Challenges in Reporting Adverse Events from Dietary Supplements.

In 2008, the Institute of Medicine (IOM) Committee on Dietary Supplement Use by Military Personnel recommended the development of service wide military policies (e.g., education or regulations) to guide commanders in management practices for safe use of dietary supplements (DS). This review summarizes the activities the military has undertaken to advance the safe use of DS by Service Members and develop best practices on reporting adverse events across the Department of Defense (DoD). In March 2022, the Department of Defense issued a DoD Instruction (DoDI) regarding the use of DS by members of the U S. military. This DoDI provides guidelines to establish an official list of prohibited substances. The DoDI also identifies Operation Supplement Safety (OPSS) at CHAMP as DoD's "go to" program for DS use and information about DS and ingredients. Noted are a number of gaps in the reporting of adverse events from DS that need to be addressed by multiple constituencies.

Perspective: Call for Re-evaluation of the Tolerable Upper Intake Level for Magnesium Supplementation in Adults.

In 1997, the US Institute of Medicine (IOM) dietary reference intakes (DRI) Committee established a magnesium (Mg) tolerable upper intake level (UL) for adults of 350 mg/d from supplemental intake alone. Diarrhea was the limiting factor. The safety of oral Mg dietary supplements exceeding the UL is currently in debate. Increasing the UL may result in more Mg supplementation, decreasing the prevalence of undernutrition for this nutrient and thus providing additional protection against numerous chronic diseases. This perspective aims to show that more recent and comprehensive evidence-based data on the occurrence of diarrhea indicate that the Mg UL for adults should be re-evaluated. To update the literature base to re-evaluate setting the Mg UL, a PubMed search was conducted to identify intervention studies published between 1997 and 2022 that used single-ingredient Mg products reporting a priori diarrhea adverse events among adults. The Food and Drug Administration Center for Food Safety and Adverse Event Reporting System (CAERS) was also searched for adverse events caused by Mg supplementation. The PubMed search identified 10 studies, including 5 meta-analyses and 5 randomized controlled trials, that met the search criteria. Seven studies (Mg intakes of 128-1200 mg/d) found no significant differences in diarrhea occurrence between the intervention and control groups. One meta-analysis found only minor differences in gastrointestinal disturbances between groups given placebo versus 520 mg Mg/d, but withdrawals were not significantly different between groups. Another meta-analysis found that 3 of 13 studies (120-973 mg/d) reported diarrhea that led to study withdrawal, but the treatment arm was not specified in 2 studies. The CAERS search, when limited to single-ingredient suspect Mg products, found only 40 attributable cases of gastrointestinal adverse events. Only one-third of these 40 cases noted a complaint of diarrhea. These updated data indicate that doses above the current UL for Mg supplements can be consumed without adverse events.

Conceptualizing a resilience research framework at The National Institutes of Health.

The National Institutes of Health (NIH) have recently gathered internal and external input towards a shared understanding of resilience in the wide context of human health and the biomedical sciences that would help accelerate advances in human health and its maintenance. This shared view is that resilience refers in general to a system's capacity to recover, grow, adapt, or resist perturbation from a challenge or stressor. Over time, a system's response to a challenge might show varied degrees of reactions that likely fluctuate in response to the type of challenge (internal and/or external), severity of the challenge, the length of time exposed to the challenge, other external factors and/or biological factors (innate and/or external). We have embarked on this special issue as an opportunity to explore commonalities amongst viewpoints on the science of resilience covered by the various NIH Institutes, Centers, and Offices (ICOs) with respect to the characterization of various systems, stressors, outcomes measures and metrics, and interventions and/or protective factors that are shared within each domain and across multiple domains. Here, resilience is characterized broadly by four areas of scientific study: molecular/cellular, physiologic, psychosocial and spiritual, and environmental/community resilience. Each area or domain provides general frameworks for designing studies that may help advance the science of resilience within the context of health maintenance. This special issue will also acknowledge the remaining gaps that impede advancement of the science of resilience and offer considerations for potential next steps towards addressing the research gaps.

Next steps: Operationalizing resilience research.

The National Institutes of Health have recently gathered internal and external input towards a shared understanding of resilience in the wide context of human health and the biomedical sciences that would help accelerate advances in human health and its maintenance. We suggest the current view that resilience refers in general to a system's capacity to recover, grow, adapt, or resist perturbation from a challenge or stressor. To help harmonize the design and reporting of resilience research studies across multiple domains we have developed and are proposing a Resilience Research Design (ResD) Tool. Researchers can use the Resilience ResD Tool to proceed through a flowchart of six questions that will guide identification of key features in a resilience research study. Through this special supplement, we have shown the application of the Resilience ResD Tool and suggest opportunities and gaps with respect to next steps towards operationalizing resilience research.

Calcium and vitamin D for increasing bone mineral density in premenopausal women.

BACKGROUND: Osteoporosis is a condition where bones become fragile due to low bone density and impaired bone quality. This results in fractures that lead to higher morbidity and reduced quality of life. Osteoporosis is considered a major public health concern worldwide. For this reason, preventive measurements need to be addressed throughout the life course. Exercise and a healthy diet are among the lifestyle factors that can help prevent the disease, the latter including intake of key micronutrients for bone, such as calcium and vitamin D. The evidence on whether supplementation with calcium and vitamin D improves bone mineral density (BMD) in premenopausal women is still inconclusive. In this age group, bone accrual is considered to be the goal of supplementation, so BMD is relevant for the future stages of life. OBJECTIVES: To evaluate the benefits and harms of calcium and vitamin D supplementation, alone or in combination, to increase the BMD, reduce fractures, and report the potential adverse events in healthy premenopausal women compared to placebo. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 12 April 2022. SELECTION CRITERIA: We included randomised controlled trials in healthy premenopausal women (with or without calcium or vitamin D deficiency) comparing supplementation of calcium or vitamin D (or both) at any dose and by any route of administration versus placebo for at least three months. Vitamin D could have been administered as cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Outcomes included total hip bone mineral density (BMD), lumbar spine BMD, quality of life, new symptomatic vertebral fractures, new symptomatic non-vertebral fractures, withdrawals due to adverse events, serious adverse events, all reported adverse events and additional withdrawals for any reason. MAIN RESULTS: We included seven RCTs with 941 participants, of whom 138 were randomised to calcium supplementation, 110 to vitamin D supplementation, 271 to vitamin D plus calcium supplementation, and 422 to placebo. Mean age ranged from 18.1 to 42.1 years. Studies reported results for total hip or lumbar spine BMD (or both) and withdrawals for various reasons, but none reported fractures or withdrawals for adverse events or serious adverse events. Results for the reported outcomes are presented for the three comparisons: calcium versus placebo, vitamin D versus placebo, and calcium plus vitamin D versus placebo. In all comparisons, there was no clinical difference in outcomes, and the certainty of the evidence was moderate to low. Most studies were at risk of selection, performance, detection, and reporting biases. Calcium versus placebo Four studies compared calcium versus placebo (138 participants in the calcium group and 123 in the placebo group) with mean ages from 18.0 to 47.3 years. Calcium supplementation may have little to no effect on total hip or lumbar spine BMD after 12 months in three studies and after six months in one study (total hip BMD: mean difference (MD) -0.04 g/cm2, 95% confidence interval (CI) -0.11 to 0.03; I2 = 71%; 3 studies, 174 participants; low-certainty evidence; lumbar spine BMD: MD 0 g/cm2, 95% CI -0.06 to 0.06; I2 = 71%; 4 studies, 202 participants; low-certainty evidence). Calcium alone supplementation does not reduce or increase the withdrawals in the trials (risk ratio (RR) 0.78, 95% CI 0.52 to 1.16; I2 = 0%; 4 studies, 261 participants: moderate-certainty evidence). Vitamin D versus placebo Two studies compared vitamin D versus placebo (110 participants in the vitamin D group and 79 in the placebo group), with mean ages from 18.0 to 32.7 years. These studies reported lumbar spine BMD as a mixture of MDs and percent of change and we were unable to pool the results. In the original studies, there were no differences in lumbar BMD between groups. Vitamin D alone supplementation does not reduce or increase withdrawals for any reason between groups (RR 0.74, 95% CI 0.46 to 1.19; moderate-certainty evidence). Calcium plus vitamin D versus placebo Two studies compared calcium plus vitamin D versus placebo (271 participants in the calcium plus vitamin D group and 270 in the placebo group; 220 participants from Woo 2007 and 50 participants from Islam 2010). The mean age range was 18.0 to 36 years. These studies measured different anatomic areas, one study reported total hip BMD and the other study reported lumbar spine BMD; therefore, data were not pooled for this outcome. The individual studies found no difference between groups in percent of change on total hip BMD (-0.03, 95% CI -0.06 to 0; moderate-certainty evidence), and lumbar spine BMD (MD 0.01, 95% CI -0.01 to 0.03; moderate-certainty evidence). Calcium plus vitamin D supplementation may not reduce or increase withdrawals for any reason (RR 0.82, 95% CI 0.29 to 2.35; I2 = 72%; 2 studies, 541 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Our results do not support the isolated or combined use of calcium and vitamin D supplementation in healthy premenopausal women as a public health intervention to improve BMD in the total hip or lumbar spine, and therefore it is unlikely to have a benefit for the prevention of fractures (vertebral and non-vertebral). The evidence found suggests that there is no need for future studies in the general population of premenopausal women; however, studies focused on populations with a predisposition to diseases related to bone metabolism, or with low bone mass or osteoporosis diagnosed BMD would be useful.

Select Dietary Supplement Ingredients for Preserving and Protecting the Immune System in Healthy Individuals: A Systematic Review.

Immune health products represent approximately 10% of all US dietary supplement sales. Claims made on products to support or boost the immune system are attractive to the otherwise healthy consumer who may or may not be experiencing certain life stressors. The purpose of this systematic review is to critically evaluate the purported benefits and/or potential harms of select dietary supplement ingredients frequently listed on the labels of products having immune health or related market claims. With a focus on resilience, research questions were related to whether dietary supplement ingredients are efficacious in preserving and protecting immune health in healthy individuals; and when faced with a stressor, whether taking a supplement prophylactically can assist in maintaining health and resisting or bouncing back more quickly. Thirty-nine randomized controlled studies involving populations including children, adults and seniors exposed to stressors, such as air travel, intense exercise, academic stress, and/or exposure to winter weather, met eligibility criteria. The studies included eight of the 27 supplement ingredients identified through a market-driven scoping review. Those ingredients used in single ingredient products were echinacea, elderberry, garlic, vitamin A, vitamin C, vitamin D, vitamin E, and zinc. Whereas some studies may point to evidence for benefit, specific gaps preclude the authors from making firm statements with regard to the overall evidence-base for these products and ingredients and in answering the research questions. As we move toward a vision of health promotion and resilience rather than a sole focus on disease prevention and treatment, further work in this area of dietary supplements is of utmost importance.

Recommendation on an updated standardization of serum magnesium reference ranges.

PURPOSE: Serum magnesium is the most frequently used laboratory test for evaluating clinical magnesium status. Hypomagnesemia (low magnesium status), which is associated with many chronic diseases, is diagnosed using the serum magnesium reference range. Currently, no international consensus for a magnesemia normal range exists. Two independent groups designated 0.85 mmol/L (2.07 mg/dL; 1.7 mEq/L) as the low cut-off point defining hypomagnesemia. MaGNet discussions revealed differences in serum magnesium reference ranges used by members' hospitals and laboratories, presenting an urgent need for standardization. METHODS: We gathered and compared serum magnesium reference range values from our institutions, hospitals, and colleagues worldwide. RESULTS: Serum magnesium levels designating "hypomagnesemia" differ widely. Of 43 collected values, only 2 met 0.85 mmol/L as the low cut-off point to define hypomagnesemia. The remainder had lower cut-off values, which may underestimate hypomagnesemia diagnosis in hospital, clinical, and research assessments. Current serum magnesium reference ranges stem from "normal" populations, which unknowingly include persons with chronic latent magnesium deficit (CLMD). Serum magnesium levels of patients with CLMD fall within widely used "normal" ranges, but their magnesium status is too low for long-term health. The lower serum magnesium reference (0.85 mmol/L) proposed specifically prevents the inclusion of patients with CLMD. CONCLUSIONS: Widely varying serum magnesium reference ranges render our use of this important medical tool imprecise, minimizing impacts of low magnesium status or hypomagnesemia as a marker of disease risk. To appropriately diagnose, increase awareness of, and manage magnesium status, it is critical to standardize lower reference values for serum magnesium at 0.85 mmol/L (2.07 mg/dL; 1.7 mEq/L).

Protective effects of dietary curcumin and astaxanthin against heat-induced ROS production and skeletal muscle injury in male and female C57BL/6J mice.

AIMS: This study aimed to: 1) investigate sex differences in heat-induced mitochondrial dysfunction, ROS production, and skeletal muscle injury in mice; 2) evaluate whether curcumin and astaxanthin, alone or together, would prevent those heat-induced changes. MAIN METHODS: Male and female C57BL/6J mice were treated with curcumin and astaxanthin for 10 days, then exposed to 39.5 °C heat for up to 3 h. Heat-induced hyperthermia, changes in mitochondrial morphology and function, and oxidative damage to skeletal muscle were evaluated. KEY FINDINGS: Although female mice had a slightly higher basal core body temperature (Tc) than male mice, peak Tc during heat exposure was significantly lower in females than in males. Heat increased ROS levels in skeletal muscle in both sexes; interestingly, the increases in ROS were greater in females than in males. Despite the above-mentioned differences, heat induced similar levels of mitochondrial fragmentation and membrane potential depolarization, caspase 3/7 activation, and injury in male and female skeletal muscle. Individual treatment of curcumin or astaxanthin did not affect basal and peak Tc but prevented heat-induced mitochondrial dysfunction, ROS increases, and apoptosis in a dose-dependent manner. Moreover, a low-dose combination of curcumin and astaxanthin, which individually showed no effect, reduced the heat-induced oxidative damage to skeletal muscle. SIGNIFICANCE: Both male and female mice can develop mitochondrial dysfunction and oxidative stress in skeletal muscle when exposed to heat stress. High doses of either curcumin or astaxanthin limit heat-induced skeletal muscle injury, but a low-dose combination of these ingredients may increase their efficacy.

Prioritized research recommendations and potential solutions: addressing gaps surrounding dietary supplement ingredients for boosting brain health and optimizing cognitive performance.

In the market of dietary supplements, a low level of certainty exists in the state of the science, coupled with not always knowing what is in the product. Together these issues make weighing benefits/risks difficult and hinder the ability to guide evidence-based practice decisions. The authors sought to identify priorities and develop potential solutions to address research gaps so that information disseminated, can ultimately, be relied upon, when trying to make appropriate and safe decisions. Using a modified-Delphi process, 8 panelists reviewed evidence, provided from systematic review, on dietary supplement ingredients for brain health, and prioritized gaps identified and offered potential solutions. Research gaps specific to dietary supplements research included the need for quality testing of products, the question of bioavailability and absorption of ingredients, and optimal composition and standardization of supplements under investigation. Other gaps related to populations studied; a general sense of bias towards focusing research on diseased rather than maintaining or optimizing performance in healthy populations. Additionally, the lack of uniform cognitive performance measures and metrics used across research is a gap, as well as whether the metrics are accurate representations of or even generalizable to "real-life" participants wishing to optimize their performance. Methodological quality and ethical concerns in the conduct and reporting of science encompass all issues. If resources map to potential solutions outlined in this paper, then these proposed next steps offered will help facilitate meaningful research, move evidence into practice recommendations, and ultimately develop better decision-making tools for consumers to trust and rely upon for making safe supplement decisions.

Beyond Nutrient Deficiency-Opportunities to Improve Nutritional Status and Promote Health Modernizing DRIs and Supplementation Recommendations.

The US Dietary Guidelines for Americans (DGA) provide dietary recommendations to meet nutrient needs, promote health, and prevent disease. Despite 40 years of DGA, the prevalence of under-consumed nutrients continues in the US and globally, although dietary supplement use can help to fill shortfalls. Nutrient recommendations are based on Dietary Reference Intakes (DRIs) to meet the nutrient requirements for nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group and many need to be updated using current evidence. There is an opportunity to modernize vitamin and mineral intake recommendations based on biomarker or surrogate endpoint levels needed to 'prevent deficiency' with DRIs based on ranges of biomarker or surrogate endpoints levels that support normal cell/organ/tissue function in healthy individuals, and to establish DRIs for bioactive compounds. We recommend vitamin K and Mg DRIs be updated and DRIs be established for lutein and eicosapentaenoic and docosahexaenoic acid (EPA + DHA). With increasing interest in personalized (or precision) nutrition, we propose greater research investment in validating biomarkers and metabolic health measures and the development and use of inexpensive diagnostic devices. Data generated from such approaches will help elucidate optimal nutrient status, provide objective evaluations of an individual's nutritional status, and serve to provide personalized nutrition guidance.

Magnesium Depletion Score (MDS) Predicts Risk of Systemic Inflammation and Cardiovascular Mortality among US Adults.

BACKGROUND: Kidney reabsorption of magnesium (Mg) is essential for homeostasis. OBJECTIVES: We developed and validated models with the kidney reabsorption-related magnesium depletion score (MDS) to predict states of magnesium deficiency and disease outcomes. METHODS: MDS was validated in predicting body magnesium status among 77 adults (aged 62 ± 8 y, 51% men) at high risk of magnesium deficiency in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (registered at clinicaltrials.gov as NCT01105169) using the magnesium tolerance test (MTT). We then validated MDS for risk stratification and for associations with inflammation and mortality among >10,000 US adults (weighted: aged 48 ± 0.3 y, 47% men) in the NHANES, a nationally representative study. A proportional hazards regression model was used for associations between magnesium intake and the MDS with risks of total and cardiovascular disease (CVD) mortality. RESULTS: In the PPCCT, the area under the receiver operating characteristic (ROC) curve (AUC) for magnesium deficiency was 0.63 (95% CI: 0.50, 0.76) for the model incorporating the MDS with sex and age compared with 0.53 (95% CI: 0.40, 0.67) for the model with serum magnesium alone. In the NHANES, mean serum C-reactive protein significantly increased with increasing MDS (P-trend < 0.01) after adjusting for age and sex and other covariates, primarily among individuals with magnesium intake less than the Estimated Average Requirement (EAR; P-trend < 0.05). Further, we found that low magnesium intake was longitudinally associated with increased risks of total and CVD mortality only among those with magnesium deficiency predicted by MDS. MDS was associated with increased risks of total and CVD mortality in a dose-response manner only among those with magnesium intake less than the EAR. CONCLUSIONS: The MDS serves as a promising measure in identifying individuals with magnesium deficiency who may benefit from increased intake of magnesium to reduce risks of systemic inflammation and CVD mortality. This lays a foundation for precision-based nutritional interventions.

Effectively Prescribing Oral Magnesium Therapy for Hypertension: A Categorized Systematic Review of 49 Clinical Trials.

Trials and meta-analyses of oral magnesium for hypertension show promising but conflicting results. An inclusive collection of 49 oral magnesium for blood pressure (BP) trials were categorized into four groups: (1) Untreated Hypertensives; (2) Uncontrolled Hypertensives; (3) Controlled Hypertensives; (4) Normotensive subjects. Each group was tabulated by ascending magnesium dose. Studies reporting statistically significant (p < 0.05) decreases in both systolic BP (SBP) and diastolic BP (DBP) from both baseline and placebo (if reported) were labeled "Decrease"; all others were deemed "No Change." Results: Studies of Untreated Hypertensives (20 studies) showed BP "Decrease" only when Mg dose was >600 mg/day; <50% of the studies at 120-486 mg Mg/day showed SBP or DBP decreases but not both while others at this Mg dosage showed no change in either BP measure. In contrast, all magnesium doses (240-607 mg/day) showed "Decrease" in 10 studies on Uncontrolled Hypertensives. Controlled Hypertensives, Normotensives and "magnesium-replete" studies showed "No Change" even at high magnesium doses (>600 mg/day). Where magnesium did not lower BP, other cardiovascular risk factors showed improvement. Conclusion: Controlled Hypertensives and Normotensives do not show a BP-lowering effect with oral Mg therapy, but oral magnesium (≥240 mg/day) safely lowers BP in Uncontrolled Hypertensive patients taking antihypertensive medications, while >600 mg/day magnesium is required to safely lower BP in Untreated Hypertensives; <600 mg/day for non-medicated hypertensives may not lower both SBP and DBP but may safely achieve other risk factor improvements without antihypertensive medication side effects.

Perspective: Characterization of Dietary Supplements Containing Calcium and Magnesium and Their Respective Ratio-Is a Rising Ratio a Cause for Concern?

Low magnesium intakes coupled with high calcium intakes and high calcium-to-magnesium (Ca:Mg) intake ratios have been associated with increased risk for multiple chronic conditions such as cardiovascular disease and metabolic syndrome, as well as some cancers (colorectal, prostate, esophageal), and total mortality. A high dietary Ca:Mg ratio (>2.60) may affect body magnesium status while, on the other hand, high intakes of magnesium could adversely impact individuals with an exceedingly low dietary Ca:Mg ratio (<1.70). Thus, a Ca:Mg ratio range of 1.70-2.60 (weight to weight) has been proposed as an optimum range. Data from NHANES surveys have shown the mean Ca:Mg intake ratio from foods alone for US adults has been >3.00 since 2000. One-third of Americans consume a magnesium supplement with a mean dose of 146 mg/d, and 35% of Americans consume a calcium supplement with a mean dose of 479 mg/d. Our review of Ca:Mg ratios in dietary supplements sold in the United States and listed in NIH's Dietary Supplement Label Database (DSLD) found a mean ratio of 2.90 across all calcium- and magnesium-containing products, with differences by product form. The ratios ranged from a low of 0.10 in liquid products to a high of 48.5 in powder products. Thirty-one percent of products fell below, 40.5% fell within, and 28.3% fell above the ratio range of 1.70-2.60. Our findings of calculated Ca:Mg ratios from dietary supplements coupled with food-intake data suggest that, in individuals with high calcium intakes from diet and/or supplements, magnesium supplementation may be warranted to establish a more favorable dietary Ca:Mg ratio in their total diet. Additional research may provide greater insight into whether the Ca:Mg ratio is a biomarker of interest for moderating chronic disease and which population groups may derive benefit from moderating that ratio.

Disintegration and Dissolution Testing of Green Tea Dietary Supplements: Application and Evaluation of United States Pharmacopeial Standards.

Approved performance quality tests are lacking in the United States Pharmacopeia (USP) for dietary supplements (DSs) containing green tea extracts. We evaluated the applicability of USP <2040 > general chapter protocols for disintegration and dissolution testing of botanicals to GT DSs. Of 28 single-ingredient GT DSs tested in 2 to 4 lots, 9 (32.1%) always passed the disintegration test, 8 (28.6%) always failed, and 11 (39.3%) showed inconsistent results. Of 34 multi-ingredient DSs tested in 2 lots, 21 (61.8%) passed and 8 (23.5%) failed in both lots, and 5 (14.7%) exhibited inconsistent performance. When stronger destructive forces were applied (disk added), all of the capsules that had failed initially, but not the tablets, passed. In dissolution testing, for the release of epigallocatechin-3-gallate (EGCG), only 6 of 20 single-ingredient DSs passed. Unexpectedly, with the addition of pepsin (prescribed by USP), only one additional DS passed. These results raise concerns that EGCG was not released properly from GT DS dosage forms. However, the general USP protocols may be inadequate for this botanical. More biorelevant destructive forces may be needed to break down capsules and tablets strengthened by the EGCG's interaction with shell material and to overcome the inhibition of digestive enzymes by EGCG.

Ankyloglossia Identification, Diagnosis, and Frenotomy : A Qualitative Study of Community Referral Pathways.

BACKGROUND: Researchers and practitioners continue to debate the most appropriate assessment, diagnostic, and treatment practices for ankyloglossia (tongue-tie). Health care workers struggle to provide evidence-based care in the absence of consistent standards. RESEARCH AIM: The aims of this pilot study were to qualitatively (a) evaluate the knowledge of, and attitudes toward tongue-tie and (b) describe how they shaped referral pathways and the establishment of practice patterns of frontline practitioners (pediatric dentists, speech-language pathologists, pediatric chiropractors, and International Board Certified Lactation Consultants). METHODS: We recruited clinicians (N = 9) using nonprobability purposive sampling. Participants were interviewed using survey schedules adjusted to reflect their specialty area. Semistructured interviews were transcribed and coded using manual and inductive coding techniques common in grounded theory. Themes were iteratively developed using memoing techniques, in which observations and potential concepts were recorded using the aforementioned codes. RESULTS: Participants were familiar with a variety of protocols and assessment tools, but did not consistently use them. No formal training about the management of tongue-tie was received through their degree programs. Instead they pursued self-guided study. Interprofessional consensus guided opinions about tongue-tie best practices, and referral pathways reflected these consensuses. International Board Certified Lactation Consultants were viewed as pivotal to the care of infants with tongue-tie while primary care physicians-primarily pediatricians-were omitted from referral pathways. CONCLUSION: Lack of formalized training, professional consensus about best practices, and insufficient resources for assessing and treating tongue-tie led participants to incomplete referral pathways and personal interpretations of the data through the lens of anecdotal evidence.