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Use of food supplements (FS) by athletes is well characterised but there is little information on 'herbal' or 'botanical' FS beyond 'natural'. This study determined, by questionnaire, whether athletes' main self-reported reason for using FS was reflective of what was written on product labels or, when these claims were unavailable, was in accordance with the scientific literature. In 217 elite (n = 55) and amateur (n = 162) athletes living on the island of Ireland, 71% (n = 153) consumed any kind of FS, with 16% (n = 34) of the entire cohort deemed botanical consumers. 'Protein' (21%, n = 46), 'vitamin D' (17%, n = 37) and 'vitamin C' (15% n = 32) were most consumed with the top reasons for use being 'to support health', 'to prevent illness/for immunity purposes' and 'recovery'. There was generally good agreement between approved nutrition and health claims for such products and athletes' main reported reasons for use. Only the amateur athletes in our pool described using botanical supplements, with reasons for use stated as 'sleep improvement' (21%), 'recovery' (14%), 'supporting health' (12%) and 'energy' (12%), resulting in poor agreement with either approved claims or scientific evidence. Only half of amateur athletes knew if their botanical FS were third-party tested. Athletes and practitioners require guidance to avoid consuming supplements for which there is little scientific evidence, and which may risk being contaminated/fraudulent., (© 2024 The Author(s). Nutrition Bulletin published by John Wiley & Sons Ltd on behalf of British Nutrition Foundation.)

In the context of diabetes, the use of cinnamon continues to be among the most popular supplements taken by patients for glucose control. To strategically evaluate the available literature comparing various cinnamon species and statistically significant glucose effects after ranking studies based on two tools to assess bias and overall study quality, to clarify cinnamon's role in glucose control. The authors performed a systematic search based upon PRISMA guidelines. The search was conducted utilizing PubMed, AMED, CINAHL, EMBASE, Cochrane, and Medline databases, with the final search performed in September 2022 with restrictions to human subjects and English language. Electronic searches were conducted utilizing the keywords "diabetes mellitus" combined with Cinnamomum zeylanicum / Cinnamomum cassia / Cinnamomum verum combined with blood glucose (BG). A second search utilized "cinnamomum zeylanicum/cinnamomum cassia/cinnamomum verum" combined with "blood glucose," and a final search utilized "diabetes mellitus" combined with "cinnamon." Data extraction and ranking of included studies utilizing the risk of bias 2 tool and modified Heyland Methodological Quality Scoring tool were performed independently by two review authors. These authors compared their results and reconciled any differences in scoring to generate a final ranking of studies. A third author was available for any discrepancies that could not be resolved but was not needed. Forty-five studies were included in the review and were scored for bias and quality. Overall 62% demonstrated statistical significance for positive effects in at least one parameter around BG control. Applying the ranking systems reduced the percentage closer to 50%. Safety was extremely well documented across studies with few adverse effects. Results are limited by heterogeneity of glucose parameters, leading to studies being ranked individually and not synthesized. Cinnamon supplementation likely has a modest positive effect on BG. Based upon the strong safety profile, utilization of this spice as an adjunct to pharmacologic therapy is reasonable.

Use of herbal medications and supplements has experienced immense growth over the last two decades, with retail sales in the USA exceeding $13 billion in 2021. Since the Dietary Supplement Health and Education Act (DSHEA) of 1994 reduced FDA oversight, these products have become less regulated. Data from 2012 shows 18% of U.S. adults used non-vitamin, non-mineral natural products. Prevalence varies regionally, with higher use in Western states. Among preoperative patients, the most commonly used herbal medications included garlic, ginseng, ginkgo, St. John's wort, and echinacea. However, 50-70% of surgical patients fail to disclose their use of herbal medications to their physicians, and most fail to discontinue them preoperatively. Since herbal medications can interact with anesthetic medications administered during surgery, the American Society of Anesthesiologists (ASA) and the American Association of Nurse Anesthetists (AANA) recommend stopping herbal medications 1-2 weeks before elective surgical procedures. Potential adverse drug effects related to preoperative use of herbal medications involve the coagulation system (e.g., increasing the risk of perioperative bleeding), the cardiovascular system (e.g., arrhythmias, hypotension, hypertension), the central nervous system (e.g., sedation, confusion, seizures), pulmonary (e.g., coughing, bronchospasm), renal (e.g., diuresis) and endocrine-metabolic (e.g., hepatic dysfunction, altered metabolism of anesthetic drugs). During the preoperative evaluation, anesthesiologists should inquire about the use of herbal medications to anticipate potential adverse drug interactions during the perioperative period., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ofelia Loani Elvir Lazo reports financial support, administrative support, statistical analysis, and writing assistance were provided by Cedars-Sinai Medical Center., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Wound healing is an intricate and continual process influenced by numerous factors that necessitate suitable environments to attain healing. The natural ability of wound healing often gets altered by several external and intrinsic factors, leading to chronic wound occurrence. Numerous wound dressings have been developed; however, the currently available alternatives fail to coalesce in all conditions obligatory for rapid skin regeneration., Area Covered: An extensive review of articles on herbal nano-composite wound dressings was conducted using PubMed, Scopus, and Google Scholar databases, from 2006 to 2024. This review entails the pathophysiology and factors leading to non-healing wounds, wound dressing types, the role of herbal bio-actives for wound healing, and the advantages of employing nanotechnology to deliver herbal actives. Numerous nano-composite wound dressings incorporated with phytoconstituents, herbal extracts, and essential oils are discussed., Expert Opinion: There is a strong substantiation that several herbal bio-actives possess anti-inflammatory, antimicrobial, antioxidant, analgesic, and angiogenesis promoter activities that accelerate the wound healing process. Nanotechnology is a promising strategy to deliver herbal bio-actives as it ascertains their controlled release, enhances bioavailability, improves permeability to underlying skin layers, and promotes wound healing. A combination of herbal actives and nano-based dressings offers a novel arena for wound management.

Introduction: Capecitabine has been widely prescribed to treat various cancers. The hand foot syndrome (HFS) is the most troublesome adverse effect. Urea cream has been pre-emptively co-prescribed, even though its efficacy is doubtful. Aloe vera gel with urea cream might potentiate each other. This trial was intended to prove the efficacy of this combination., Materials and Methods: The investigators conducted a randomized single-blinded phase II study. The participants were randomized 1:1 to receive the combination of aloe vera gel and 10% urea cream (n = 30), the experimental A+U arm and 10% urea cream alone (n = 31), the U arm. The sample size was calculated to have 90% power to show the significant 20% reduction in the incidence of HFS grade 2-3 of the combination therapy with alpha level = 0.05. Both the CTCAE criteria version 5 and the dermatology life quality index (DLQI) were assessed to determine the severity of HFS and quality of life, respectively., Results: Most of the participants had rectal cancer (A+U: 43.3%; U: 41.9%). In the A+U group, 86.7% had grade 0-1 HFS and 13.3% had grade 2-3 HFS. In the U group, 64.5% had grade 0-1 HFS and 35.5% had grade 2-3 HFS (Mann-Whitney U test, p = 0.045). Grade 2-3 HFS was significantly lower in the combination group., Conclusion: Combination of aloe vera gel and 10% urea cream ameliorated the severity of HFS in participants taking capecitabine; however, no significant difference in DLQI between the groups was demonstrated.

"Children are not small adults with respect to the treatment with medicinal products." This statement of the WHO was the basis for the initiative of the European Commission for the establishment of a paediatric regulation in 2007 to improve the health of children by facilitating the development of medicines for children and adolescents. Seventeen years later, in the field of herbal medicinal products, results are still sobering. Therefore, the Foundation Plants for Health, Society for Medicinal Plants and Natural Products Research, and German Society for Phytotherapy organised a symposium to assess the status quo for the paediatric use of herbal medicinal products (HMPs), to analyse the causes of the current situation, and to discuss strategies for establishing the proof of safe and efficacious HMPs for children.The current situation for HMPs and their use in children is not fulfilling the requirements of legislation. HMPs in paediatrics are effective and safe, but considering the needs of children is necessary. In European countries, the use, registration, and marketing of HMPs are different, depending on the respective national regulations and specific traditions. EU herbal monographs are the best common denominator for such procedures. Emerging safety discussions must be considered. New approaches with real-world data might be a solution. The regulatory framework is to be adapted. Defining rationalised dosing for HMPs can be achieved by the extrapolation of data from adults, by using existing clinical data for children, and by using RWD. Therefore, a strong need for revising restrictions for the use of HMPs in children and rationalising defined dosage regimes is obvious., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Chemical plaque control with mouthwashes as an adjunct to mechanical plaque control with a toothbrush and dental floss has been considered an effective method for controlling gingivitis. The anti-inflammatory effects of chemical plaque control benefit the oral tissues by reducing inflammation and bleeding., Objectives: The aim of the present study was to evaluate and compare the clinical efficacy of probiotic, Aloe vera, povidine-iodine, and chlorhexidine (CHX) mouthwashes in treating gingivitis patients by assessing changes in their clinical parameters., Material and Methods: This prospective study was conducted on 40 patients from our outpatient department, divided into 4 groups of 10 patients each: probiotic mouthwash group (group 1); herbal (Aloe vera) mouthwash group (group 2); povidone-iodine mouthwash group (group 3); and CHX mouthwash group (group 4). All participants were provided with the same type of manual toothbrush, the Pepsodent® toothpaste and a respective mouthwash for twice-daily use until the end of a 28-day observation period. Clinical parameters, such as the marginal plaque index (MPI) and bleeding on interdental brushing (BOIB), were recorded at baseline, and on the 14th and 28th day of the study period., Results: All groups showed a significant decrease in the MPI and BOIB scores. The results were similar in patients who used a probiotic mouthwash and those who used a CHX mouthwash. A comparable change in the mean scores was observed among the herbal and povidone-iodine groups from baseline to day 28., Conclusions: In the treatment of chronic gingivitis patients,a probiotic mouthwash was nearly as effective as CHX in reducing the plaque and bleeding scores. It showed better results in all clinical parameters than herbal and povidone-iodine mouthwashes. Using a mouthwash along with routine tooth brushing can help in treating gingivitis and slow the progression of the periodontal disease.

Competing Interests: The authors declare no competing interests.

The utilization of nanotechnology-based herbal medication delivery systems is gaining attention as a novel approach to treating diabetes mellitus. The incorporation of nanotechnology into herbal medicine provides benefits such as enhanced Stability, solubility, and bioavailability of herbal medications. The purpose of this paper is to summarise the present status of research on herbal medicine delivery systems based on nanotechnology for the treatment of diabetic patients. The paper evaluates the various nanocarriers and herbal drugs used, the challenges and opportunities in the development of these systems, and their potential efficacy and safety. Additionally, the paper highlights the need for further research to optimize the formulation and delivery of these systems. This review's overarching objective is to provide a complete understanding of the possibilities of herbal medication delivery systems based on nanotechnology in diabetes mellitus treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Psoriasis (Pso) is an autoimmune inflammatory skin disease characterized by red plaques covered in silver scales. The existing treatments provide limited benefits and are associated with certain drawbacks which limit their use. Thus, there is a need to explore more options that are highly target-specific and associated with minimal side effects. Researchers have thoroughly investigated the use of herbal drugs for their therapeutic potential. Preclinical studies demonstrate that phytochemicals such as curcumin, psoralen, and dithranol have antipsoriatic effects. These phytoconstituents inhibit the signalling pathways, such as the interleukin (IL) 23/Th17 axis and IL-36 inflammatory loop involved in the pathogenesis of Pso. These phytoconstituents down-regulate the pro-inflammatory cytokines like IL-17 and tumor necrosis factor (TNF)-α. However, their application in clinical settings is limited due to poor bioavailability and access to target sites. Combining phytoconstituents with modern delivery platforms like nanocarriers can address these shortcomings and improve therapeutic efficacy. This review explores the potential of herbal remedies as a substitute for conventional therapies, emphasizing the clinical trials conducted with these herbal medicines. The paper is supported by the discussion on nanocarriers like liposomes, niosomes, emulsomes, ethosomes, nanostructured lipid carriers, nanoemulsions, and dendrimers that are used to deliver herbal medicines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In recent years, herbal nanomedicines have gained tremendous popularity for novel drug discovery. Nanotechnology has provided several advances in the healthcare sector, emerging several novel nanocarriers that potentiate the bioavailability and therapeutic efficacy of the herbal drug. The recent advances in nanotechnology with accelerated strategies of ophthalmic nanosystems have paved a new path for overcoming the limitations associated with ocular drug delivery systems, such as low bioavailability, poor absorption, stability, and precorneal drug loss. Ophthalmic drug delivery is challenging due to anatomical and physiological barriers. Due to the presence of these barriers, the herbal drug entry into the eyes can be affected when administered by following multiple routes, i.e., topical, injectables, or systemic. However, the advancement of nanotechnology with intelligent systems enables the herbal active constituent to successfully entrap within the system, which is usually difficult to reach employing conventional herbal formulations. Herbal-loaded nanocarrier drug delivery systems demonstrated enhanced herbal drug permeation and prolonged herbal drug delivery. In this current manuscript, an extensive search is conducted for original research papers using databases Viz. , PubMed, Google Scholar, Science Direct, Web of Science, etc. Further painstaking efforts are made to compile and update the novel herbal nanocarriers such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructure lipid carriers, micelles, niosomes, nanoemulsions, dendrimers, etc., which are mostly used for ophthalmic drug delivery system. This article presents a comprehensive survey of diverse applications used for the preventative measures and treatment therapy of varied eye disorders. Further, this article highlights the recent findings that the innovators are exclusively working on ophthalmic nanosystems for herbal drug delivery systems. The nanocarriers are promising drug delivery systems that enable an effective and supreme therapeutic potential circumventing the limitations associated with conventional ocular drug delivery systems. The nanotechnology-based approach is useful to encapsulate the herbal bioactive and prevent them from degradation and therefore providing them for controlled and sustained release with enhanced herbal drug permeation. Extensive research is still being carried out in the field of herbal nanotechnology to design an ophthalmic nanosystem with improved biopharmaceutical properties., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that initially affects small joints and then spreads to the bigger joints. It also affects other organs of the body such as lungs, eyes, kidneys, heart, and skin. In RA, there is destruction of cartilage and joints, and ligaments and tendons become brittle. Damage to the joints leads to abnormalities and bone degradation, which may be quite painful for the patient., Method: The nano-carriers such as liposomes, phytosomes, nanoparticles, microcapsules, and niosomes are developed to deliver the encapsulated phytoconstituents to targeted sites for the better management of RA., Results: The phytoconstituents loaded nano-carriers have been used in order to increase bioavailability, stability and reduce the dose of an active compound. In one study, the curcumin-loaded phytosomes increase the bioavailability of curcumin and also provides relief from RA symptoms. The drug-loaded nano-carriers are the better option for the management of RA., Conclusion: In conclusion, there are many anti-arthritic herbal and synthetic medicine available in the market that are currently used in the treatment of RA. However, chronic use of these medications may result in a variety of side effects. Because therapy for RA is frequently necessary for the rest of ones life. The use of natural products may be a better option for RA management. These phytoconstituents, however, have several disadvantages, including limited bioavailability, low stability, and the need for a greater dosage. These problems can be rectified by using nano-technology., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Using skin patches to deliver drugs is dependable and doesn't have the same issues as permeation enhancers, which help drugs get through the skin but struggle because of the skin's natural barrier. Strategies are required to increase topical bioavailability to enhance drug absorption. Natural compounds offer a promising solution by temporarily reducing skin barrier resistance and improving drug absorption. Natural substances allow a wider variety of medications to be distributed through the stratum corneum, offering a dependable approach to enhancing transdermal drug delivery. Natural substances have distinct advantages as permeability enhancers. They are pharmacologically effective and safe, inactive, non-allergenic, and non-irritating. These characteristics ensure their suitability for use without causing adverse effects. Natural compounds are readily available and well tolerated by the body. Studies investigating the structure-activity relationship of natural chemicals have demonstrated significant enhancer effects. By understanding the connection between chemical composition and enhancer activity, researchers can identify effective natural compounds for improving drug penetration. In conclusion, current research focuses on utilizing natural compounds as permeability enhancers in transdermal therapy systems. These substances offer safety, non-toxicity, pharmacological inactivity, and non-irritation. Through structure-activity relationship investigations, promising advancements have been made in enhancing drug delivery. Using natural compounds holds enormous potential for improving the penetration of trans-dermally delivered medications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: Kikyo-to (Kt), a herbal medicine composed of glycyrrhiza root (Chinese licorice) and Platycodon root extracts (Chinese bellflower), is commonly used in Japan for relief of throat symptoms related to acute upper respiratory tract infection (URTI). Its effectiveness on URTI-associated sore throat pain over 30 min is examined here in comparison with a placebo. Design: Randomized double-blinded multicenter trial. Settings/Location: Two local Japanese medical centers with primary care. Subjects: Patients aged 20-65 years with URTI-related sore throat. Interventions: Patients were randomized to receive either 2500 mg of Kt, or 2500 mg of placebo (lactose). Randomization was stratified by age (< 45 vs. ≥ 45 years) and baseline sore throat score according to visual analogue scale (VAS) (< 50 vs. ≥ 50). Outcome measures: Primary outcome was change to sore throat score according to VAS 30 min after administration of Kt. Perceived impact of the sore throat on daily life at 30 mins after administration was another outcome. Outcomes are analyzed in the intention-to-treat population. Results: Among 70 participants, (Kt group: 36; placebo group: 34), each group contained 34 patients for analysis ( n  = 68, total). Difference between the groups in the mean change of sore throat score according to VAS at 30 min was without statistical significance (Kt 15.3, placebo 17.2; p  = 0.66). Patients reporting that their sore throat had a moderate or greater impact on daily life were also similar in proportion between the groups (Kt 61.8% vs. placebo 55.9%; p  = 0.80). Side effects were not reported. Conclusions: Kt did not relieve acute URTI-associated sore throats significantly more than a placebo. (UMIN trial ID: UMIN000035591).

Objectives: Pharmacists are ideal partners for engaging with the needs and expectations of patients. They can play a vital role by providing information and supplying herbal medicines. In some community settings, pharmacists are also the main first point of care. This study explored Jordanian community pharmacists' perspectives and knowledge of herbal medicines available in pharmacies., Design: A cross-sectional study using an online survey was developed, and it was distributed via social media platforms. The one-way analysis of variance (ANOVA) test was used to compare the mean knowledge scores between different demographic groups. Multiple linear regression analysis was used to identify predictors of herbal medicines knowledge., Setting: Jordanian community pharmacies., Participants: 401 Jordanian community pharmacists., Results: Herbal supplements are sold in practically all pharmacies (98.5%). Slimming aids (14.7%), followed by sexual and sports enhancements (14%) and maintaining general health (12.1%) were most requested by Jordanian customers. While supplements for maintaining general health (12%), followed by slimming aids (11.4%) and skin conditions (9.3%) were most recommended by Jordanian pharmacists. 63.1% were not aware of potential herb-drug interactions, 95.6% did not receive complaints from customers about herbal medicines and 41.2% would not report adverse reactions to the national pharmacovigilance services. The mean knowledge score for knowledge of use, regulation, adverse reactions, and drug interactions was 3.7 (SD: 0.7), 3.5 (SD: 0.8), 3.6 (SD: 0.8), and 3.6 (SD: 0.8) (out of 5), respectively. ANOVA test showed that total pharmacists' knowledge scores significantly differed based on the length of time practising pharmacy (p<0.05)., Conclusion: This study highlights some key concerns relating to recommendations, awareness and reporting of herbal medicines among Jordanian community pharmacists. Pharmacists need enhanced education to provide objective and evidence-based information on the benefits-risks of herbal medicines. Future studies need to be carried out to confirm whether our findings are transferable to other Middle Eastern countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ethnopharmacological Relevance: In African traditional medicine, there are several plant species that are used in combination with either other plant species or non-plant derived combinations such as sugar and honey, salt and vinegar, milk, fat etc. This review examines the role of these combinations and postulates the scientific and therapeutic validation of such combinations., Aim of the Study: This study reviewed the ethnopharmacological literature and documented the use of southern African plant combinations to find a scientific rationale for such combinations, and provide recommendations for future studies., Materials and Methods: Ethnobotanical books and online databases such as Scopus, ScienceDirect, PubMed and Google Scholar were used to find ethnobotanical studies within the southern African context that focus on the combinations of plants with other plants or various additional ingredients. The scientific literature was examined to determine if evidence was available to substantiate such combinations., Results: One hundred and eighty-seven medicinal plant (plant-to-plant) combinations that are used in the southern African traditional healing system were recorded. These plant combinations were used against infections of the gastrointestinal tract, respiratory tract, and skin as well other non-infectious diseases such as reproductive and psychiatric disorders. Respiratory infections were the most documented infections to be treated using plant combinations. The plant that was documented to be most commonly used in combination with other plants was Artemisia afra Jacq. ex Willd. While plant-plant combinations have drawn a marked interest, comparatively, plant-adjuvant (e.g. milk, sugar, honey, salt, vinegar, fats) combinations have attracted less research interest. Milk was reported as the most used additional ingredient in combination with medicinal plants. The combination of animal urine and dung with medicinal plants has been reported as a treatment for treat prostate infections, the human immunodeficiency virus (HIV). Other ingredients such as clay and flour were also documented, and these are often mixed with medicinal plants to treat fever, stomach ailments, sexually transmitted infections (STI) and skin conditions. Although combination therapy has been frequently reported in ethnobotanical records, over 90% of the combinations reviewed still need to be scientifically validated., Conclusion: Scientific reports on the antimicrobial, anti-oxidant, anti-inflammatory and other pharmacological effects of these combinations may offer an understanding of traditional combination therapy. In addition, investigation into the mechanisms of action of these combinations are also recommended to supplement the findings. Nonetheless, the use of plant combinations is still an untapped research area in southern Africa and there is a need to validate the use of those documented combinations to obtain a better understanding of combined traditional medicinal plant use., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The consumption of nephrotoxic plants is quite frequent in Morocco and could explain the high prevalence of indeterminate nephropathy in patients with End-Stage Kidney Disease (ESKD)., Aim of the Study: to determine, in a population of chronic hemodialysis (CHD) patients and before the occurrence of ESKD, the prevalence of the use of nephrotoxic plants, in particular, Aristolochia longa L. (Bereztam) and the etiological role of plants in the rapid progression of known and unknown nephropathy toward the end stage of chronic hemodialysis., Materials and Methods: This was a multicentric cross-sectional study spread over 12 months (May 2019-May 2020), carried out in public hemodialysis centers in the eastern region of Morocco. Clinical data were collected from medical records. Herbal and sociodemographic data were collected from a detailed and precise interview with each enrolled CHD patient., Results: A total of 404 CHD patients participated in the study. 71.5%, had used medicinal plants before the occurrence of ESKD and 32.9% had indeterminate nephropathy. Among the plants consumed, we identified plants whose kidney toxicity was well demonstrated, mainly Rhamnus alaternus L. (Mlilas) in 66.7%, Artemisia herba alba Asso (Chih) in 54.32%, Aristolochia longa L.(Bereztam) in 52.6%, and Rubia tinctorum L. (Fowa) in 47.4%. 27.7% of CHD patients had presented complications following the use of the plants before the occurrence of ESKD. In multivariate analysis, the use of plants to treat digestive disorders (OR 9.57; 95%CI [4.49-20.37], P < 0.001) and asthenia associated with anemia (OR 8.59; 95%CI [3.92-18.81], P < 0.001), as well as side effects observed after taking the plants (OR 4; 95%CI [1.09, 14.7], P = 0.03), were identified as significant risk factors for the occurrence of severe indeterminate nephropathy., Conclusions: This study showed the high prevalence of consumption of nephrotoxic herbs which may be the root cause of chronic renal failure in CHD patients., (Copyright © 2022. Published by Elsevier B.V.)

Ethnopharmacological Relevance: While the interest in finding medical solutions for the worldwide antibiotics crisis is rising, the legal possibility of simplified authorization of herbal veterinary medicinal products is dwindling. An important basis for both the preservation and development of knowledge in veterinary herbal medicine are pharmacological and clinical studies on the performance of herbal remedies, based on historical written sources on the treatment of farm animals with medicinal plants, as well as current ethnoveterinary research. Nevertheless, there is only limited systematic ethnoveterinary research in Europe, with the exceptions of the Mediterranean region, Switzerland and Austria. We conducted a survey on the ethnoveterinary knowledge of farmers in Bavaria, and analyzed two regional historical textbooks., Aim of the Study: We documented the local veterinary knowledge about livestock in Bavaria based upon local historical textbooks and upon ethnoveterinary interviews to discover opportunities for the future development of European veterinary herbal medicine., Material and Methods: In 2018/2019 we conducted 77 semi-structured interviews with 101 farmers from different types of farms. Detailed information about homemade herbal remedies (plant species, plant part, manufacturing process, source of knowledge) and the corresponding use reports (target animal species, category of use, route of administration, dosage, source of knowledge, frequency of use, last time of use and farmers' satisfaction) were collected. To compare our data with the literature, the use reports of two local historical textbooks were analyzed and compared with the data from the interviews., Results: 716 homemade remedy reports (HRs) for altogether 884 use reports (URs) were documented in this study. We picked the 363 HRs that consisted of a single plant species with or without other natural products (HSHRs) for a deeper analysis. These HSHRs were prepared from 108 plant species that belonged to 57 botanical families. The most URs were documented for the families of: Asteraceae, Linaceae and Urticaceae. Calendula officinalis L. (Asteraceae), Linum usitatissimum L. (Linaceae) and Urtica dioica L. (Urticaceae) were the most often documented single species. A total of 448 URs were gathered for the 363 HSHRs. The largest number of URs was for treatments of gastrointestinal disorders and metabolic dysfunctions, followed by skin alterations and sores. For nearly half of the URs the source of knowledge was family and friends. For 80 URs the source of knowledge was different from that of the corresponding HSHRs. For 68% of the URs farmers mentioned at least one use during the last 5 years. Half of the plant species that were mentioned in the historical literature were also mentioned in URs by the interviewees., Conclusion: In Bavaria, medicinal plants are actively used by farmers to treat their livestock with a high level of satisfaction. The knowledge is not passed on from generation to generation in a purely static way, but is dynamically developed by the users in almost one fifth of the URs. Ethnoveterinary research combined with data from regional historical textbooks may facilitate pharmacological and clinical studies in veterinary medicine, and the discussion about a simplified registration for traditional herbal veterinary medicinal products., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Indigenous groups of the Amazon have developed intricate methods for the application of psychoactives, among which particularly the dieta or diet method of Peruvian-Amazonian traditional medicine stands out. It is a retreat-like intervention involving lengthy periods of social, behavioural, and alimentary restrictions, while ingesting specially prepared plant substances. The interplay of the dietary conditions and plants ingested sensitizes the dieter to receive healing, strength, guidance, and knowledge. From a clinical scientific point of view, the method has remained largely underexplored, but seems more pertinent than ever given the increasing interest in Amazonian psychoactive preparations including ayahuasca (Banisteriopsis caapi) and the burgeoning field of psychedelic-assisted therapies in general., Aim of the Study: This study offers a descriptive account and emic interpretation of the Peruvian-Amazonian dieta. More specifically we document in detail the procedure, its context and purpose of application, effects, modes of action, adverse effects, and risks, from the perspectives of a sample of Peruvian traditional healers. The Peruvian-Amazonian dieta is a multi-purpose method for making use of medicinal plants, many of which (but not all), are psychoactive; the current work especially focuses on its therapeutic applications in conjunction with psychoactives., Methods: We interviewed 16 healers working in the Ucayali, San Martín, and Loreto provinces of Peru using a semi-structured interview approach. Interviews were audio-recorded and transcribed verbatim. The extensive data derived from these interviews were analysed by means of computer-assisted manifest qualitative content analysis using a theory-advancing approach. Over 500 coded text segments were categorized, resulting in 7 main theme clusters and corresponding sub-themes., Results: The interviewed healers described a complex intervention with multifaceted applications (treatment, prevention, training) and effects in various domains (body, mind, spirit, energy). The process was portrayed as transformative, with benefits attributed to the effects of the so-called teacher plants in conjunction with the diet's conditions, along with the skill of the healer guiding the intervention. Further, a detailed risk assessment revealed sophisticated safety measures and tools designed to address adverse responses. The importance of adequate training of the healer that administers the diet was particularly highlighted in this context., Conclusions: The dieta is a central therapeutic concept and tool in Peruvian-Amazonian traditional medicine and a unique method for using psychoactive plants. Multidisciplinary health research that includes traditional treatment methods from Indigenous cultures, Amazonian and other, should not be neglected in the current global interest in psychedelic therapies; such research may in the long-term contribute to a more inclusive psychedelic research paradigm as well as healthcare practice in countries where rich traditional healing systems exist, and perhaps beyond. It may also contribute to the recognition of the Indigenous healers as not only historical forerunners, but also current leading experts in psychedelic medicine., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Angelica (A.) sinensis is used as a traditional medical herb for the treatment of neurodegeneration, aging, and inflammation in Asia. A. sinensis optimal formula (AOF) is the best combination in A. sinensis that has been screened to rescue the cognitive ability in β-amyloid peptide (Aβ 25-35 )-treated Alzheimer's disease (AD) rats. The objective of this study was to investigate the effect of AOF on the learning and memory of AD rats as well as to explore the underlying mechanisms., Methods: Male Wistar rats were infused with Aβ 25-35 for AD model induction or saline (negative control). Five groups of AD rats were fed on AOF at 20, 40, or 80 mL/kg every day, donepezil at 0.9 mg/kg every day (positive control), or an equal volume of water (AD model) intragastrically once a day for 4 weeks, while the negative control rats were fed on water. The Morris water maze test was used to evaluate the cognitive function of the rats. The Aβ accumulation, cholinergic levels, and antioxidative ability were detected by ELISA. Additionally, the candidate mechanism was determined by gene sequencing and quantitative real-time polymerase chain reaction., Results: The results showed that AOF administration significantly ameliorated Aβ 25-35 -induced memory impairment. AOF decreased the levels of amyloid-β precursor protein and Aβ in the hippocampus, rescued the cholinergic levels, increased the activity of superoxide dismutase, and decreased the malondialdehyde level. In addition, AOF inhibited the expression of IL1b, Mpo, and Prkcg in the hippocampus., Conclusion: These experimental findings illustrate that AOF prevents the decrease in cognitive function and Aβ deposits in Aβ 25-35 -treated rats via modulating neuroinflammation and oxidative stress, thus highlighting a potential therapeutic avenue to promote the co-administration of formulas that act on different nodes to maximize beneficial effects and minimize negative side effects., (© 2022. The Author(s).)

Objectives: 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant., Methods: Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats., Key Findings: The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration., Conclusions: The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with inflammatory bowel disease (IBD) have higher incidence of extraintestinal manifestations (EIM), including liver disorders, sarcopenia, and neuroinflammation. Fermented rice bran (FRB), generated from rice bran (RB), is rich in bioactive compounds, and exhibits anti-colitis activity. However, its role in EIM prevention is still unclear. Here, for the first time, we investigated whether EIM in female C57Bl/6N mice is attenuated by FRB supplementation. EIM was induced by repeated administration of 1.5% dextran sulfate sodium (DSS) in drinking water (4 d) followed by drinking water (12 d). Mice were divided into 3 groups-control (AIN93M), 10% RB, and 10% FRB. FRB ameliorated relapsing colitis and inflammation in muscle by significantly lowering proinflammatory cytokines Tnf-α and Il-6 in serum and advanced glycation end product-specific receptor (Ager) in serum and muscle when compared with the RB and control groups. As FRB reduced aspartate aminotransferase levels and oxidative stress, it might prevent liver disorders. FRB downregulated proinflammatory cytokine and chemokine transcripts responsible for neuroinflammation in the hippocampus and upregulated mRNA expression of G protein coupled receptors (GPRs), Gpr41 and Gpr43, in small and large intestines, which may explain the FRB-mediated protective mechanism. Hence, FRB can be used as a supplement to prevent IBD-associated EIM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Moringa oleifera (MO) is a multipurpose plant with a high polyphenol content, which is being increasingly consumed to lessen the risk of chronic metabolic diseases such as Type 2 diabetes; however, scientific evidence from clinical trials is scarce. A double-blind, randomized, placebo-controlled, parallel group intervention study with MO leaves as a food supplement was conducted in subjects with prediabetes. They consumed six daily capsules of MO dry leaf powder (2400 mg/day) (MO, n = 31) or placebo (PLC, n = 34) over 12 weeks. Glycemia, appetite-controlling hormones and gut microbiota composition were studied. ANCOVA with the fixed factor "treatment" and the basal value as covariate was used to compare the change score between the groups. The results showed significant differences between groups in the rate of change of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c), which showed opposite directions during the intervention, decreasing in MO and increasing in PLC. No different change scores were found between the groups in microbiota, hepatic and renal function markers or the appetite-controlling hormones measured. In conclusion, MO supplementation resulted in favorable changes in glycaemia markers compared to placebo in the subjects with prediabetes studied, suggesting that MO might act as a natural antihyperglycemic agent.

Aim: To determine the therapeutic efficacy of Kali haldi in the management of Oral submucous Fibrosis (OSMF) v/s steroid therapy., Materials and Methods: A clinical prospective study was conducted on 42 patients of oral submucous fibrosis were equally divided into 2 groups. Group A patients were treated with a mixture of powdered Kali Haldi and aloe vera gel in equal ratio 3 times a day for 3 months. Group B patients were treated with intralesional injection of hydrocortisone and hyaluronidase for 6 weeks with oral antioxidant supplements for 3 months. Burning sensation, cheek flexibility, mouth opening, and tongue protrusion were evaluated before, during, and after treatment at an interval of 15 days, 1 month, 2, month and 3 months., Results: Statistically significant results were obtained at the end of 3 months duration for both the groups (P < 0.001). The Symptomatic correction was more evident in the case of Group A patients than Group B. Response of the ayurvedic regimen was potentially better as compared to the regular steroid therapy., Conclusion: The study concludes that Combination therapy works wonders in the case of OSMF in stages I, II, III and can be a good option, comparatively safe and with negligible side effects, but potent and equally effective management of oral submucous fibrosis. Henceforth, it will be better to do such kinds of studies on a vast scale including larger samples and longer duration to check the efficacy and durability of this ancient ayurvedic regimen.

Abstract: In south China, traditional herbal medicines have been widely used as functional foods or dietary supplements for daily health care. Many plant-derived chemical substances with biological activity are inadvertently ingested by collegiate athletes daily through canton-style herbal tea or herbal slow-cooked soup. In the view of the complexity of herbal ingredients, it is still no full survey reported for the sports risk of plant-derived sports doping. This research is firstly a descriptive statistical analysis. Collegiate athletes with different socio-economic characteristics from medical colleges in 3 different regions in China participated in the questionnaire survey. Three survey forms, including the oral interview, email inquiry, handing out and recovering the questionnaires in live, were developed and performed by researchers. It was first found that collegiate athletes resorted to some traditional herbal materials to protect their health care that there were regional differences (P < .01). Collegiate athletes with Health Fitness and Traditional Wushu as their sports expertise showed a higher frequency of recognition or ingestion in the use of traditional herbal materials (P < .01), while their different living types and cuisine preferences did not seem to be associated with the ingestion frequency of traditional herbal materials. In addition, in the view of the significant differences in the use of herbal preparations to relieve sports stress among young athletes in different regions (P < .01), the findings strongly suggested that athletes should strictly control their use of various herbal preparations during sports training and competition, including herbal wines, herbal oils, topical plasters, analgesic tablets., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate the safety and tolerability of an oral herbal supplement containing glucosinolates, phytosterols, and citrus flavonoids (Warmi®, Lima Perú;) in otherwise healthy adult women., Methods: This was a phase-I, randomized parallel three arms, double-blinded, and a placebo-controlled clinical trial. A total of 55 participants aged 18-40 were randomly assigned to one of three groups to receive for three months: (1) an oral herbal supplement of 1650 mg/day; (2) an oral herbal supplement of 3300 mg/day; or (3) an oral placebo 3300 mg/day. The primary endpoints were oral safety and tolerability of the supplement. The secondary endpoint was its effect on vital functions, anthropometrics, and laboratory tests. We used an exploratory approach by covariance analysis (ANCOVA) adjusted for the variables' baseline value for the secondary outcomes., Results: All women completed three months of follow-up, reporting no side effects. Our exploratory analysis revealed that treatment with the herbal supplement of 1650 mg/day was associated with increased glucose and uric acid levels. In comparison, the herbal supplement 3300 mg/day was associated with reduced breathing rate, increased basal temperature, and systolic blood pressure, both compared to the placebo group. However, despite significant differences, none of these was clinically significant., Conclusion: The oral herbal supplement had a favorable safety and tolerability profile in studied women. There is a need to study its potential as an option to treat menopausal symptoms.

Hormonal replacement therapy (HRT), as the first-line management of chronic menopausal syndrome (CMS) in women, has limited application due to adverse effects. We aimed to evaluate the therapeutic potential of a herbal alternative (HALT), durva swaras (DS) of Cynodon dactylon L. Pers., in a CMS rat model. Female Sprague-Dawley rats were subjected to Sham and ovariectomy (OVX) surgery. OVX rats received either 0.11 mg/kg oestrogen as a positive treatment control or 1 (DS1), 2 (DS2), and 4 (DS3) g/kg DS for 160 days. Vaginal smear tests indicated the menopausal status. Routine clinical examinations, weekly body weights (BW), serum calcium, proinflammatory cytokines, and reproductive hormones levels were monitored. Clinical chemistry, body composition, bone mineral density (BMD), uterotrophic response, bone morphometry, and histopathology of major organs were evaluated. BW of OVX rats increased by 18-25% compared to Sham. Total fat and fat percentage were significantly elevated in the oestrogen group compared to DS2, DS3, and OVX group. DS treatment groups showed the levels of TNF- α was slightly reduced, while IL-1β and IL-6 levels were significantly reduced (P < 0.05) compared to the oestrogen treated group. DS treatment restored serum calcium levels, while BMD, bone quality, osteoblast/osteoclast ratio, and collagen levels improved in both DS and oestrogen treatment groups. The uterotrophic assay demonstrated non-oestrogenic activity of DS. Endometrial hyperplastic change was observed in oestrogen-treated rats. The preclinical non-oestrogenic activity of DS has therapeutic potential in CMS through anti-inflammatory and osteo-protective effects. Further clinical research into DS, as a viable HALT to HRT, is required., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: the use of medicinal plants has increased significantly in recent years. According to the World Health Organization, 80% of the world's population uses medicinal plants to treat themselves. Our study aims to estimate the prevalence of medicinal plant use by cancer patients, list the different plants and identify their adverse effects cited by users and their reported efficacy., Methods: this study was realised among 100 patients via a questionnaire with 14-items. Socio-economic and clinical characteristics have been analysed. The bivariate and multivariate analyses have been used to demonstrate the association between the socio-demographic characteristics of the participants, the duration of the disease and the use of medicinal plants., Results: 45% of participants used medicinal plants. The most commonly reported reason for using medicinal plants was cancer cure (22%). During this study, 32 plants were identified. The Honey was the most commonly used (25%), thyme was also consumed at 15%, fenugreek at 13% and garlic at 7%. According to the multivariate analysis, the residence is predictor of medicinal plant use, urban residents used medicinal plants more than rural patients with an OR: 3,098, IC, 95%: [1,183-8,113] and P = 0,021. Fifty patients reported the moderate efficacy of the use of medicinal plants, and 20% described some side effects such as abdominal pain in 34%., Conclusion: in order to avoid any interaction with oncological drugs and to improve their effectiveness, a great importance must be given to information, education and awareness sessions., Competing Interests: The authors declare no competing interests., (Copyright: Nadia El Orfi et al.)

Background: Although numerous medicinal herbal compounds demonstrate promising therapeutic potential, their clinical application is often limited by their poor oral bioavailability. To circumvent this barrier, various lipid-based herbal formulations have been developed and trialled with promising experimental results., Purpose: This scoping review aims to describe the effect of lipid-based formulations on the oral bioavailability of herbal compounds., Methods: A systematic search was conducted across three electronic databases (Medline, Embase and Cochrane Library) between January 2010 and January 2021 to identify relevant studies. The articles were rigorously screened for eligibility. Data from eligible studies were then extracted and collated for synthesis and descriptive analysis using Covidence., Results: A total of 109 studies were included in the present review: 105 animal studies and four clinical trials. Among the formulations investigated, 50% were emulsions, 34% lipid particulate systems, 12% vesicular systems, and 4% were other types of lipid-based formulations. Within the emulsion system classification, self-emulsifying drug delivery systems were observed to produce the best improvements in oral bioavailability, followed by mixed micellar formulations. The introduction of composite lipid-based formulations and the use of uncommon surfactants such as sodium oleate in emulsion preparation was shown to consistently enhance the bioavailability of herbal compounds with poor oral absorption. Interestingly, the lipid-based formulations of magnesium lithospermate B and Pulsatilla chinensis produced an absolute bioavailability greater than 100% indicating the possibility of prolonged systemic circulation. With respect to chemical conjugation, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was the most frequently used and significantly improved the bioavailability of its phytoconstituents., Conclusion: Our findings suggest that there is no distinct lipid-based formulation superior to the other. Bioavailability improvements were largely dependent on the nature of the phytoconstituents. This scoping review, however, provided a detailed summary of the most up-to-date evidence on phytoconstituents formulated into lipid preparations and their oral bioavailability. We conclude that a systematic review and meta-analysis between bioavailability improvements of individual phytoconstituents (such as kaempferol, morin and myricetin) in various lipid-based formulations will provide a more detailed association. Such a review will be highly beneficial for both researchers and herbal manufacturers., (Copyright © 2021. Published by Elsevier GmbH.)

Salt intake is often estimated by the amount of sodium excreted in urine, and miso has been reported to increase it. This cross-sectional study investigated the relationship between obesity and high estimated salt intake with and without habitual miso consumption. Estimates of salt intake (g/day) were calculated using urinary sodium excretion, and a high estimated intake was defined as greater than the median amount of 9.5 g/day. Participants were divided into four groups based on estimated salt intake and miso consumption. Among 300 people, the proportions of obesity were 77.8% ( n = 14/18), 40.2% ( n = 53/132), 26.0% ( n = 33/127), and 34.8% ( n = 8/23) in the (+/-), (+/+), (-/+), and (-/-) groups of high estimated salt intake/habitual miso consumption, respectively. Compared with the (+/-) group, the adjusted odds ratios for obesity were 0.07 (95% confidence interval (CI): 0.02-0.26, p < 0.001), 0.16 (95% CI: 0.03-0.76, p = 0.022), and 0.14 (95% CI: 0.04-0.51, p = 0.003) in the (-/+), (-/-), and (+/+) groups, respectively. The presence of obesity was not much higher in people with high estimated salt intake with habitual miso consumption than that in people without. Clinicians should be aware that miso consumption promotes salt excretion, which may lead to an apparently higher estimated salt intake than actual.

Helicobacter pylori-induced oxidative stress plays an important role in gastric diseases. H. pylori disturbs gut microbiota. The objective is to investigate the effects of cranberry beverages on oxidative stress biomarkers and gut microbiota in H. pylori positive subjects. 171 H. pylori positive participants were randomly assigned to one of the three groups: high-dose (HCb; 480 mL cranberry beverage), low-dose (LCb; 240 mL cranberry beverage plus 240 mL placebo) and placebo (480 mL). Subjects consumed the beverages daily for 4 weeks. Fasting blood samples were analyzed for oxidative stress biomarkers. The intestinal microbiome was analyzed by 16S rRNA sequencing. Compared with the placebo, HCb resulted in a significantly higher increase of total antioxidant capacity (mean ± SD: 1.39 ± 1.69 IU mL-1vs. 0.34 ± 1.73 IU mL-1; p < 0.001) and a higher decrease of the lipid peroxidation product malondialdehyde (-7.29 ± 10.83 nmol mg-1vs. -0.84 ± 15.66 nmol mg-1; p = 0.025). A significant dose-dependent effect on the elevation of superoxide dismutase was observed (p < 0.001). Microbiome data showed that consuming HCb and LCb led to a significant reduction of Pseudomonas (p < 0.05). In conclusion, the current research showed that consuming cranberry beverages significantly improved the antioxidant status in H. pylori positive subjects, which may be related to the reshaping of gut microbiota.

Although there are several treatments for rheumatoid arthritis (RA), outcomes are unsatisfactory and often associated with many side effects. We attempted to improve RA therapeutic outcomes by intra-articular administration of dual drug-loaded poly(lactic) acid (PLA)-coated herbal colloidal carriers (HCCs). Curcumin (CU) and resveratrol (RES) were loaded into HCCs because of their safety and significant anti-inflammatory activity. HCCs were prepared using a high-pressure, hot homogenization technique and evaluated in vitro and in vivo using a complete Freund's adjuvant-induced arthritis model. Transmission electron microscope (TEM) evaluated coating selected formulations with PLA, which increased particle sizes from 52 to 89.14 nm. The entrapment efficiency of both formulations was approximately 76%. HCCs significantly increased the amount of RES and CU released compared with the drug suspensions alone. The in vivo treated groups showed a significant improvement in joint healing. PLA-coated HCCs, followed by uncoated HCCs, yielded the highest reductions in knee diameter, myeloperoxidase (MPO) levels, and tumor necrosis factor-alpha (TNFα) levels. Histological examination of the dissected joints revealed that PLA-coated HCCs followed by uncoated HCCs exhibited the most significant joint healing effects. Our results demonstrate the superiority of intra-articularly administered HCCs to suppress RA progression compared with RES or CU suspensions alone.

Introduction: Sickle Cell Disease (SCD) is the leading genetic disease in sub-Saharan Africa and therefore remains a global public health threat. Use of complementary and alternative medicines (CAM) most especially herbal medicine (HM) in chronic diseases such as sickle cell disease has widely been reported in Africa where advanced technologies are greatly lacking. Despite a large presence of the sickle cell disease in Uganda, the extent to which herbal medicines are used in management of children with sickle cell disease has not been documented. This study purposed to determine the prevalence of herbal medicine (HM) use and associated factors among caregivers of children with SCD at Mulago National Referral Hospital., Methods: a total of 384 child caretakers were interviewed in a descriptive cross-sectional quantitative study conducted at the Mulago Sickle cell clinic in March 2019. Enrolment was done consecutively and a structured interviewer administered questionnaire administered to collect data from the caretakers which was managed using SPSS version 23. Multivariate logistic regression was used to identify the factors associated with herbal medicine (HM) use. Factors with p-value <0.05 were regarded significant., Results: the rate of herbal use was 77.6% (298 of 384 caregivers). At multivariate analysis, the odds of a caregiver who agreed that; HM cures symptoms faster than conventional medicine (CM) were 3 times those who disagreed with this statement (AOR =3.439, 95% CI: 1.447 - 8.176). The odds that a caregiver who agreed that HM has fewer side effects than CM were almost 4 times those that disagreed with this statement (AOR = 3.528, 95% CI: 1.917 -6.494). The odds that a caregiver who agreed that marketing HM through televisions adverts encourages HM use were 4 times those who disagreed with this statement (AOR = 4.185, 95% CI: 2.036 -8.603)., Conclusion: this study reports a high prevalence of HM use among caregivers of children with SCD at Mulago Hospital, in Uganda. The practice is significantly influenced by caretakers´ perception that HM cures symptoms faster than CM, has fewer side effects and that telemarketing has greatly facilitated its use over CM. More effort is therefore needed to encourage clinic attendances and CM use and limit the unfounded TV adverts on HM. There is also need for studies to identify the common HM used so that their efficacy and safety are well studied., Competing Interests: The authors declare no competing interests., (Copyright: Martin Lubega et al.)

In developing countries, populations have employed herbal medicines for primary health care because they are believed to be more appropriate to the human body and have less side effects than chemically synthesized drugs. The present study aimed to develop and evaluate herbal tablets incorporated with a Thai traditional medicinal extract, U-pa-ri-waat (URW), using microwave-assisted extraction (MAE). The extraction efficiency for URW using MAE and traditional solvent extraction was compared based on the percent yield after spray drying. URW tablets were prepared using the dry granulation method. The optimized products were assessed using standard characterization methods based on the United States and British Pharmacopeias. DPPH and ABTS radical scavenging assays were performed to analyze the antioxidant capacity of the microwave-assisted extracts. The results revealed that the flowability of the dry granule with added maltodextrin was improved compared to a granule without additives, as indicated by an angle of repose of 33.69 ± 2.0°, a compressibility index of 15.38 ± 0.66, and a Hausner's ratio of 1.18 ± 0.06. The resulting formulation produced flat tablets with uniform weight variation, hardness, thickness, friability, and optimum disintegration time. The URW extracts showed antioxidant activity and MAE with maltodextrin carrier displayed the strongest DPPH and ABTS radical activities with IC50 values of 1.60 ± 0.02 μg/mL and 4.02 ± 0.24 μg/mL, respectively. The URW tablet formulation passed the quality control tests. Storage of the formulation tablets for 90 days under accelerated conditions had minimal effects on tablet characteristics.

Foxtail millet (FM) is receiving ongoing increased attention due to its beneficial health effects, including the hypoglycemic effect. However, the underlying mechanisms of the hypoglycemic effect have been underexplored. In the present study, the hypoglycemic effect of FM supplementation was confirmed again in high-fat diet and streptozotocin-induced diabetic rats with significantly decreased fasting glucose (FG), glycated serum protein, and areas under the glucose tolerance test ( p < 0.05). We employed 16S rRNA and liver RNA sequencing technologies to identify the target gut microbes and signaling pathways involved in the hypoglycemic effect of FM supplementation. The results showed that FM supplementation significantly increased the relative abundance of Lactobacillus and Ruminococcus&#95;2, which were significantly negatively correlated with FG and 2-h glucose. FM supplementation significantly reversed the trends of gene expression in diabetic rats. Specifically, FM supplementation inhibited gluconeogenesis, stimulated glycolysis, and restored fatty acid synthesis through activation of the PI3K/AKT signaling pathway. FM also reduced inflammation through inhibition of the NF-κB signaling pathway. Spearman's correlation analysis indicated a complicated set of interdependencies among the gut microbiota, signaling pathways, and metabolic parameters. Collectively, the above results suggest that the hypoglycemic effect of FM was at least partially mediated by the increased relative abundance of Lactobacillus, activation of the PI3K/AKT signaling pathway, and inhibition of the NF-κB signaling pathway.

Objective: Lactate dehydrogenase (LDH) is a critical intracellular enzyme responsible for anaerobic respiration in pyruvate metabolism which becomes detectable in extracellular spaces after cellular breakdown. This clinical investigation examined the effects of brushing with a test toothpaste containing natural ingredients, i.e., clove (Syzygium aromaticum), aloe vera (Aloe barbadensis), amla (Emblica officinalis), neem (Azadirachta indica), tulsi (Ocimum basillicum), and honey (from Apis mellifera), and 0.96% zinc (zinc oxide, zinc citrate) and 0.76% SMFP (1000 ppm F) in a calcium carbonate base formulated with natural ingredients (Ved Shakti, Colgate Palmolive India) and a fluoride toothpaste containing 0.76% SMFP (1000 ppm F) in a calcium carbonate base (Colgate Cavity Protection, Colgate Palmolive; henceforth control) on salivary LDH in conjunction with the assessments of dental plaque and gingivitis representing oral hygiene parameters., Materials and Methods: This double-blind, two-cell study enrolled 70 adults (age range 20-59 years). Subjects completed a washout and provided baseline saliva samples for LDH analysis and clinical assessments of dental plaque and gingivitis using the Turesky Modification of Quigley-Hein and Loe-Silness methods respectively. Subjects were randomly assigned to brush their teeth with either the test or control. Post-treatment sample collection and clinical evaluations were conducted after 3 weeks, 6 weeks, and 12 week sof brushing with all assessments conducted 12 h after hygiene. Statistical analyses were conducted independently for each parameter by t-test for within treatment evaluation and analysis of covariance (ANCOVA) for between treatment comparisons., Results: At baseline, treatment groups demonstrated no significant differences for LDH or dental plaque and gingival index scores. Brushing with the test demonstrated progressive reductions in salivary LDH, plaque and gingival index scores over the study duration in comparison to the control. The test demonstrated reductions in LDH of 9.5-15.4% over the study period in comparison to the control representing statistically significant effects (p < 0.05). The test also demonstrated reductions in dental plaque that ranged between 6.4 and 16.2% over the study period and gingivitis reductions that ranged between 8.2 and 23.8% representing statistically significant results (p < 0.05)., Conclusions: Brushing with a novel herbal toothpaste demonstrated significant reductions in salivary LDH representing improvements in cellular integrity with concurrent reductions in dental plaque and gingivitis as compared to the control dentifrice., Clinical Relevance: Salivary LDH measurements offer a non-invasive and objective measurement of mucosal cellular integrity complementing other evaluations and clinical assessments such as plaque and gingival index scores.

Aim of the Study: Vaginal atrophy is of the most common problems during menopause with significant psychosocial and medical consequences. Estrogen as an approved therapy for vaginal atrophy can be associated with adverse effects and several contraindications in menopause patients. The aim is to compare the effect of Aloe Vera vaginal cream with commercially available estrogen vaginal cream for management of vaginal atrophy in menopause females., Materials and Methods: This is a double-blinded randomized controlled trial on 60menopause female with complaints of vaginal atrophy symptoms. Subjects were randomly allocated in two groups of 30 patients, named as estrogen and Aloe Vera groups. Vaginal health index (VHI), maturity value (MV), vaginal cytologic smear, transvaginal sonography (TVS) and severity of symptoms related to vaginal atrophy were assessed before and after 6-weeks of vaginal cream administration., Results: Comparison of MV before and after treatment revealed that superficial cells were significantly increased after administration of both vaginal cream (6.67 VS 54.33 in Aloe Vera group; 4.33 VS 59.67 in estrogen group). In addition, VHI (13.83 vs 20.13 in Aloe Vera group; 13.97 vs 19.93 in estrogen group) and symptoms of vaginal atrophy (3.63 vs 1.10 in Aloe Vera group; 3.90 vs 0.66 in estrogen groups) were also significantly improved after treatment in both groups. There was no significant difference between groups after treatment except for fluid volume with a superiority in Aloe Vera group (P-value = 0.004) CONCLUSION: Aloe Vera vaginal cream can be as effective as estrogen vaginal cream in the management of vaginal atrophy in menopause females., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Corticosteroids as the main treatment of hand eczema can cause major side effects. This study compared the effect of topical preparation of Sambucus ebulus L. leaves and hydrocortisone on the severity of hand eczema. Design: Ninety-four patients with hand eczema aging 18-60 years were recruited in two groups ( S. ebulus vs. hydrocortisone). Interventions: The patients used topical medications twice a day and were followed for 4 weeks. The observations were made at the first visit, and also second and fourth weeks of the study. Outcome measures: The primary outcomes were changes in the severity of hand eczema (hand eczema severity index [HECSI]) and life quality (dermatology life quality index [DLQI]). Secondary outcomes were the rate of healing and the severity of itching. Results: Thirty-eight patients in hydrocortisone and 43 in S. ebulus fulfilled all phases of the follow-up. In both groups, the HECSI, itching scores decreased over time without any significant difference between the groups ( p  = 0.49, 0.57, respectively). The DLQI scores were significantly better in the S. ebulus group ( p  = 0.02) after 4 weeks of medication. There was no significant difference between the healing rates of the two groups ( p  = 0.33). Conclusions: Topical use of S. ebulus can be as effective as that of hydrocortisone when it comes to reducing the severity of hand eczema.

Objective: To evaluate the efficacy and safety of Hemoheal cream, an anti-hemorrhoid herbal preparation, (inspired by Persian medicine literatures in a double-blind, randomized placebo-controlled trial., Methods: Hemoheal cream consists of aqueous extract of Allium ampeloprasum L., Commiphora mukul (Hook. Ex Stocks) Engl and the oil of Sesamum indicum L. Fifty-two patients with symptomatic hemorrhoids were randomized to receive hemoheal cream or placebo for 3 weeks. The patients were evaluated before and after the intervention in terms of the severity of anal irritation, bleeding, anal itching, pain, defecation discomfort and swelling sense, and overall subjective improvement (%), as well as any reported adverse events., Results: The results showed that after 3 weeks of treatment, distribution of anal irritation, bleeding, pain as well as swelling sense were significantly different (P < 0.05), while the analysis showed no significant differences between two groups for anal itching and defecation discomfort (P > 0.05). Furthermore, a significant difference was observed between the overall subjective improvement of Hemoheal cream and placebo groups (P = 0.012). One patient in the treatment group complained of rashes on the application site., Conclusion: The present study showed a positive effect of Hemoheal cream in improving clinical signs and symptoms in patients with hemorrhoids.

Background: Pharmacopuncture is a combination of acupuncture and herbal medicine, which involves the injection of herbal extracts into acupuncture points (acupoints). Pharmacopuncture has become one of the major therapeutic tools used in Korea; however, safety is one of the major concerns associated with it. We aim to systematically review clinical studies on the adverse events of pharmacopuncture in Korea., Methods: To collect data on the incidence and characteristics of adverse events (AEs) and to evaluate pharmacopuncture safety, 2 or more researchers will conduct a comprehensive search of pertinent English and Korean databases using the keywords "pharmacopuncture" and "adverse events." Regardless of the participants' conditions or treatment types, we will include clinical studies on the AEs of pharmacopuncture. Studies that were not conducted in Korea, and acupoint injections containing Western medications, vitamins, or autologous serum will be excluded from this study. The severity of AEs will be classified using the common terminology criteria for adverse events, and the causality between pharmacopuncture and AEs will be assessed using the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality scale. The quality of identifying and reporting the AEs will be assessed using the McHarm scale. The risk of selection bias will be assessed using the Cochrane risk of bias and the risk of bias for non-randomized studies tools. Studies will be assessed for heterogeneity utilizing Higgins's I2 statistics, and the risk of publication bias will be assessed and expressed in the form of a contour-enhanced funnel plot., Results and Conclusion: Comprehensive investigation of all types of clinical studies in Korea will provide clearer evidence of the safety of pharmacopuncture. The results of this study will be useful for traditional medical doctors and patients who use such treatments and interventions.Systematic Review Registration: Open Science Foundation (osf.io/umhyz)., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Obesity is associated with increased serum leptin level, endothelial dysfunction and angiogenesis. In vitro studies have shown that vascular endothelial growth factor (VEGF) synthesis is increased by leptin. Animal studies revealed the effectiveness of Plantago supplementation treatment of obesity. The study aim was to evaluate the effect of Plantago major supplementation on serum leptin and VEGF blood concentration, endothelial dysfunction and angiogenesis in obese women. Seventy-two obese women received oral Plantago major supplement (Plantago group, n = 35) or placebo (placebo group, n = 37) for 12 weeks. At baseline and after completion, anthropometric and body composition measurements were performed, and blood samples were collected. Serum concentrations of leptin, VEGF-A, adiponectin, tumour necrosis factor α and soluble intercellular adhesion molecule have been determined. At completion, the leptin level was higher in the Plantago group (39 781.55 ± 20 360.73 pg ml-1) compared to both the baseline (36 138.71 ± 25 401.51 pg ml-1) and placebo group (30 502.81 ± 19 003.18 pg ml-1). Also, leptin concentration in the Plantago group at completion correlated positively with an increase in VEGF-A level (R = 0.45), and baseline VEGF-A level correlated negatively with the increase in leptin concentration (R = -0.47). Plantago major supplementation increases leptin serum level, enhances leptin influence on VEGF-A serum level increase and by this mechanism may intensify endothelial dysfunction and angiogenesis in obese women.

Midazolam (MDZ) is routinely employed as a marker compound of cytochrome P450 3A (CYP3A) activity. Despite the many HPLC-UV methods described to quantify MDZ in plasma, all of them use acetonitrile (ACN) or a mixture of methanol-isopropanol as organic solvent of the mobile phase. Since the ACN shortage in 2008, efforts have been made to replace this solvent during HPLC analysis. A simple, sensitive, accurate and repeatable HPLC-UV method (220 nm) was developed and validated to quantify MDZ in rat plasma using methanol instead. The method was applied during a herb-drug interaction study involving Maytenus ilicifolia, a Brazilian folk medicine used to treat gastric disorders. Plasma samples were alkalinized and MDZ plus alprazolam (internal standard) were extracted with diethyl ether. After solvent removal, the residue was reconstituted with methanol-water (1:1). The analyte was eluted throughout a C 18 column using sodium acetate buffer (10 mm, pH 7.4)-methanol (40:60, v/v). The precision at the lower limit of quantification never exceeded 19.40%, and 13.86% at the higher levels of quality control standards, whereas the accuracy ranged from -19.81 to 14.33%. The analytical curve was linear from 50 to 2,000 ng/ml. The activity of the hepatic CYP3A enzymes was not affected by the extract., (© 2020 John Wiley & Sons, Ltd.)

Background: In recent decades, ritualistic use of ayahuasca has spread throughout the world. Retrospective studies have suggested a good psychological safety profile, but prospective studies involving ceremony ayahuasca-naive participants are lacking., Methods: We conducted the study using a subsample from a previous study, for which first-time ceremony ayahuasca participants were recruited. The subsample consisted of 7 subjects who experienced acute and challenging psychological reactions. The semistructured Mini-International Neuropsychiatric Interview and psychometric questionnaires were administered before participants attended the ayahuasca ceremony and at 1 and 6 months after exposure. Subjective experiences were also recorded., Results: Seven subjects from a sample of 40 reported having experienced intense challenging psychological effects during the ayahuasca ceremony. Four of those 7 subjects met the diagnostic criteria for 1 or more psychiatric disorder before the ayahuasca ceremony. One month after the ceremony, 2 of those subjects no longer showed psychiatric symptoms, whereas the symptoms of the other 2 were reduced considerably. Those results persisted at the 6-month follow-up. Inappropriate setting/context (poor guiding skills and screening) contributed to some of the challenging reactions. Most of the participants (6 of 7) did not take ayahuasca again during the study period., Conclusions: Based on the cases reported here, we suggest that although it is possible that participating in ayahuasca ceremonies may entail acute psychological negative reactions, those challenging experiences can also have positive long-term effects. Prospective research on the safety profile of ayahuasca and how it is affected by the context of different practices and safety strategies is therefore necessary., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Maoto, a traditional kampo medicine, has been clinically prescribed for influenza infection and is reported to relieve symptoms and tissue damage. In this study, we evaluated the effects of maoto as an herbal multi-compound medicine on host responses in a mouse model of influenza infection. On the fifth day of oral administration to mice intranasally infected with influenza virus [A/PR/8/34 (H1N1)], maoto significantly improved survival rate, decreased viral titer, and ameliorated the infection-induced phenotype as compared with control mice. Analysis of the lung and plasma transcriptome and lipid mediator metabolite profile showed that maoto altered the profile of lipid mediators derived from ω-6 and ω-3 fatty acids to restore a normal state, and significantly up-regulated the expression of macrophage- and T-cell-related genes. Collectively, these results suggest that maoto regulates the host's inflammatory response by altering the lipid mediator profile and thereby ameliorating the symptoms of influenza.

Rationale: Treatment of immune thrombocytopenia (ITP) usually involves long-term use of immunosuppressive corticosteroids and splenectomy. However, these treatments often have side effects in patients. The Mongolian medicine Qishunbaolier (QSBLE) has a high curative effect, reduces the chances of relapse, and has no obvious side effects. This study was designed to identify potential therapeutic targets of QSBLE for treating ITP., Methods: To reveal differences in protein expression between ITP patients (ITPs) before and after QSBLE treatment, comparative proteomics studies were performed using isobaric tags for relative and absolute quantification (iTRAQ). The analysis used nanospray liquid chromatography/tandem mass spectrometry (nano-LC/MS/MS) in positive ion electrospray ionization mode. Key proteins relevant to ITP were revealed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and other bioinformatics tools. Real-time polymerase chain reaction (RT-PCR) analysis was carried out for confirmation of differentially expressed proteins., Results: A total of 982 differentially expressed proteins were identified in ITPs compared with the controls. Compared with the pre-QSBLE treatment group, 61 differentially expressed proteins were identified in the post-QSBLE treatment group, with 48 proteins being significantly upregulated and 13 downregulated. Twenty-nine pathways were significantly enriched. Q6N030 and other proteins were the key players in the protein-pathway network. Twenty proteins that may play important roles in the treatment of ITP were further filtered. RT-PCR and Western blot analyses further confirmed that MIF, PGK1 and IGHM were upregulated in ITPs after QSBLE treatment, in accordance with the proteomics data., Conclusions: It is believed that the identified proteins and the results of bioinformatics analysis will provide a potential therapeutic target site for QSBLE for ITP therapy and biomarkers., (© 2020 The Authors. Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)

Materials and Methods: Mice were divided into four groups: normal, untreated, low- (2 mg), and high-dose (8 mg) beluga lentil treatment groups. Beluga lentil was orally administered for 2 weeks, followed by bilateral renal ischemia for 20 min and reperfusion for 30 min. Blood samples and kidney tissues were collected and analyzed to investigate renal function, histopathology, epithelial and endothelial cell damage, apoptosis, oxidative stress, and inflammatory responses., Results: The pretreated groups maintained renal function, with significantly lower blood urea nitrogen (BUN) and creatinine levels, compared with the other groups. The histopathological analysis showed reduced proximal tubule injury and decreased injury-related molecule (kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) secretion in the pretreated groups compared with the other groups. Terminal deoxynucleotidyl transferase dUTP nick-end labeling- (TUNEL-) positive cells and the secretion of apoptosis-related molecules (Fas and caspase 3) were significantly reduced in the pretreated groups compared with the other groups. The pretreated groups showed positive microvessel-associated gene (cluster of differentiation (CD31)) expression and negative adhesion molecule (intracellular adhesion molecule 1 (ICAM-1)) expression. An antioxidant effect was observed in the pretreatment groups, with reduced malonaldehyde (MDA) expression and increased antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)) secretion. In the pretreated groups, F4/80+ macrophages and CD4+ T cell infiltration were inhibited and proinflammatory cytokine (interleukin- (IL-) 1 β , IL-6, and tumor necrosis factor- (TNF-) α ) levels decreased; however, the levels of anti-inflammatory cytokines (transforming growth factor- (TGF-) β , IL-10, and IL-22) increased., Conclusions: Beluga lentil pretreatment demonstrated protective effects against I/R-induced renal damage, via antiapoptotic, anti-inflammatory, and antioxidant activities., Competing Interests: There are no conflicts of interest., (Copyright © 2021 Syng-ook Lee et al.)

Ethnopharmacological Relevance: Plants from the family Ericaceae, and in particular those in the genus Rhododendron are frequently reported to contain grayanotoxins. Plant products such as honey and herbal medicines made from these plants occasionally contain grayanotoxins, and in turn may lead to intoxication. The balance between the benefits and risk of poisoning from Rhododendrons is of concerns. This study explores the ethnobotanical knowledge of the people in Yunnan, China as regards the consumption of Rhododendron flowers, and gives special focus to their assessment of the benefit-risk balance., Materials and Methods: An ethnobotanical survey was conducted across 14 county-level local markets in north and central Yunnan province, during which a total of 82 stalls selling Rhododendron flowers were visited and 204 people were interviewed. Voucher specimens were obtained under the guidance of collectors, and details about local practices and knowledge were recorded using semi-structured interviews and participatory observations., Results: The consumption of the corollas of Rhododendron decorum Franch. Flowers (RDf) or Rhododendron pachypodum Balf. f. & W.W. Sm. Flowers (RPf) as a seasonal delicacy is a long-standing tradition in the study area. RDf are widely consumed in northwest and northeast Yunnan, while RPf are more prevalent in the central regions of Yunnan, and there is a high consistency in the knowledge of the process for detoxification or palatability for each species. The main reasons for eating the flowers were listed as health benefits (mostly clear heat), wild collected, tradition and good flavor. All RPf consumers stated that the corolla from this species is not toxic, while 67.4% of the RDf consumers claim that the corolla from RDf is toxic. We compared the two species and analyzed their process intensities, poisoning cases and cautions, market trade forms and existing toxicity studies, which agreed well and consistently that the corolla of RDf deserve more toxicity attention than RPf., Conclusion: Our study provides a window to look into the ways, beyond honey and herbal medicine, by which Rhododendron species have influenced human wellbeing. The local culture can justify eating Rhododendron flowers, and meanwhile, has developed a series of skills to avoid the side effects of eating them, and therefore the study also provides a good case to answer more general questions about the rationality of eating any plant products by assessing the trade-off between benefits and side effects., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Migraine is a chronic paroxysmal incapacitating neurological disorder, which endangers the health of human worldwide ranking as the third most prevalent medical condition. There are no comprehensive estimates of treatments for migraine. We will conduct this systematic review and Bayesian network meta-analysis (NMA) to synthesis quantitative and comparative evidence on the efficacy and tolerability of all the known pharmacological and non-pharmacological interventions for migraine., Method: We will perform the systematic electronic search of the literature utilizing MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing & Allied Health (CINAHL), and PsycINFO. We will only include randomized controlled trials (RCTs) of high quality which appraise the efficacy or safety of any potential pharmacological or non-pharmacological interventions in the treatment of patients with migraine. The traditional pairwise meta-analyses will be performed to anticipate the heterogeneities and publication bias and the NMA will be conducted within a Bayesian hierarchical model framework to obtain estimates for all valuable treatments for migraine. The entire heterogeneity will be quantified by Q statistic and I2 index. Other analyses included sensitivity analyses, meta-regression, and subgroup analyses will also be conducted. The whole process will be conducted using in R-3.6.0 software., Results: This study will obtain the efficacy and tolerability of all potential treatments for migraine, aiming at providing consolidated evidence to help make the best choice of interventions. The results will be published in a peer-reviewed journal., Discussion: This Bayesian network meta-analysis may be the first attempt to quantitatively synthesize the efficacy and tolerability of all potential treatments for migraine. And this method can ensure us to fully utilize both the direct and indirect evidence as well as gain the comparative estimates displayed in the derived hierarchies. Besides, we have registered this protocol on the international prospective register of systematic review (PROSPERO) (CRD42020157278)., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)