Clinical Quickies (Nov-Dec 2023)

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  1. Aloe Vera Gel May Improve Diabetic Foot Ulcer Healing
  2. A Supplement with Andrographolide, spirulina, and humic acid Combination Appears to Reduce Duration and Severity of Acute Upper Respiratory Infections
  3. Running Therapy is as Effective as Antidepressants in Managing Depression/Anxiety, But Likely More Beneficial in the Long Run
  4. NAC Administered via IV Therapy Improves Sputum Expectoration and Reduces Sputum Viscosity
  5. Cannabidiol and Cannabigerol Appear to Help Pain Management and Bone Healing in Fractures
  6. Modified Citrus Pectin Should be Considered in Patients with Non-Metastatic Biochemically Relapsed Prostate Cancer
  7. Asian-Adapted Mediterranean Diet Plus Pentadecanoic Acid Did not Improve Fatty Liver, but Further Reduced LDL-Cholesterol
  8. Simple Ginger Extract Reduces Constipations, Nausea, Bloating, and Abdominal Pain in Patients with Relapsing-Remitting Multiple Sclerosis
  9. Topical Oil Containing Boswellic Acid can Decrease Pain and Help with Osteoarthritis Management
  10. Bee Propolis Tablets may Improve Insulin Resistance and Reduce Testosterone Level in Patients with PCOS
  11. Gum Arabic may Help Reduce Dental Plaque and Gingivitis
  12. Lion’s Mane Supplement may Reduce High-Pitch Hearing Loss in Seniors Over 65 Years of Age

1. Aloe Vera Gel May Improve Diabetic Foot Ulcer Healing

BACKGROUND: Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that can result in severe consequences. The cost of treating DFUs is high, and there is a lack of new therapies available in developing countries. This has created a demand for complementary and alternative treatments. The objective of this study was to assess the impact of aloe vera gel on the healing process of diabetic foot ulcers.

METHODS AND MATERIALS: The study was a double-blind, randomized, controlled clinical trial. The study samples were 66 patients with diabetic foot ulcers who were randomly assigned to two groups (intervention and control). All ulcers in both groups were washed with normal saline and dressed in sterile gauze. The ulcers in the intervention group were covered with a thin layer of Aloe Vera gel before the dressing. The Bates-Jensen Wound Assessment Tool (BWAT) was used on three occasions, including before the intervention period and at the end of each week. Data were analyzed using SPSS 16.

RESULTS: After three weeks, there was a notable contrast in the recovery pattern of the two groups. The patients who had aloe vera gel added to their dressing showed a more substantial decrease in the mean scores of their BWAT.

CONCLUSION: These findings are promising and suggest that Aloe vera may be a safe and effective adjunctive treatment for diabetic foot ulcers. However, further research is needed to confirm these results and to investigate the underlying mechanisms of aloe vera’s therapeutic effect on diabetic foot ulcers.

Irani PS, et al. The Effect of Aloe Vera on the Healing of Diabetic Foot Ulcer: A Randomized, Double-blind Clinical Trial. Curr Drug Discov Technol. 2023 Sep 4. doi: 10.2174/1570163820666230904150945. Online ahead of print.

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2. A Supplement with Andrographolide, spirulina, and humic acid Combination Appears to Reduce Duration and Severity of Acute Upper Respiratory Infections

INTRODUCTION: Acute upper respiratory tract infections (AURTIs) are associated with a significant burden on society attributed to medical care and loss of productivity. Novel therapies that are able to shorten disease duration, while providing symptom relief and being well tolerated, are an unmet medical need.

AIM: The main objective of this trial was to investigate the efficacy and safety of Aviron Rapid, a dietary supplement containing andrographolide, proprietary spirulina, and humic acid, in the management of AURTIs in adolescents and children.

MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled trial was conducted between January 2020 and March 2020 in 85 general practitioner practices in Bulgaria. Adolescents (13–17 years) and children (5–12 years) with a clinical diagnosis of AURTI were randomly assigned to receive standard symptomatic therapy + Aviron Rapid or placebo for 5 and 7 days, respectively. The primary endpoints of this trial were the number (and percentage) of clinically recovered patients and the mean disease duration.

RESULTS: In total, 380 adolescents and 401 children were enrolled in 2 age cohorts and randomly assigned to treatment with Aviron Rapid or placebo. The percentage of patients meeting the criteria for clinical recovery was significantly higher in the Aviron Rapid group compared with the placebo group from 24 and 48 hours after initiation of treatment in adolescents and children, respectively. Aviron Rapid treatment significantly reduced the duration of disease, of fever, and of antipyretics intake in both adolescents and children. When compared to placebo, a significantly higher percentage of adolescents and children on Aviron Rapid achieved a persistent decrease in temperature of less than 37°C as soon as 24 hours after starting treatment. Overall, a low number of adverse events was reported and no major differences in the incidence of individual adverse events were observed between the two treatment groups in both cohorts.

CONCLUSIONS: This clinical trial demonstrated the efficacy of Aviron Rapid in the management of acute upper respiratory tract infections in adolescents and children. Aviron Rapid treatment rapidly increased the number of clinically recovered patients and reduced overall disease duration and duration of symptoms, in particular fever, while being well tolerated.

Markova RM, et al. Efficacy and safety of Aviron Rapid® in adolescents and children with viral acute upper respiratory tract infection: a multi-center, randomized, double blind, placebo-controlled clinical trial. Folia Med (Plovdiv). 2023 Aug 31;65(4):546-568. doi: 10.3897/folmed.65.e108153.

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3. Running Therapy is as Effective as Antidepressants in Managing Depression/Anxiety, But Likely More Beneficial in the Long Run

BACKGROUND: Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different pathophysiological mechanisms and could differ in their impact on physical health. This study examined effects of antidepressants versus running therapy on both mental and physical health.

METHODS: According to a partially randomized patient preference design, 141 patients with depression and/or anxiety disorder were randomized or offered preferred 16-week treatment: antidepressant medication (escitalopram or sertraline) or group-based running therapy ≥2 per week. Baseline (T0) and post-treatment assessment at week 16 (T16) included mental (diagnosis status and symptom severity) and physical health indicators (metabolic and immune indicators, heart rate (variability), weight, lung function, hand grip strength, fitness).

RESULTS: Of the 141 participants (mean age 38.2 years; 58.2 % female), 45 participants received antidepressant medication and 96 underwent running therapy. Intention-to-treat analyses showed that remission rates at T16 were comparable (antidepressants: 44.8 %; running: 43.3 %; p = .881). However, the groups differed significantly on various changes in physical health: weight (d = 0.57; p = .001), waist circumference (d = 0.44; p = .011), systolic (d = 0.45; p = .011) and diastolic (d = 0.53; p = .002) blood pressure, heart rate (d = 0.36; p = .033) and heart rate variability (d = 0.48; p = .006).

LIMITATIONS: A minority of the participants was willing to be randomized; the running therapy was larger due to greater preference for this intervention.

CONCLUSIONS: While the interventions had comparable effects on mental health, running therapy outperformed antidepressants on physical health, due to both larger improvements in the running therapy group as well as larger deterioration in the antidepressant group.

Verhoeven JE, et al. Antidepressants or running therapy: Comparing effects on mental and physical health in patients with depression and anxiety disorders. J Affect Disord. 2023 May 15:329:19-29. doi: 10.1016/j.jad.2023.02.064. Epub 2023 Feb 23.

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4. NAC Administered via IV Therapy Improves Sputum Expectoration and Reduces Sputum Viscosity

OBJECTIVE: Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter, randomized, controlled, subject, and rater-blinded study whether IV NAC is superior to placebo and non-inferior to ambroxol in improving sputum viscosity and expectoration difficulty.

PATIENTS AND METHODS: A total of 333 hospitalized subjects from 28 centers in China with respiratory disease (such as acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, and bronchiectasis) and abnormal mucus secretion were randomly allocated in a 1:1:1 ratio to receive NAC 600 mg, ambroxol hydrochloride 30 mg, or placebo as an IV infusion twice daily for 7 days. Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics.

RESULTS: NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference 0.24 (0.763), p<0.001 vs. placebo] and expectoration difficulty score [mean (SD) difference 0.29 (0.783), p=0.002 vs. placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified.

CONCLUSIONS: This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.

Tang W, et al. Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion. Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127 DOI: 10.26355/eurrev_202306_32628 

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5. Cannabidiol and Cannabigerol Appear to Help Pain Management and Bone Healing in Fractures

BACKGROUND: Bone fractures are among the most prevalent musculoskeletal injuries, and pain management is an essential part of fracture treatment. Fractures heal through an early inflammatory phase, followed by repair and remodeling. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for fracture pain control as they potently inhibit the inflammatory phase and, thus, impair the healing. Opioids do not provide a better alternative for several reasons, including abuse potential. Accordingly, there is an unmet clinical need for analgesics that effectively ameliorate postfracture pain without impeding the healing.

Here, we investigated the analgesic efficacy of two nonpsychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model for tibial fracture. Mice with fractured tibiae exhibited increased sensitivity to mechanical, cold, and hot stimuli. Both CBD and CBG normalized pain sensitivity to all tested stimuli, and their analgesic effects were comparable to those of the NSAIDs. Interestingly, CBD and CBG promoted bone healing via multiple mechanisms during the early and late phases. During the early inflammatory phase, both cannabinoids increased the abundance of periosteal bone progenitors in the healing hematoma and promoted the osteogenic commitment of these progenitors.

During the later phases of healing, CBD and CBG accelerated the fibrocartilaginous callus mineralization and enhanced the viability and proliferation of bone and bone-marrow cells. These effects culminated in higher bone volume fraction, higher bone mineral density, and improved mechanical quality of the newly formed bone. Together, our data suggest CBD and CBG as therapeutic agents that can replace NSAIDs in managing postfracture pain as both cannabinoids exert potent analgesic effects and, at the same time, promote bone healing. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Khajuria DK, et al. Cannabidiol and Cannabigerol, Nonpsychotropic Cannabinoids, as Analgesics that Effectively Manage Bone Fracture Pain and Promote Healing in Mice. J Bone Miner Res. 2023 Nov;38(11):1560-1576. doi: 10.1002/jbmr.4902. Epub 2023 Sep 25.

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6. Modified Citrus Pectin Should be Considered in Patients with Non-Metastatic Biochemically Relapsed Prostate Cancer

INTRODUCTION: The optimal therapy for patients with non-metastatic biochemically relapsed prostate cancer (BRPC-M0) after local therapy is elusive. Thus, the evaluation of new non-toxic compounds in BRPC-M0 patients is warranted. PectaSol®-Modified citrus pectin (P-MCP) is a food supplement categorized as GRAS (Generally Recognized As Safe) by the FDA. It is a competitive inhibitor of the galectin-3 protein, which is involved in cancer pathogenesis. In an early report of the present phase 2 study, P-MCP treatment for 6 months led to prostate-specific antigen doubling time (PSADT) improvement in 75% of patients with BRPC-M0. Herein, we report the second long-term treatment phase of an additional 12 months of P-MCP therapy (4.8 g × 3/day orally) in patients without disease progression after the initial 6 months of therapy. Of the 46 patients that entered the second treatment phase, 7 patients withdrew consent and decided to continue therapy out of pocket, and 39 initiated the second treatment phase. After a total of 18 months of P-MCP treatment, 85% (n = 33) had a durable long-term response, with 62% (n = 24) showing decreased/stable PSA, 90% (n = 35) PSADT improvement, and all with negative scans. No patient had grade 3/4 toxicity. In conclusion, P-MCP may have long-term durable efficacy and is safe in BRPC-M0.

Keizman D, et al. Modified Citrus Pectin Treatment in Non-Metastatic Biochemically Relapsed Prostate Cancer: Long-Term Results of a Prospective Phase II Study. Nutrients. 2023 Aug 11;15(16):3533. doi: 10.3390/nu15163533.

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7. Asian-Adapted Mediterranean Diet Plus Pentadecanoic Acid Did not Improve Fatty Liver, but Further Reduced LDL-Cholesterol. 

BACKGROUND: Weight loss is the most effective treatment for non-alcoholic fatty liver disease (NAFLD). There is evidence that Mediterranean diets rich in unsaturated fatty acids and fiber have beneficial effects on weight homeostasis and metabolic risk factors in individuals with NAFLD. Studies have also shown that higher circulating concentrations of pentadecanoic acid (C15:0) are associated with lower risk for NAFLD.

OBJECTIVES: To examine the effects of a Mediterranean-like, culturally contextualized Asian diet rich in fiber and unsaturated fatty acids, with or without C15:0 supplementation, in Chinese females with NAFLD.

METHODS: In a double-blinded, parallel-design, randomized controlled trial, 88 Chinese females with NAFLD were randomized to one of three groups for 12-weeks: diet with C15:0 supplementation (n=31), diet without C15:0 supplementation (n=28), or control (habitual diet and no C15:0 supplementation, n=29). At baseline and after the intervention, body fat percentage, intrahepatic lipid content, muscle and abdominal fat, liver enzymes, cardiometabolic risk factors and gut microbiome were assessed.

RESULTS: In intention-to-treat analysis, weight reductions of 4.0±0.5 kg (5.3%), 3.4±0.5 kg (4.5%), and 1.5±0.5 kg (2.1%) were achieved in the diet-with-C15:0, diet-without-C15:0, and the control groups, respectively. The proton density fat fraction (PDFF) of the liver decreased by 33%, 30% and 10%, respectively. Both diet groups achieved significantly greater reductions in body weight, liver PDFF, total cholesterol, gamma-glutamyl transferase, and triglyceride concentrations compared to the control group. C15:0 supplementation reduced LDL-cholesterol further, and increased abundance of Bifidobacterium adolescentis. Fat mass, visceral adipose tissue, subcutaneous abdominal adipose tissue (deep and superficial), insulin, glycated hemoglobin and blood pressure decreased significantly in all groups, in parallel with weight loss.

CONCLUSION: Mild weight loss induced by a Mediterranean-like diet adapted for Asians has multiple beneficial health effects in women with NAFLD. C15:0 supplementation lowers LDL-cholesterol and may cause beneficial shifts in gut microbiome.

Chooi YC, et al. Effect of an Asian-adapted Mediterranean diet and pentadecanoic acid on fatty liver disease: The TANGO randomized controlled trial. Am J Clin Nutr. 2023 Nov 28:S0002-9165(23)66285-9. doi: 10.1016/j.ajcnut.2023.11.013. Online ahead of print.

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8. Simple Ginger Extract Reduces Constipations, Nausea, Bloating, and Abdominal Pain in Patients with Relapsing-Remitting Multiple Sclerosis

BACKGROUND: Gastrointestinal (GI) symptoms affect more than 80% of individuals with relapsing-remitting multiple sclerosis (RRMS). Ginger is widely known for its GI relieving properties. Therefore, we investigated the effect of ginger supplementation on common GI symptoms in RRMS patients.

METHODS: This study was a 12-week double-blind parallel randomized controlled trial with a 3-week run-in period. The intervention (n = 26) and control (n = 26) groups received 500 mg ginger and placebo (as corn) supplements 3 times a day along with main meals, respectively. At the beginning and end of the trial, the frequency and severity of constipation, dysphagia, abdominal pain, diarrhea, bloating, belching, flatulence, heartburn, anorexia, and nausea were assessed using the visual analogue scale ranging from 0 to 100 mm. Totally, 49 participants completed the study. However, data analysis was performed on all 52 participants based on the intention-to-treat principle.

RESULTS: In comparison with placebo, ginger supplementation resulted in significant or near-significant reductions in the frequency (-23.63 ± 5.36 vs. 14.81 ± 2.78, P < 0.001) and severity (-24.15 ± 5.10 vs. 11.39 ± 3.23, P < 0.001) of constipation, the frequency (-12.41 ± 3.75 vs. 3.75 ± 1.82, P < 0.001) and severity (-13.43 ± 4.91 vs. 6.88 ± 2.69, P = 0.001) of nausea, the frequency (-9.31 ± 4.44 vs. 1.56 ± 4.05, P = 0.098) and severity (-11.57 ± 5.09 vs. 3.97 ± 3.99, P = 0.047) of bloating, and the severity of abdominal pain (-5.69 ± 3.66 vs. 3.43 ± 3.26, P = 0.069).

CONCLUSION: Ginger consumption can improve constipation, nausea, bloating, and abdominal pain in patients with RRMS.

Foshati S, et al. The effects of ginger supplementation on common gastrointestinal symptoms in patients with relapsing-remitting multiple sclerosis: a double-blind randomized placebo-controlled trial. BMC Complement Med Ther. 2023 Oct 27;23(1):383. doi: 10.1186/s12906-023-04227-x.

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9. Topical Oil Containing Boswellic Acid can Decrease Pain and Help with Osteoarthritis Management

OBJECTIVE: Pharmacological treatments of osteoarthritis (OA) have several side effects. Boswellia serrata resin (frankincense) is rich in boswellic acids that have antioxidant and anti-inflammatory effects; though, their oral bioavailability is low. The aim of this study was evaluation of the clinical effectiveness of frankincense extract in the treatment of knee OA. In a randomized double-blind placebo-controlled clinical trial, eligible patients with knee OA were randomly divided into two groups of drug (33 patients) and control (37 patients), to use oily solution of frankincense extract or placebo, respectively, on the involved knee three times daily for four weeks. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), VAS (visual analogue scale; for pain severity), and PGA (patient global assessment) scores were determined before and after intervention.

RESULTS: For all evaluated outcome variables, there was a significant decrease from baseline in both groups (P < 0.001 for all). Furthermore, the end-of-intervention values for all parameters were significantly lower in drug group than placebo group (P < 0.001 for all), showing more effectiveness of drug compared to placebo.

CONCLUSION: Topical oily solution containing enriched extract of boswellic acids could decrease pain severity and improve the function in patients with knee OA. Trial Registration Trial registration number: IRCT20150721023282N14. Trial registration date: September 20, 2020. The study was retrospectively registered in Iranian Registry of Clinical Trials (IRCT).

Mohsenzadeh A, et al. Evaluation of the effectiveness of topical oily solution containing frankincense extract in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial. BMC Res Notes. 2023 Mar 4;16(1):28. doi: 10.1186/s13104-023-06291-5.

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10. Bee Propolis Tablets may Improve Insulin Resistance and Reduce Testosterone Level in Patients with PCOS

ABSTRACT: One of the most prevalent ovulation disorders is polycystic ovarian syndrome (PCOS). According to the anti-inflammatory and beneficial effects of propolis, this triple-blind controlled trial was designed to evaluate the effect of propolis on metabolic factors, high-sensitivity C-reactive protein, and testosterone in women with PCOS.

Recruited patients from the gynecologist clinic were randomized based on a stratified permuted four-block randomization procedure to supplement with propolis tablets, two tablets/day (500 mg propolis/day) (n = 30) or identical placebo tablets (n = 30) for 12 weeks in 2021 until 2022. Data were collected using a demographic questionnaire, blood samples, and a checklist to record the measured parameters.

A total of 57 patients completed the trial. ANCOVA test showed that hip circumference (HC)) p = 0.03), fasting insulin (p = 0.007), homeostatic model assessment for insulin resistance (p = 0.004), testosterone (p = 0.004), and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) (p = 0.02) were significantly decreased in the propolis versus the placebo group after adjustment for confounders. Although fasting blood glucose (p = 0.04) decreased significantly in the propolis group compared to the placebo, after adjusting for confounders, significance was lost (p = 0.09). Supplementation with propolis elicited positive effects on fasting insulin and insulin resistance, in addition to reducing the testosterone level, LDL/HDL, and HC, in PCOS women.

Abbasi E, et al. The effects of propolis supplementation on high-sensitivity C-reactive protein, testosterone hormone, and metabolic profile in women with polycystic ovary syndrome: A randomized, triple-blinded, placebo-controlled clinical trial. Phytother Res. 2023 Nov;37(11):5366-5377. doi: 10.1002/ptr.7977. Epub 2023 Sep 2.

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11. Gum Arabic may Help Reduce Dental Plaque and Gingivitis

BACKGROUND: New approaches to treating periodontal diseases aim to balance sustaining the natural oral microbiota and modifying the host immune response. Gum Arabic (GA) is a natural polysaccharide rich in prebiotics.The aim of this study was to assess the effect of GA on clinical (Plaque Index (PI), Gingival Index (GI)) and immunological (Gingival Crevicular Fluid Interleukin 1 Beta (GCF IL-1 β)) parameters in patients with plaque-induced gingivitis.

MATERIALS AND METHODS: This placebo-controlled, double-blinded randomised clinical trial was conducted at the Department of Periodontology at Khartoum Dental Teaching Hospital, Khartoum, Sudan, from July to October 2016. Patients diagnosed with plaque-induced gingivitis meeting the study eligibility criteria were enrolled. At baseline, PI, GI and GCF IL-1β were measured. Patients received full-mouth scaling and were randomly assigned to receive either GA powder (intervention group) or Microcrystalline cellulose powder (placebo group). The patients were instructed to apply the treatment twice a day throughout the study. The PI, GI and GCF IL-1β were reassessed after 30 and 60 days.

RESULTS: A total of 60 patients were enrolled (30 in each group). Compared to the placebo group, the intervention group showed a statistically significant reduction in GI scores after 30 days and improved PI scores at 30 and 60 days. Between baseline and 60 days, patients who received GA exhibited a significant reduction in GCF IL-1β levels compared to the placebo group.

CONCLUSION: GA was found to be effective in controlling plaque and gingivitis. 

Gafar AM, et al. Effect of Gum Arabic on plaque-induced gingivitis: A randomised controlled trial. Saudi Dent J. 2022 Sep;34(6):494-502. doi: 10.1016/j.sdentj.2022.06.002. Epub 2022 Jun 13.

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12. Lion’s Mane Supplement may Reduce High-Pitch Hearing Loss in Seniors Ove 65 Years of Age

ABSTRACT: We aimed to investigate the effects and mechanisms of Hericium erinaceus (HE) on hearing degeneration. By a double-blind, randomized, clinical trial, all 80 hearing-impaired patients aged 50–79 were randomly divided into the two groups, which received HE mycelia (2000 mg/day) and placebo boluses for eight months, respectively. A student’s t-test was used to evaluate the differences of the average pure tone hearing threshold of all, low, and high frequencies (PTA-all, PTA-low, and PTA-high); speech recognition threshold (SRT); speech discrimination score (SDS); and serum concentrations of brain-derived neurotrophic factor (BDNF) and neurotrophic growth factor (NGF) between the two study groups. Subgroup analysis by age showed that PTA-high-Right, PTA-all-Left, PTA-high-Left, SRT-Right, SRT-Left, and NGF were significantly different between the two groups among patients aged ≧ 65. HE mycelia treatment could ameliorate hearing loss, especially for high frequencies and speech recognition, and increase NGF in patients aged ≧ 65.

Chan YC, et al. Effects of erinacine A-enriched Hericium erinaceus on elderly hearing-impaired patients: A double-blind, randomized, placebo-controlled clinical trial. J Funct Foods. October 2022;97:105220. doi: 10.1016/j.jff.2022.105220.