of standardized preparations of valerian and include standard measures of sleep quality and safety.

Saw palmetto and lower urinary tract symptoms: what is the latest evidence?

The use of dietary supplements for treating a wide range of health conditions has grown rapidly in the United States. In the field of men's health, the most common dietary supplement used is an extract of the berry of the saw palmetto plant, with which men commonly self-medicate in order to treat lower urinary tract symptoms. Throughout the past two decades, substantial literature has emerged examining the biologic and clinical effects of saw palmetto extracts. Several lines of evidence suggest that saw palmetto may exert physiologic effects consistent with a beneficial clinical effect on the mechanisms of benign prostatic hyperplasia. Although most clinical studies tend to suggest a modest efficacy benefit of saw palmetto, more recent studies are less consistent and the precise clinical value of saw palmetto for treating lower urinary tract symptoms remains undefined. Overall, there appear to be few safety concerns with short-term use of this herbal medicine, although large-scale and longer-term safety studies have not been performed. Higher-quality studies are currently underway to better define the potential benefits and risks of plant-based extracts for treating symptoms related to benign prostatic hyperplasia.