Panax ginseng Meyer root preparation (HRG80) and traditionally harvested six-year-old white P. ginseng standard preparation (PGS) with placebo in preventing symptoms of stress. Methods: The effects of HRG80, PGS, and placebo capsules were studied in 50 tired healthy subjects in a three-arm, randomized, double-blinded, placebo-controlled crossover trial. Efficacy-outcome measures included the accuracy of processing the d2 test for cognitive functions, obtained accuracy score in a computerized memory test, and the perceived-stress (PS) score. Results: A statistically significant interaction effect between time and treatment (p < 0.0001) was observed in the attention d2 and memory tests, indicating that HRG80 treatment was more beneficial than that with a placebo. The effects of PGS were better than those of the placebo, but the difference was not statistically significant. There was significant difference between the effects of HRG80 and PGS (p < 0.0001) that were observed after single (Day 1) and repeated administrations on Days 5 and 12 of treatment. Conclusion: Overall, HRG80 treatment was significantly superior compared to that with the PGS and placebo regarding attention, memory, and PS scores after single and repeated administrations for 5 and 12 days.Background: The aim of this pilot study was to compare the efficacy of hydroponically cultivated red  Panax ginseng Meyer root has been traditionally used in China, Korea, and Japan for thousands of years for the treatment of many conditions, including the age-related decline of cognitive function, general weakness, and for enhancing longevity [The ongevity ,5,6,7,8.ongevity ,8,9,10. ongevity ,13,14,15The results of many clinical trials suggesting the beneficial effects of ginseng on stress and cognitive functions were critically reviewed in several comprehensive and systematic review articles ,17,18,19Preparation HRG80 was obtained for the first time by the hydroponic cultivation of ginseng by vertical-farming technology according to an FSSCC2 2000 certified standards ensuring the strict control and stability of growing conditions and, therefore, the reproducible chemical composition and high purity of white ginseng, which is converted into red ginseng HRG80 by steam cooking. The ginsenoside profile of this preparation is similar to ginseng cultivated in the field, but the ginsenoside content is two- to threefold higher. Further processing of this white-ginseng preparation into red-ginseng preparation HRG80 results in the conversion of major highly glycosylated ginsenosides into rare ginsenosides Rg6, Rh4, Rg3, Ck, Rk1, and Rh3.Currently, there is no scientific evidence that HRG80 preparation is effective in preventing and mitigating the stress-induced deterioration of cognitive functions in healthy subjects. Assuming that new clinical evidence is required for the well-established use of white ginseng in preventing and mitigating stress-induced failure of cognitive functions in healthy subjects, the aim of our study was to demonstrate the clinical efficacy of both hydroponically cultivated red-ginseng preparation (HRG80) and traditionally harvested six-year-old white-ginseng standard preparation (PGS) in commercially available dosage forms. The effects of HRG80, PGS Arkopharma, and placebo capsules on preventing symptoms of stress such as fatigue, impaired memory, difficulty in concentration, and attention deficit related to the daily work situation of healthy teleoperators and information-technology (IT) personnel were studied in a three-arm, randomized, double-blinded, placebo-controlled crossover trial.p > 0.8, ANOVA, Kruskal–Wallis test), at the baseline between subgroups  entered in the study.Overall, 55 participants were assessed for eligibility; five did not meet the inclusion criteria . Fifty hTreatment compliance assessed by a capsule count of the returned preparation comprised 100%; every participant returned 2 of 30 capsules per package, implying that they had consumed 28 capsules during 14 days of treatment (less than nine returned capsules were considered as compliant).Error rate (E%) in the attention test was significantly increased at the end of a stressful workday after single and repeated placebo administrations, represented as a change in errors percentage (attention score) from the baseline (morning)  in the afternoon test than in the morning tests after both single and repeated administrations of control ginseng (Arkophama) preparation (p = 0.7 (HRG80 significantly decreased Δ (compared to baseline Day 1—no treatment), which was negative during all 12 days of treatment, indicating that mental performance was significantly higher with single and repeated administrations of HRG80. Within-group comparison showed a statistically significant decrease of errors from Day 0, = 0.0047 . The errparation . Within-(p = 0.7 .p < 0.0001) was observed in the attention d2 test, indicating that HRG80 treatment was more beneficial than that with a placebo . There was significant difference between the effects of ginseng HRG80 and ginseng Arkopharma control (p < 0.0001), which was observed after single (Day 1) and repeated administrations on Days 5 and 12 of treatment  to postworkload Δ < 0, ).p < 0.05 (p = 0.0005 (HRG80 significantly increased Δ (compared to baseline day 1—no treatment), which was positive during 12 days of treatment, indicating that mental performance was higher with single and repeated administrations of HRG80. A significant effect was observed on Day 12. Within-group comparison showed statistical significance, p < 0.05 . A signi= 0.0005 .p < 0.0001) was observed in the MT, indicating that HRG80 treatment was more beneficial than that with the placebo on Days 5 and 12. The ginseng control treatment effect compared to the placebo effect was also statistically significant  to post-workload (Δ was about 0), whereas it was significantly increased after repeated administrations of the placebo on Days 5 and 12 .p < 0.0001) after 5 days of treatment, whereas ginseng control decreased PSS after only 12 days of treatment. Within-group comparisons showed a higher effect size and statistical significance for HRG80 treatment .p = 0.0004) was observed in PSS, indicating that the HRG80 treatment was more beneficial than the ginseng control treatment : diarrhea in one subject taking PGS, and abdominal distention and weariness in two participants taking placebo or HRG80.No statistically significant difference between HRG80 and placebo was observed regarding toxic adverse events; treatment was well-tolerated, and serious adverse events were not observed.P. ginseng Meyer) are used in two differently processed forms: air-dried into white ginseng (known in China as renshen), and steamed at 100 °C to red ginseng (hongshen), which contains no less than 0.40% of the sum of ginsenosides Rg1 and Rb1 (dried drug) [Ginseng radix and rhizome (ed drug) . Consequed drug) , antifated drug) , antidiaed drug) , and neued drug) .P. ginseng, also known as Korean ginseng; >80 of them are isolated from raw or processed ginseng, and the others are acid/base hydrolysates, semisynthetic saponins, or metabolites [To date, 112 saponins have been reported as components of abolites ,39. A toabolites . The effabolites .P. ginseng preparation is about 2.6%, as determined by the mass of the root powder  and cell culture, but also organ cultures , is a promising approach to increase the content of targeted secondary metabolites under controlled conditions [P. ginseng in hydroponics and observed higher ginsenoside and phenolic content in its leaves.Cultivation of nditions . It is pnditions ,54. In pnditions ,56, inclnditions ,58. Paranditions ,56,59. Cnditions  cultivatP. ginseng preparation HRG80 with a placebo and an active control white-ginseng preparation (Arkopharma), with respect to the effects on cognitive functions, memory, and stress-induced fatigue in healthy subjects.The primary objective of the study was to compare the efficacy and tolerability of hydroponically cultivated Social-stress impact often becomes the trigger for acute mental fatigue and the onset of chronic-fatigue syndrome as a result of the persistent accumulation of acute fatigue . Mental Efficacy was studied and evaluated using commonly accepted tests ,62,63 foA statistically significant interaction effect between time and treatment was observed in the attention d2 and memory tests, indicating that HRG80 treatment was more beneficial than that with the placebo. There was no significant difference between the effects of PGS and placebo, even though the effect of PGS was superior. There was significant difference between the effects of HRG80 and PGS, which were observed after single (Day 1) and repeated administrations on Days 5 and 12 of treatment. A statistically significant interaction effect between time and treatment was observed in the PS test, indicating that HRG80 treatment was more beneficial than that with the PGS, but not in the MT, in which the difference between HRG80 and PGS was statistically nonsignificant. The number and types of adverse events were the same in all groups; no serious adverse events were observed.The results of this study are in line with the results of an ex vivo study in rats where HRG80 was more active than SGP in the hippocampal long-term-potentiation (LTP) model; administration of HRG80 and SGP induced higher excitability of hippocampal pyramidal cells in vitro, leading to LTP compared to the placebo .A randomized, double blind, placebo-controlled study to determine if red-ginseng preparation HRG80 is superior to conventionally grown ginseng and a placebo on electrical brain activity in elderly subjects during performance of various cognitive tasks is now in progress .Overall, further confirmatory studies with a higher number of patients and a longer treatment period are needed to provide more evidence for the superiority of red ginseng versus white ginseng and a placebo.Results of the clinical efficacy of various ginseng preparations in mental and chronic fatigue are conflicting. Thus, Hallstrom et al. (1982) studied the effects of radix ginseng in fatigued night nurses and concluded that ginseng exhibits antifatigue activity in a placebo-controlled, double-blind crossover trial . HoweverP. ginseng extract (G115) by showing improvements in the cognitive performance and memory of healthy volunteers in serial clinical studies [Ten trials with good methodology  evaluated the efficacy of ginseng on psychomotor function using white or red ginseng ,30,31. T studies ,24,25,26 studies ,25.In this context, the results of our study suggesting that ginseng HRG80 is a promising treatment for fatigue are in line with the results of clinical studies of other adaptogenic plant extracts that exhibit antifatigue effects increasing the mental performance and cognitive functions of healthy subjects and patients with chronic fatigue . In contP. ginseng HRG80 preparation in healthy subjects with symptoms of stress and fatigue was conducted in the Sports Medicine and Antidoping Service Republican Center  with approval of their Ethics Committee . The study was performed in accordance with the Declaration of Helsinki .A study of the efficacy of the proprietary https://clinicaltrials.gov/ct2/show/NCT03947554?term=ep-1005&rank=1). All participants provided written informed consent to participate in the study prior to being screened.This trial was registered at ClinicalTrials.gov  analysis. Participants were eligible for participation in this trial in the period from April to June 2019. Individuals were recruited by doctors from SMADC, and they included the teleoperators, engineers, and IT personnel of VivaCell-MTS Ltd. . All subjects included in the study were healthy and had almost the same level of occupational stress, which does not fall into the category of pathological stress. There was not a cut-off for PS score at inclusion. This subjective self-assessment score at the baseline did not have Gaussian distribution, but the sample size of 50 subjects was homogeneous before treatments, with standard deviation of 2.24 at a mean value of 16.2, and 13.8% coefficient of variation that was suitable for the nonparametric statistical assessment of PSS used in this study.During the initial visit of the study site, SMADC, inclusion and exclusion criteria were evaluated, and individuals interested in study participation received information about the study. If individuals were suited for study participation, an appointment for medical screening, including anamnestic evaluation, was made. Subjects who were temporarily taking over-the-counter symptomatic medications or dietary supplements that may have potential effects on cognitive functions were told to stop that treatment at least 2 weeks before beginning the study (wash-out period). They were also informed to not consume more than one cup of coffee daily (in the morning) during the study (1 week).The target population comprised subjects experiencing stress and fatigue during 8 h of working at the computer, but who were otherwise healthy. The inclusion criteria were as follows: men and women 18–65 years of age (any race and ethnicity) who could understand and provide signed informed consent and were able to participate in an 11-week study.The exclusion criteria were as follows: taking over-the-counter medications or dietary supplements that may have potential effects on cognitive functions; consuming more than one cup of coffee daily (in the morning); allergy to ginseng preparations; and any other condition that precluded participation according to the judgement of the investigator.Participants were free to withdraw from the study at any time without giving a reason and with no negative consequences. There were no cases of participant withdrawal from the study.P. ginseng Meyer root preparation (HRG80) compared to traditionally harvested 6-year-old red PGS preparation Arkopharma (positive control) and a placebo (negative control) in preventing symptoms of stress such as fatigue, impaired memory, difficulty in concentration, and attention deficit related to the daily work situation of healthy subjects. The effects of HRG80, PGS Arkopharma, and placebo capsules, taken for 14 days, were studied  root in controlled conditions to contain 12%–15% total ginsenosides and 10%–12% rare ginsenosides. Harvested ginseng roots were air-dried and steamed at 130 °C for 2 h to obtain red ginseng roots. Then, the red ginseng was powdered and sifted at 300 µm, and standardized for rare-ginsenoside content and ginsenoside profile. One HRG80 capsule (418 mg), manufactured by Botalys SA, was standardized for the content of 209 mg powdered P. ginseng Meyer root powder corresponding to 31.8 mg of ginsenosides Rg1, Re, Rf, Rh1, Rg2, Rb1, Rc, Rb2, Rd, Rg6, Rh4, Rg3, PPT, Rk1, C(K), Rh2, Rh3, and PPD; 25.9 mg of rare ginsenosides Rh1, Rg2, Rg6, Rh4, Rg3, PPT, Rk1, C(K), Rh2, Rh3, and PPD; and 209 mg of inactive excipient rice flour. The comparator was P. ginseng Arkopharma capsules; one capsule contained 382 mg powdered P. ginseng Meyer root corresponding to 9.8 mg of total ginsenosides Rg1, Re, Rf, Rh1, Rg2, Rb1, Rc, Rb2, Rd, Rg6, Rh4, Rg3, PPT, Rk1, C(K), Rh2, Rh3, and PPD; and 3.056 mg of rare ginsenosides Rh1, Rg2, Rg6, Rh4, Rg3, PPT, Rk1, C(K), Rh2, Rh3, and PPD, calculated as ginsenoside Rb1. The placebo capsule contained 418 mg rice flour and brown sugar. Herbal-preparation quality was tested by HPLC (B) in accordance with specifications using appropriate reference standards. All analytical methods were validated for selectivity, accuracy, and precision. Study preparations were packed and labeled by Botalys SA as per national requirements regarding their use for clinical-trial investigations. The label included the drug name, study code, and storage conditions. Reference samples were retained and stored at Botalys SA.The herbal-medicine intervention used in this trial was an HRG80 420 mg capsule containing 210 mg powdered herbal preparation of red ginseng root HRG80 . The powdered herbal preparation was obtained from hydroponically cultivated Korean ginseng (P. ginseng root); or placebo, 400 mg capsules, containing brown sugar and rice flour that had to be taken orally.Participants received a labeled paper box containing either: HRG80, 418 mg capsules (containing 31.7 mg ginsenosides corresponding to 209 mg powdered ginseng roots); PGS Arkopharma, 384 mg capsules . It contained information about the content of each package, namely, how the placebo, HRG80, and PGS Arkopharma containers were encoded. The GraphPad-generated table contained four columns and 51 lines; the left column had the subjects’ numbers from 1 to 50; the other columns showed the assigned treatments  that were taken during Phases 1, 2, and 3. These three columns were filled with randomly distributed unique letters A, B, and C (treatment code). The treatment code showed that HRG80 was assigned as Treatment A, placebo as Treatment B, and the comparator Arkopharma capsules as Treatment C.Study preparations were randomly labeled by a qualified pharmacist  at the manufacturing site in accordance with a random sequence generated using the random-number generator in GraphPad software  until the study was completed. It was provided to the PI before statistical evaluation of the study results, when all patients had completed treatment.At the first visit, all participants received a consecutive number starting from 1 to 50. Participants were sequentially enrolled by the PI. Each participant was assigned a random treatment number and received the treatment in the corresponding package (treatment code No.). Participants’ allocation sequences, the participant list, identifying the subjects and the study-supplement packages (treatment code No.) were generated and maintained by the PI, who assigned each patient to a treatment code No. (from 1 to 50) and filled the patient name in the case report form (CRF) and on the label of the package. The participant list was used for statistical analysis at the end of the study with the random sequence received from the QP. The treatment code providing information about the actual assignments of the placebo, HRG80, and PGS Arkopharma containers was revealed by the QP after statistical analysis of the results of the study was completed, and the obtained data from the treatment groups were compared. Blinding of trial subjects was performed by using labeled packages containing jars with capsules of identical appearance. Study medication was delivered to the study site prelabeled and coded according to the random sequence. The randomization code was kept secret from the investigators, and the code was only revealed after termination of the study. In this way, the investigators were blinded to the study medication and placebo control, thus ensuring a double-blind design. Information concerning the allocation of participants was kept in sequentially numbered and sealed envelopes that were stored by the chief executive officer (CEO) of the contract research organization. Individual treatment codes, indicating treatment randomization for each randomized participant, were available to the investigator and the sponsor in sealed envelopes. However, there were no break cases from the randomization codes.Participants were asked to take a daily dose of two capsules. Participants were questioned about their overall compliance with the study protocol upon their visits, and the remaining capsules were counted by the study personnel. Compliance was monitored by the PI of the study, who checked the participants’ records in a special form that was attached to the case report form (CRF). The study monitor checked overall compliance with the study protocol upon their visits, and the remaining capsules were counted at the end of the study. All unused capsules (two capsules in each package) were retained in the archive storage of the study site in Armenia.The overview of all visits is presented in On Visit 1, the screening visit, participants were informed about the details of the pending study, provided with the study medication, and accordingly recruited. All volunteers were checked for eligibility and signed written informed consent, including obligations that they would not take medicine or dietary supplements that may have potential effects on cognitive functions and would not consume more than one cup of coffee daily (in the morning) during the course of the study (1 week). During the first visit, the participants took all tests for cognitive functions and stress twice: in the morning  and in the evening (16:00–18:00). On Visits 2–5 (no treatment), participants took tests for cognitive functions in the morning  and at the end of the workday .On Visit 6 , participants took all tests for cognitive functions and stress in the morning before starting work . Then, the PI randomly assigned participants to the treatments and gave them the test compound. Participants orally took the Phase I treatment and repeated all tests at 16:00–18:00, at the end of the workday. The treatment lasted 14 consecutive days between Days 8 and 21 of the study. Participants took two capsules per day (two in the morning at 10:00). They also took all tests for cognitive functions and stress on Visit 7 (Day 12) and Visit 8 (Day 21) in the morning (09:00–10:00) and at the end of the workday . After the Phase I treatment, participants had a washout period of 14 days (Days 24–37 of the study).On Visit 9 , participants took all tests for cognitive functions and stress in the morning before starting work (09:00–10:00). Then, participants orally took Phase II treatment and repeated all tests at 16:00–18:00, at the end of the workday. Treatment lasted 14 consecutive days between Days 38 and 49 of the study. Participants took two capsules per day (two in the morning at 10:00). They also took all tests for cognitive functions and stress on Visits 10 (Day 42) and 11 (Day 49) in the morning (09:00–10:00) and at the end of workday . After Phase II treatment, participants had a washout period of 2 weeks (Days 52–65 of the study).On Visit 12 (no treatment), participants took all tests for cognitive functions and stress the morning before starting work (09:00–10:00). Then, they orally took the Phase III treatment and repeated all tests at 16:00–18:00, after the workday. Treatment lasted 14 consecutive days, between Days 66 and 77 of the study. Participants took two capsules per day (two in the morning at 10:00). They also took all tests for cognitive functions and stress on Visits 13 (Day 70) and 14 (Day 77) in the morning (09:00–10:00) and at the end of the workday . Then, the study was completed.The methods of efficacy and safety assessment are described in detail in The primary efficacy outcome measure was the processing accuracy of the d2 attention test (d2 test) for attention, concentration, and visual-scanning speed, which was expressed as an error-rate (ER) score (E%), defined as the ratio of errors made to the total number of correct responses during 4 min and 40 s.change between baseline  and final workload, as presented by the error-rate score, Δ (post–pre) workload;change between baseline and 1, 5, and 12 days of treatment, as presented by Δ error rate score; anddifferences between HRG80, positive control, and placebo at 1, 5, and 12 days of treatment in error-rate score change from baseline, Δ (post–pre) workload.The primary endpoints were:accuracy score obtained by a computerized memory test (MT) for assessment of cognitive functions , which is expressed as the number of correct responses during 2 min expressed in % ; andperceived-stress (PS) score that is the only empirically established index of general stress appraisal.Secondary efficacy outcome measures were:change between baseline  and final workload in PS and MT scores, Δ (post–pre) workload;change between baseline and 1, 5, and 12 days of treatment in Δ PS and MT scores; anddifferences between HRG80, positive control, and placebo at 1, 5, and 12 days of treatment in PS and MT scores changes from baseline.Secondary endpoints were:change between baseline  and final workload in heart rate;change between baseline and 1, 5, and 12 days of treatment in heart rate; anddifferences between HRG80, positive control, and placebo at 1, 5, and 12 days of treatment in heart-rate changes from baseline.Other endpoints were:Safety outcome measures included incidence and severity of adverse events; serious adverse events were assessed by their nature and incidence according to Common Toxicity Criteria, version 4.0.p < 0.05, and the level for tendency was p < 0.10. No corrections were made for mass significance. Assessment of baseline characteristics between two groups was done using the Mann–Whitney nonparametric rank-order test or parametric independent-measures t-test. Change significance from baseline at the same time point was tested using the one-sample t-test for parametric variables or the Wilcoxon signed-rank test for nonparametric variables. Analysis of change within treatment groups during the study course was performed with the Friedman nonparametric rank test for repeated measures (4 repeated conditions) in participants who completed all of the tests. The Kruskal–Wallis nonparametric one-way analysis-of-variance (ANOVA) rank-order test, with post hoc Dunn’s multiple-comparison test, was performed on the ITT population in participants who had received at least one dose of study medication. Assessment of the efficacy of the study medications was achieved by comparing the mean changes from the baseline (differences before and after the treatment of every patient) using the Mann–Whitney nonparametric rank-order test or two-way ANOVA, in which an interaction effect indicated a different response over time between the two groups, and would therefore signal a treatment effect.The clinical data from each visit were recorded using a standardized clinician assessment form. Edited and corrected data were added to an Excel database that was used as input to GraphPad statistical software  and Prism software (version 3.03 for Windows). Statistical analysis involved evaluating a patient’s change in scores from the initial visit (baseline) to the intermediate and final visit, and at each scheduled visit of the study. Analysis was performed using “observed” data. The primary population was the ITT population, which was defined as all randomly assigned participants who received at least one dose of study medication. Statistical analysis was performed on an ITT basis for time-to-event endpoints. The alpha level was We enrolled 50 patients (50 per treatment condition). This was a preliminary study to obtain estimates of parameters that were used to assess and justify the sample-size requirements for a fully powered study. We identified trends in the data that assisted us in refining or modifying the aims of a subsequent proposal. The proposed sample size  had 90% power to detect an effect size of 0.74 and 80% power to detect an effect size of 0.85 using a two-group t-test with a 0.05 two-sided significance level. Effect size was calculated as the absolute difference in means between the two groups being compared, divided by their common standard deviation . We anticipated that we may not have been able to observe a statistically significant difference between treatment conditions in this study, as the observed effect sizes in some recent studies of pharmaceutical agents have been smaller. However, although we anticipated that we could observe an effect size smaller than 0.74 , we expected to observe nonsignificant trends between treatment conditions, allowing the estimated effect sizes from this project to be used to power a large-scale study of ginseng that is planned as a follow-up to this exploratory study.Overall, HRG80 treatment was significantly superior to the positive control and placebo regarding attention, memory, and PS scores after single and repeated administrations at 5 and 12 days. It also had a good tolerability profile.


There is a substantial theoretical knowledge of the biogeochemistry and microbiology of processes in the absence of O2. Noteworthy are processes involved in the sequential degradation of organic matter coupled with the sequential reduction of electron acceptors, and, finally, the formation of CH4. These processes follow basic thermodynamic and kinetic principles, but also require the presence of microorganisms as catalysts. Meanwhile, there is a lot of empirical data that combines the observation of process function with the structure of microbial communities. While most of these observations confirmed existing theoretical knowledge, some resulted in new information. One important example was the observation that methanogens, which have been believed to be strictly anaerobic, can tolerate O2 to quite some extent and thus survive desiccation of flooded soil environments amazingly well. Another example is the strong indication of the importance of redox-active soil organic carbon compounds, which may affect the rates and pathways of CH4 production. It is noteworthy that drainage and aeration turns flooded soils, not generally, into sinks for atmospheric CH4, probably due to the peculiarities of the resident methanotrophic bacteria.Flooding and desiccation of soil environments mainly affect the availability of water and oxygen. While water is necessary for all life, oxygen is required for aerobic microorganisms. In the absence of O The methanogenic pathway is catalyzed by a complex microbial community basically consisting of fermenting bacteria and methanogenic archaea. The entire process is anaerobic, since it only takes place in the absence of O2 and other oxidants (reducible inorganic electron acceptors). Therefore, it is not surprising that most reports of environmental CH4 production refer to anoxic environments, such as animal gut systems, aquatic sediments, flooded soils, peatlands and coastal wetlands ). Therefore, it is plausible that oxidation processes in flooded soils and other wetlands become rapidly limited by O2. Once O2 is depleted, other oxidized inorganic compounds, such as nitrate, ferric iron, or sulfate can serve as oxidants. The propensity for using a particular oxidant depends on the redox potential of the electron-accepting reaction; i.e., degradation processes with the most negative Gibbs free energy will dominate [2, nitrate, ferric iron, and sulfate, which undergo sequential reduction along with the oxidative degradation of organic matter. Once inorganic oxidants are no longer available, however, anaerobic degradation of organic matter can only proceed by disproportionation resulting in the production of CO2 (oxidized compound) and CH4 (reduced compound). According to this theoretical picture, organic matter degradation to CH4 should not start before all the available inorganic electron acceptors have been depleted to such an extent that the ΔG of the oxidation reactions is less negative than the ΔG of the CH4-producing disproportionation reaction. Disproportionation of polymeric organic matter, e.g., cellulose, results in the formation of equal amounts of CO2 and CH4. Stoichiometry of methanogenic degradation of cellulose, or other organic compounds with a carbon oxidation state of zero, also constrains the pathways of CH4 formation resulting in >2/3 of CH4 being produced from acetate and <1/3 being produced from H2/CO2 [Our understanding of environmental methanogenesis in anoxic environments is based on physicochemical and microbiological theories, of which the most relevant are the following. Chemically, complete degradation of organic matter to COdominate ,12. The m H2/CO2 ,14,15.2, CO2 and simple organic compounds, which are subsequently further fermented to acetate, H2 and CO2. These compounds are the substrates for methanogenic archaea, which convert them to CH4 and CO2 [The microbiological theory adds knowledge about the activity of individual microorganisms, which all together make up the environmental microbial community. Of course, the activity of microorganisms cannot overcome the laws of physics or chemistry, but the microbial enzyme machinery provides important catalysts without which most of the chemical processes would proceed very slowly or not at all. Therefore, microorganisms with particular catalytic functions must be present in sufficient numbers to allow a process to proceed. If such microorganisms are absent or inactive, processes may fail to proceed even when thermodynamic conditions are favorable. In soils with the potential for methanogenesis, important microbial functions include hydrolysis of complex organic matter, various fermentation processes, methanogenic processes and processes involved in the sequential reduction of inorganic compounds. Hydrolytic and fermenting bacteria degrade complex organic matter to H and CO2 ,14,16,172 and sometimes even a low (<−330 mV) redox potential [2, and their activity is strongly inhibited [A sufficiently high water potential is a precondition for all microbial activity, which usually strongly decreases below −6 bar, although potential for growth of particular bacteria may be maintained down to −70 bar ,19. The otential . Methano a low <−30 mV redmax, µmax, respectively) and the substrate concentrations  at which the rates are half-maximal. The lower threshold (T) for utilization of the methanogenic substrate is another important parameter [max, KS, T) will win the competition over a limiting substrate and, for example, outgrow a competitor. Please note that the result is comparable  to that caused by chemical competition according to the ΔG values that are also dependent on the concentrations of substrates  according to Nernst law. For example, different hydrogenotrophic methanogenic species have different characteristic kinetic parameters, in particular thresholds for H2 consumption [2 that operate with different modifications of the CO2 reduction pathway [Methanothrix spp. versus Methanosarcina spp.) having different enzyme systems for acetate activation and which consequently dominate at different acetate concentrations in the environment [Another important theoretical microbiological background concerns the concentrations of the growth substrates required for energy generation. Both the catalytic activities and the growth rates of microbial populations depend on substrate concentrations. The relationship is usually a hyperbolic one, described by the Michaelis–Menten and the Monod equations for catalytic activity and for population growth, respectively ,22. Botharameter ,24. As asumption ,26,27,28 pathway . There aironment ,31,32.4 [2 and potential inorganic electron acceptors are all reduced. From a physicochemical point of view, this expectation is straightforward. However, from a microbiological point of view, it cannot be predicted that all the necessary functional types of microorganisms are actually present in all the different soil environments. This is particularly true for methanogenic microbial communities, which are expected to consist of anaerobic microorganisms that are sensitive to O2 and, thus, should not survive desiccation events.Flooding and desiccation are key events for methanogenic processes in wetlands, which include peatlands , coastal4 . On the 4 . Theoret2 sensitivity of microorganisms and the role of soil organic carbon (SOC) compounds. These aspects will be covered in the next three sections  are kept low by the presence of reducible inorganic compounds [4 production [4 production until these compounds are reduced again [4 production, mainly due to creating adverse thermodynamic conditions [2) results in the partial regeneration of ferric iron and sulfate, prolonging suppression of CH4 even when nitrate has been completely reduced [The physicochemical and microbiological theories outlined in n starts ,41. (2) ompounds . (3) Thioduction . (4) Aered again ,45. (5) nditions ,47. (6)  reduced .2 [4 production. For instance, the inhibition of methanogens by bromoethane sulfonate or chloroform, or the specific inhibition of acetotrophic methanogens by methyl fluoride, results in accumulation of the respective precursor metabolites and allows mass balance calculations for fermentation processes or stable isotope fractionation [4 in flooded soils requires the presence of a sufficient number of the microbes involved. Even more importantly, it is necessary that the microbes are not only present but express sufficient activity [4 production are more or less sensitive to O2. This observation, in particular, requires closer inspection.Similarly, many observations supported the microbiological theories, e.g., observations made in flooded rice field soils. (1) The sequential methanogenic degradation of organic matter is paralleled by changes in the composition of the microbial community initiated upon depletion of O2 ,50,51.  were found to be not completely killed by exposure to O2, although CH4 production is inhibited [2, they are able to survive and even partially utilize O2 as an electron acceptor [2. The tolerant ones can be distinguished from the intolerant ones based on their functional gene content, and are hierarchically clustered into two classes, II and I, respectively [2 tolerance has to be modified, i.e., that some taxa of obligately anaerobic methanogens can survive (maybe even exploit to some extent) oxic conditions.The most important microbiology hypothesis probably concerns the relation of microorganisms to Oexposure , albeit exposure ,59. Indempletely . In genedepleted ,62. Thisdepleted ,63. Addinhibited . Later oacceptor ,65. Methacceptor ,67. Howeectively . Hence, 2-sensitive microorganisms, in particular fermenting bacteria and methanogenic archaea. Thus, environments with more frequent drainage should contain more O2-tolerant and/or desiccation-tolerant microorganisms, such as class-II methanogens and endospore-forming Firmicutes. We also hypothesized that these populations and their biochemical functions change upon desiccation and reflooding in different ways according to the category of the soil environment. Thus, we expected that more frequently drained soil environments exhibit smaller population changes than permanently flooded environments upon drainage or permanently dry environments upon flooding. We distinguished four categories: (1) permanently flooded lake sediments [4 production, the abundance of bacterial and archaeal microbiota, and the community composition of methanogenic archaea and (fermenting) bacteria. In the following, the observations will briefly be reviewed to demonstrate to what extent they are consistent with our hypotheses  ediments ,72,73;  until they were depleted, and by growth of anaerobic microorganisms . Indeed, numbers of methanogenic archaea were typically low in dry upland soils or desert soil crusts, where they only increased upon flooding. By contrast, all the other soil environments always contained large populations of methanogens, which just required reducing conditions and sufficient substrate  concentrations to become active  [2 sensitivity. However, O2 sensitivity was apparently not the sole criterion. For example, in permanently flooded lake sediments [Methanomicrobiales belonging to class II decreased upon desiccation, and, in some paddy soils, [Methanobacteriales belonging to class I increased. Methanogens that were actively assimilating carbon in aerated soils belonged to methanogens of both class I and class II [2 sensitivity is apparently not the sole explanation for the occurrence of methanogenic taxa; at least, it does not explain the population dynamics of Methanosaetaceae, Methanomicrobiales and Methanobacteriales, which seem to follow criteria other than O2 sensitivity.Once sufficiently large populations sizes of methanogens were established, drainage of soil did not result in immediate decrease, showing that the methanogens were relatively insensitive to desiccation and Oulations ,76,78. Tclass II . Methanoeriales) ,73. Hencediments , Methanoy soils, ,76 Methaclass II ,67. As aFirmicutes were an important group of fermenting bacteria in virtually all anoxic soil environments  is arguably the rate-limiting step in the production of CH4 [The CHiccation . In somethe same . The rean of CH4 ,81,82.4 production in different soil environments was usually higher than 50% hydrogenotrophic methanogenesis, except in flooded rice fields, where it was close to the expected value of <33% . Desert soil has been found to become a net sink of atmospheric CH4 once water is sufficiently available, apparently because high-affinity methanotrophs are activated [Flooded soil environments usually have a strong potential for CHurce see . Literatt swamps ,100, rivt swamps  and acidt swamps . Howevertrations . Such sotions [4 . Thus, dns [4 [4 ,106,107,otential . Only fltrations . These hctivated ,111.2 and the operation of methanogenic microbial processes. Empirical studies of the structure and function of soil microbial communities confirm the validity of pertinent biogeochemical and microbiological theories, but also demonstrate some unexpected processes. In particular, it has become apparent that some groups of anaerobic microbes  are not thus strictly anaerobic, as formerly believed. Some groups of methanogens were found to tolerate O2 to quite some extent and also to express this characteristic in various soil environments ranging from permanently flooded to dry upland soils. Without such substantial O2 tolerance, many wetlands could probably not act as a source for atmospheric CH4, so that natural and artificial wetlands would not constitute one of the most important sources (accounting for about 250–300 Tg a−1 or 50% in the global CH4 budget [4. The reason for this behavior may be differences in the methanotrophic microbial communities among the various soil environments, which deserves further research.Flooding and drainage of soil environments control the availability of O4 budget . Biogeoc


Recent studies on whether dairy consumption is associated with type 2 diabetes mellitus (T2DM) have yielded inconsistent results, so we explored the relationship between dairy consumption and T2DM through a large-sample, cross-sectional study and a meta-analysis. In the meta-analysis, summary relative risks (RRs) of 23 articles were compiled with a random effects model, and a restricted cubic spline regression model was used to explore whether there is a nonlinear relationship between dairy intake and T2DM risk. This cross-sectional study used baseline data from 38,735 participants of the Henan Rural Cohort study and the association between dairy consumption and T2DM was analyzed by a logistic regression model. The meta-analysis revealed a borderline negative significant association between total dairy intake and risk of T2DM, the RR and 95% confidence interval (CI) was 0.94; , and the risk was lowest at 270 g daily dairy intake. In the cross-sectional study, there were 3654 T2DM patients and 68.3 percent of the respondents had no dairy intake. The average intake of dairy in the total population was 12 g per day. Fully adjusted analyses suggested positive associations, with an odds ratio (OR) comparing the highest with the zero intake of 1.34  for all participants, which was unaffected by sex. Dairy intake in rural areas of Henan province is low, and we found, in the context of overall low dairy intake, that a high intake was positively associated with T2DM, which is inconsistent with the meta-analysis results suggesting that dairy has marginal protective effects against T2DM.  The global prevalence of type 2 diabetes mellitus (T2DM) is growing, and China is seeing a similar increase . AccordiA cohort study from the United States showed that dietary factors, such as dietary patterns, dietary habits, energy intake, carbohydrate, protein, and fat intake, are a daily life behavior factor that can greatly affect the prevalence of T2DM . The 201By the end of 2019, there were around 23 cohort and cross-sectional studies on total dairy intake and T2DM ,35,36,37n = 61); (b) lack of information about blood glucose and T2DM (n = 71); (c) patients with cancer disease or lack of relevant information (n = 392). The final analysis included 38,735 participants.Data used in this cross-sectional study came from the Henan Rural Cohort Study, and the number of participants in the baseline survey was 39,259. The study population was the rural population of Henan province, of which 60.5% were female with ages between 18 and 79. A more detailed introduction to the Henan Rural Cohort Study can be found in a previous publication . The stuThis survey was approved by the Zhengzhou University Life Science Ethics Committee. All participants completed informed consent forms, and the study met the ethical standards set out in the Declaration of Helsinki.Dietary intake in this study was assessed using a food frequency questionnaire (FFQ) consisting of thirteen main foods based on Dietary Guidelines for Chinese Residents and the dietary characteristics of rural residents of Henan province. The reliability and validity of this FFQ have been verified and more details can be found elsewhere . The fooWe collected fasting blood glucose data of participants in laboratory tests, combined with relevant medical records, and asked participants about their diabetes disease and medication status. The diagnostic criteria of T2DM in this study are based on American Diabetes Association (ADA) diagnostic standards , as foll2. Venous blood was collected after at least 8 h of fasting and fasting blood glucose was measured. Biochemical analysis included total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).The data of other covariates in this study were obtained face to face through standardized questionnaires, which included demographic characteristics, lifestyle factors, individual and family disease history, etc. The details are as follows: age, sex, education level, occupation, family income, smoking status, alcohol consumption, physical activity level, whether the individual and his/her parents and siblings suffer from coronary heart disease, hypertension, diabetes, cancer, etc. Trained staff obtained anthropometric measurements of the subjects, including height, body fat, weight, lung capacity, grip strength, waist and hip circumference, blood pressure, etc. Body mass index (BMI) can be derived from height and weight, and the formula is as follows: BMI = weight (kilograms)/height (meters)2, ≥25 kg/m2) and family history of diabetes , and into three levels based on physical activity level .The continuous variables and the categorical variables are represented as mean ± SD and percentages, respectively. Analysis of variance (ANOVA) and Chi-squared tests were used to compare the basic characteristics of each group . Logistic regression analysis was conducted to calculate the odds ratio (OR) for T2DM among dairy consumption groups, using the no intake group as the reference. Models were adjusted for age, gender (model 1), model 1+ smoking, alcohol, economic status, education, physical activity, total energy intake, intake of other food, high fat total, BMI, waist circumference and family history of T2DM (model 2). TC, HDL-C, LDL-C and TG were added into model 2 to detect the mediating effect of lipid metabolism markers (model 3). In accord with socio-demographic characteristics and lifestyle variables, the relationship between dairy intake and T2DM was conducted through stratified analyses. The study population was stratified into two levels based on age , BMI (<25 kg/mp < 0.05 (two-sided).All statistical analyses were performed with SPSS Statistics ver. 22.0 . The test level was set at We conducted a meta-analysis with prospective cohort studies and cross-sectional studies that reported research on dairy intake and T2DM by searching the CNKI, Wanfang, PubMed, Embase and Web of Science electronic databases for the period up to December 2019. The search strategy is shown in Because dairy products included milk, cheese, butter, ice cream and yogurt in the meta-analysis, which were inconsistent with the definition of dairy products in the cross-sectional study, the cross-sectional results were not included in the meta-analysis. Inclusion and exclusion criteria for this meta-analysis were as follows: a cohort study or cross-sectional study; the results included T2D; the study’s results must include OR, relative risks (RR) or hazard ratio (HR); the study must report on dairy intake; all studies had a quality score of at least 6 points as assessed by the Newcastle Ottawa Scale(NOS) . The inf2 statistics, if I2 was greater than 50%, potential heterogeneity was considered; [For studies reporting HRs or ORs for T2DM, we assumed that the HRs and ORs were approximately RRs. A high vs. low meta-analysis (pooled RR for the highest versus the lowest categories of dairy intake), a linear dose–response meta-analysis   and a nosidered;  we assessidered; .p-value was used with a level of 0.05. All data analyses were performed by using Stata 12.1 .A two-sided p < 0.05 for all).p < 0.05 for all). Furthermore, participants with higher dairy consumption generally were not overweight or obese, but they were more likely to have a family history of diabetes .Based on the dairy intake of each group, p for trend > 0.05). After multivariable adjustment (model 3), higher intake of dairy products was associated with higher T2DM prevalence across all participants with an OR and 95% confidence interval (CI) of 1.34 . Fully adjusted models comparing highest intake with no dairy intake groups revealed an OR of 1.44  for men and an increased OR of 1.33  for women compared to the basic model. All results of stratified analysis were consistent with the results above, showing that there is a positive association between total dairy intake and T2DM (In and T2DM . This stand T2DM .p = 0.032) between dairy intake and T2DM risk in cohort studies, and the risk of T2DM was lowest with the daily consumption of 270 g/day (2 = 82.0%); however, a borderline negative association was found in the cohort-study meta-analysis  (2 = 21.8%). Begg–Mazumdar’s test and Egger’s test, as well as the visual funnel plot, all suggested that no significant publication bias was present in our meta-analysis  both showed that dairy intake was marginally significantly associated with a decreased risk for T2DM, as shown in 70 g/day . Evidenc= 49.0%) . In partanalysis .Dairy intake in rural areas of Henan province is low, and we found, in the context of overall low dairy intake, that a high intake was positively associated with T2DM in the rural population of Henan, China, both in men, women and in the entire study population. It is acknowledged that this is the first study to explore the status quo of dairy intake and investigate in depth the association between dairy consumption and T2DM in the rural population in Henan, China. We also conducted a meta-analysis on dairy intake and T2DM risk, which concluded that there was a borderline positive association between dairy consumption and the risk of T2DM; the risk of T2DM was lowest when the daily consumption was 270 g/day, and in Asia and Australia, a significant protective effect of dairy intake on T2DM was found. Our study raises the possibility that differences may exist between dairy intake and T2DM among different countries, dietary patterns and ethnic groups.Dairy products, a major source of daily protein, are rich in beneficial substances required for the physiological activities of human body, especially probiotics, unsaturated fatty acids, trans-palmitoleate, calcium and vitamin D in fermented milk, which may play a significant role in the prevention of diabetes, as indicated by several cohort studies, randomized controlled trials and animal studies ,48,49,50An important point which must be emphasized is the low intake of dairy in this study region. Dairy consumption in China is much lower than that in America due to dietary patterns, living environment and ethnic differences . A revieCompared to the basic model, after further adjusting the other variables in the final model, the positive correlation between dairy intake and T2DM was strengthened in men and total participants, and a trend towards a positive association with T2DM and dairy intake was observed for women. These results are consistent with a 2019 cohort study from the Netherlands , which sThis study not only explored the association between dairy intake and T2DM risk but also conducted an updated meta-analysis. A comprehensive analysis of a total of 23 articles was conducted and found that total dairy intake was marginally significantly associated with a decreased risk for T2DM, a conclusion reached in the results reported in the cohort studies analysis in the stratified analysis. Moreover, previous meta-analyses on the protective effect of dairy intake on T2DM have provided similar evidence ,14,57. IThis study is the first study to explore the status quo of dairy intake and to investigate the association between dairy intake and T2DM risk in rural China. Secondly, this study is based on the Henan Rural Cohort Study, which has a large sample size, rigorous design, good quality control and comprehensive collection of information, so it is representative and reliable. Inevitably, there are still some limitations in this study; the cross-sectional study design prevented us from determining the causal association between dairy intake and T2DM and we did not conduct a dairy subgroup analysis. While we know that dairy intake and T2DM are positively related, we cannot conclude that dairy consumption is a risk factor for T2DM. One possibility is that patients who learned they had diabetes changed their diet and increased their milk intake, so it is necessary to add a time factor and a factor of dairy composition variability to the cohort study analysis to obtain more accurate results that reflect causality. In future studies, we will use follow-up data to examine whether diabetic patients may change their eating habits and increase their dairy intake due to disease. Another point is that the dietary data were obtained by participants recalling their dietary intake over the past year. Therefore, there may be some recall bias, leading to some errors in the results. To test whether retrospective lag between the timing of ingestion and data collection would make the data unreliable, previous study by our team  conducteIn conclusion, the consumption of total dairy products in rural Henan province is far lower than that recommended by Chinese dietary guidelines. The fact that nearly 70 percent of people have not consumed dairy in the past year also reflects the lack of nutrition in rural areas of Henan province. We found that high dairy intake is positively associated with T2DM within the low dairy intake environment of the study population, but this was inconsistent with the results of the meta-analysis, where total dairy intake was borderline significantly associated with a decreased risk of T2DM. These discrepant findings suggest that cohort studies and randomized clinical trials are needed to further investigate the cause and effect of dairy intake on T2DM risk. The results of this cross-sectional study also point out the direction for future studies on the relationship between dairy and T2DM in rural China.


Coronavirus disease 2019 (COVID-19) has induced a prioritization of acute care and telehealth, affecting the quantity of patients seen and the modality of their care.Retrospective review.Single-institution study conducted within the Division of Otolaryngology at the Yale School of Medicine.Data on all outpatient appointments within the Division of Otolaryngology were obtained from administrative records of billing and scheduling from March 16 to April 10, 2020. For comparison, a corresponding period from 2019 was also utilized.P < .001). Older adults (≥65 years) were less likely to have telehealth visits than younger adults .Of 5913 scheduled visits, 3665 (62.0%) were seen between March 18 and April 12, 2019, in comparison with 649 of 5044 (12.9%) during the corresponding COVID-19–affected period. The majority of completed visits performed in weeks 1 and 2 were in person, while the majority in weeks 3 and 4 were via telehealth. Among subspecialties, a larger proportion of completed visits in 2020 were performed by pediatric and head and neck oncology otolaryngologists as compared with general/specialty otolaryngologists (A major decrease in the completion rates of scheduled visits was seen in the COVID-19–affected period, though this was not proportional among subspecialties. An associated increase in telehealth visits was observed. After COVID-19–related hospital policy changes, approximately 2 weeks passed before telehealth visits surpassed in-person visits, though this was not true among older adults. In light of this, there has been a widespread shift among otolaryngologists toward minimizing direct patient interaction in nonacute settings.8 Several otolaryngology divisions and departments have documented their subjective response to this changing landscape, but little objective measurement on COVID-19’s impact has been reported.10As health care systems grapple with increasing numbers of patients, attempts to protect patients and providers, in addition to preserving personal protective equipment, have elicited a necessary triaging of care. This has taken form in rescheduling nonacute appointments and utilizing telehealth programs.Herein, we discuss the affect that COVID-19 has had on our institution. The primary objectives were to examine the quantitative change in patient visits, as well as the modality in which they were completed, over the first month of the virus’s impact within the United States, in comparison with the prior year. Secondarily, we analyzed trends in weekly visitations, differences among otolaryngology subspecialties, and disparities among patients of varying ages.This was a single-institution study conducted within the entirety of the Division of Otolaryngology at the Yale School of Medicine. This is an academic tertiary care center but also includes community clinics. The geographic area of our clinics and patients is throughout southern Connecticut. This study was exempted from review by the Yale Human Investigation Committee due to secondary research on existing data sets.As the focus of study was on COVID-19’s impact on otolaryngology services, we queried the first 4 weeks of the crisis during which departmental functions were affected—from March 16 to April 10, 2020 . For a comparison group, we queried the corresponding period from the previous year—March 18 to April 12, 2019 . Data on all outpatient appointment within the otolaryngology division were obtained from administrative records of billing and scheduling.The data consisted of the following variables: date of scheduled appointment, completion status of that appointment, reason for cancellation (if it was canceled), type of appointment , provider name, and patient age.Dates were grouped into weeks 1 to 4 for each period. Appointment completion status was grouped into completed, cancelled, no-show, or left without being seen. If the appointment was cancelled, cancellation reasons were grouped into COVID-19 and non–COVID-19 administrative-directed cancellations or patient-directed cancellations. To qualify as a COVID-19 administrative-directed cancellation, the appointment must have been in 2020 and must have a cancellation reason of “crisis planning” or “bump.” No instances of the former reason existed in 2019, though 12 of 108 (11.1%) bumps occurred in 2019 (which were categorized as non–COVID-19 administrative-directed cancellations). “Video” or “telephone” visits were determined to be telehealth visits, and all other visit types were grouped as in person.Provider name was utilized to categorize appointments by subspecialty: pediatric otolaryngology, head and neck oncology, general/specialty otolaryngology , speech and language pathology (SLP), audiology, and advanced practice providers (nurse practitioners and physician assistants). Physician categorization was determined a priori and based on hospital service workflow and institutional clinic distribution at our academic center. Patients were grouped into functional age cohorts: ≤2, 3-10, 11-17, 18-44, 45-64, 65-79, and ≥80 years.Descriptive statistics are presented for scheduled appointments within each period, characterizing the number of completed and cancelled visits overall and stratified by week, specialty, and age. We also provide descriptive statistics analyzing the evolution in use of telehealth overall, as stratified by subspecialty and age. Chi-square tests were performed to analyze the differences in appointment completion rates between 2019 in-person and 2020 telehealth appointments, between proportions of completed visits of the 3 groups of otolaryngology–head and neck surgery physicians in 2019 and 2020, and telehealth utilization between younger (18-64) and older (≥65) adults for completed visits in 2020.P < .05.All figures were created in GraphPad Prism 7 (GraphPad Software). Statistical analysis was performed via SPSS 25.0 (IBM Corp), and significance was set at Between March 18 and April 12, 2019, 5913 visits were scheduled within the otolaryngology division at the Yale School of Medicine. This was distributed to 38 providers: 10 general/specialty otolaryngologists, 7 head and neck oncologists, 3 pediatric otolaryngologists, 3 speech and language pathologists, 10 audiologists, and 5 advanced practice providers. Of these, 3665 (62.0%) visits were completed. In the corresponding COVID-19–affected period , 5044 visits were scheduled, of which 649 were completed (12.9%). More than half of the scheduled visits  in the 2020 period were cancelled due to COVID-19 reasons  were completed, of which 224 (61.9%) and 138 (38.1%) were performed via video and telephone, respectively. The overall cancellation and “no-show/left without being seen” rates were roughly equal  and between weeks 2 and 3 (90 vs 179). Week 4 had the most scheduled telehealth visits, at 206. In week 1, 38.7% of scheduled telehealth visits were completed; however, for the majority of scheduled visits, the patient did not virtually attend or left without being seen (54.8%). The rates of telehealth visit completion rate rose each week; by week 4, only 18.0% of visits were cancelled and 4.9% were categorized as patient no-show/left without being seen , and the highest was seen in SLP (69.1%). During the 2020 period, appointment completion rates fell for all specialties  and was highest for head and neck oncology (25.5%). The telehealth utilization rate for completed appointments in 2020 was highest in pediatric otolaryngology . Telehealth utilization rates were 61.8% (159 of 257), 68.8% (97 of 141), and 66.6% (10 of 15) in general/specialty otolaryngology, head and neck oncology, and midlevel providers, respectively. Telehealth utilization was low in audiology  and SLP . During the 2020 period, appointment completion rates significantly decreased across all age groups  and was lowest for the ≥80-year age group, at 8.4%. With the exception of those at the extremes of age (≤2 and ≥65 years), the majority of completed appointments were telehealth visits . The telehealth utilization rate for those ≤2 years was 43.9% (25 of 57); 65 to 79 years, 47.6% (68 of 143); and ≥80 years, 34.6%  to head and neck cancer, a shift in the quantity and modality of clinical visits is expected and encouraged. Many institutions have fashioned and employed guidelines regarding triaging patient care conditioned on the acuity of the otolaryngologic condition.10 Nevertheless, with a lack of complete understanding of COVID-19 and its impact, there is expected variability within these recommendations.Comparable to the drastic adjustment in routine daily living that COVID-19 has necessitated, health care administration has transformed considerably.At the Yale School of Medicine’s Division of Otolaryngology, routine nonurgent care has been cancelled, rescheduled, or transitioned to telehealth. Patients with features and symptoms concerning for more malignant pathologies are seen in person initially or triaged via telehealth preceding an in-person encounter. This has allowed for fewer direct interactions in the setting of a global pandemic while still providing necessary acute care. In assessing this transition, we analyzed administrative records of our otolaryngology division’s outpatient practice patterns during the first 4 weeks following hospital-wide aggressive COVID-19 policy changes—March 16 to April 10, 2020—and compared them with the corresponding period from 1 year prior. We specifically examined all board-certified otolaryngology–head and neck surgeons, speech and language pathologists, audiologists, and otolaryngologic advanced practice providers (including nurse practitioners and physician assistants).20 Consistent with our findings, the COVID-19–affected period saw a significant decline in outpatient visits from baseline. Interestingly, relative to other ambulatory practices, otolaryngology had the second-greatest decline of in-person visitations—approximately 75%—second only to ophthalmology (79%). As mentioned, concern for increased risk of transmission with close examination of the head and neck may contribute to this and would also apply to ophthalmology. In addition, a relatively large volume of elective, semielective, and nonurgent evaluations likely factors in, especially for the surgical subspecialties.Of 5044 scheduled encounters, only 649 (12.9%) were completed in the 2020 period, with the majority of visits cancelled secondary to COVID-19, as compared with 62% of 5913 scheduled visits in the 2019 period. Of the 2020 completed visits, 55.8% were via telehealth. In the corresponding 2019 period, no telehealth visits were completed (P < .001). Patient and institutional comfort and dexterity with a new interactive format likely contributed considerably to this finding . While the precise reasoning for higher pediatric and head and neck oncology telehealth utilization rates is unclear, it should be noted that the Yale School of Medicine oversees outpatient visits for general and specialty otolaryngology, while Yale New Haven Hospital, a separate organization, manages the head and neck oncology and pediatric otolaryngology clinics. Another explanation may again include the acuity of care necessitating increased efforts to coordinate visits. Within pediatrics, preexisting comfort level with technology and telehealth among younger parents and teenagers may be a contributing factor. Not surprising, the total number of SLP and audiology visits dropped precipitously in 2020 as compared with 2019, and the majority of 2020 visits occurred in person. SLP and audiology represent fields in which patients are commonly referred for less acute pathologies and examinations are more difficult to perform remotely.Specifically, in regard to provider type, all subspecialty practices incurred a decrease in appointment completion rates in the 2020 period. However, this drop was lowest among head and neck oncology patients, which may reflect a higher acuity in their pathology. Furthermore, telehealth utilization rates were highest in the pediatric and head and neck oncology subspecialties, though all specialties exhibited a trend of increasing telehealth usage over the course of 1 month (General and specialty otolaryngology visits accounted for 63.3% of overall visits in 2019 but only 52% of visits in 2020. Of all physician visits in 2020, 28.6% and 19.3% were seen by head and neck oncology and pediatric otolaryngology, respectively, a 5%-6% relative increase in each (22 Thus, the slower transition to telehealth for these patients is a cause for concern and further analysis.Appointment completion rates fell across all age groups in 2020 by 10% to 15%, with the lowest completion rates in patients ≥80 years old. There was a subsequent rise in telehealth visits universally. However, while the majority of patients’ care transitioned to telehealth, patients aged ≤2 and ≥80 years received mostly in-person care (43.9% and 34.6% seen via telehealth, respectively; 23One inherent limitation of the current study is its retrospective nature. Additionally, only a 4-week time frame was utilized, limiting the number of scheduled visits and the analysis included. It is likely that these trends continue to evolve. Last, this was a single institution’s experience, which can limit the globalization of its findings. Nonetheless, quantitative data can allow other institutions to glean useful information on possible transitioning methods and expected practice alterations. Continuing to monitor trends within health care systems during the COVID-19 pandemic is crucial. Consistent findings of increased in-person interaction among at-risk populations, for example, may promote innovative and useful action in the application of safe care. Furthermore, with a broader call for health care reform and universal access to affordable care, efficient use of resources, via patient triaging and telehealth, can have a profound impact beyond the COVID-19 pandemic.COVID-19 has had a rapid and global impact on the triaging and administration of health care. The majority of outpatient visits in our otolaryngology division were rescheduled or cancelled in response to this pandemic. We identified a sharp rise in the number of telehealth visits, which became more efficient in their completion rates over time. Importantly, older adults were more likely to be seen in person and less likely to have telehealth visits as compared with younger adults. Further identification of health care trends is vital to promoting safe and efficient care.


Although the clinical efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) in the treatment of chronic tinnitus have been frequently examined, the results remain contradictory. Therefore, we performed a systematic review and meta-analysed clinical trials examining the effects of rTMS to evaluate its clinical efficacy and safety.Studies of rTMS for chronic tinnitus were retrieved from PubMed, Embase, and Cochrane Library through April 2020. Review Manager 5.3 software was employed for data synthesis, and Stata 13.0 software was used for analyses of publication bias and sensitivity.P = 0.925).Twenty-nine randomized studies involving 1228 chronic tinnitus patients were included. Compared with sham-rTMS, rTMS exhibited significant improvements in the tinnitus handicap inventory (THI) scores at 1 week , 1 month , and 6 months  post intervention; there were significant mean changes in THI scores at 1 month  and 6 months  post intervention, and the tinnitus questionnaire (TQ) score at 1 week post intervention . Nonsignificant efficacy of rTMS was found regarding the THI score 2 weeks post intervention ; the mean change in TQ scores 1 month post intervention ; TQ scores 1  and 6 months  post intervention; and adverse events . Egger’s and Begg’s tests indicated no publication bias (This meta-analysis demonstrated that rTMS is effective for chronic tinnitus; however, its safety needs more validation. Restrained by the insufficient number of included studies and the small sample size, more large randomized double-blind multi-centre trials are needed for further verification. Tinnitus is a common auditory symptom that brings severe psychological stress to patients and is associated with co-existing symptoms, such as hearing loss, dizziness, and concentration problems. Studies have estimated that the incidence of tinnitus in adults ranges from 10 to 19% , and it In recent years, there has been a growing annual prevalence of tinnitus, which might be related to the lack of a cure for most patients and a lack of effective standardized treatments. Several studies have ascertained supportive evidence that rTMS is effective in the treatment of chronic tinnitus , 6. rTMSTheoretically, hyperactive auditory neurons in the hearing centre can be adjusted through rTMS, thus reducing the occurrence of tinnitus and showing treatment efficacy. Although the clinical efficacy and safety of rTMS in chronic tinnitus have recently been reported, the results have been divergent and even contradictory. The efficacy of rTMS on chronic tinnitus was first systematically reviewed in 2011; the review included 5 randomized studies and concluded that rTMS was useful for tinnitus . HoweverIn this study, we retrieved the published literature on rTMS as a treatment for chronic tinnitus and extracted highly relevant data to meta-analyse its efficacy and safety. This study provides a reference and encourages more clinical studies for the treatment of chronic tinnitus.This study was executed in line with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  and repoTwo independent investigators (Z-RL and GC) analysed the initially selected articles to verify their relevance to the topic of rTMS as the treatment for chronic tinnitus. Studies were included if they (i) reported the clinical efficacy and safety of rTMS in chronic tinnitus, (ii) were RCTs, and (iii) recruited participants without limitations to regions, ages, or social status. Studies were excluded if they fulfilled the following criteria: non-randomized controlled studies, duplicate trials or overlapping data, animal experiments, conference abstracts, letters, and review articles. In case of any disagreement, the results were discussed and a decision made by the senior authors.Data were extracted from the eligible studies and independently categorized by two authors (Z-RL and GC) using a predefined data extraction form. All disagreements were resolved by discussion. The study design, baseline characteristics of the population , interventions, scores for clinical efficacy, adverse events, and others were stratified into the rTMS and control groups using a standardized evidence table. All data were cross-checked to ensure accuracy. The procedures for study selection are shown in the PRISMA flow diagram.The methodological quality of the included studies was evaluated by two independent reviewers (Z-RL and GC) using Cochrane Handbook Version 5.3 from six dimensions: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data reporting; selective reporting of outcomes; and other sources of bias.I-square (I2) test was performed to assess the influence of heterogeneity on the output of the meta-analysis. I2 statistics of 0, 25, 50, and 75% corresponded to no, low, medium, and high heterogeneity, respectively. According to the Cochrane review guidelines, a random effects model was used when I2 ≥ 50% (high heterogeneity). Otherwise, a fixed effects model was used. A P-value of less than 0.05 was accepted as the threshold for statistical significance. The leave-one-out sensitivity analysis [The meta-analysis and statistical analysis were performed using Cochrane Collaboration Review Manager software . We used the risk ratios (RRs) or odds ratios (ORs) for comparisons of dichotomous variables and the weighted mean difference (WMD) for comparisons of continuous variables. The analysis  was condDuring our database search, 897 studies were initially retrieved, and 524 were selected after eliminating duplicates. Then, 477 studies without high relevance to our topic were discarded after reading titles and abstracts, and 47 studies were further evaluated by reading the full manuscripts. As a result, 18 full-text articles were abandoned for the following reasons: 4 described topics irrelevant to the efficacy and safety of rTMS on chronic tinnitus; 1 was a viewpoint; 2 were protocol designs; 8 were non-randomized controlled studies; and 3 did not provide free online full-text materials. Ultimately, 29 RCTs with 1228 patients were included in this systematic review and meta-analysis. The flow chart depicting the study selection process is shown in Fig. The 29 eligible studies were randomized controlled studies published from 2004 to 2017. Six were conducted in the USA, 4 in Germany, 3 in China (including 1 in Taiwan), Turkey, and South Korea, 2 in the Czech Republic, and 1 in Italy, Egypt, Brazil, Australia, Netherlands, Finland, the UK, and Belgium. These clinical trials exhibited sample sizes that varied between 8 and 146 participants, a mean duration of tinnitus between 6 and 420 months, and a mean treatment course between 5 and 20 days. Of the 29 studies included (34 comparisons), 27 studies (32 comparisons) assessed the auditory cortex, 1 examined the motor cortex, and 1 did not target a specific cerebral area. Among the 32 comparisons in the 27 studies focusing on the auditory cortex, 19 comparison analyses showed the superiority of rTMS over sham-rTMS. Additionally, the 1 study focusing on the motor cortex confirmed the advantage of rTMS compared to sham-rTMS. In terms of the number of rTMS sessions, 11 studies (15 comparisons) reported a treatment time of 10 days, 12 (12 comparisons) of 5 days, 4 (4 comparisons) of 20 days, 1 (1 comparison) of 4 days, and 1 (2 comparisons) did not provide the stimulation duration. Regarding insights into different courses of rTMS treatment, 9 comparison analyses about a 5-day treatment showed that rTMS had better efficacy than sham-rTMS; however, the advantage of rTMS was nonsignificant after 20 days of treatment in all studies. Of the 29 studies (34 comparisons) included, 20 (23 comparisons) explored the left auditory cortex in patients with unilateral or bilateral tinnitus. In all eligible studies, 2 included only patients with bilateral tinnitus, 3 did not describe the tinnitus-affected side, and the remaining 24 included patients with either unilateral or bilateral tinnitus. Fifteen studies (18 comparisons) reported hearing loss in some or all of the included patients. The basic characteristics of the 29 studies are summarized in Table I2 = 0%, P = 0.57) among the studies, a fixed effects model was utilized. The outcome manifested a statistically significant difference between the rTMS and sham-rTMS groups  . The results exhibited no statistically significant differences in the 2-week post-intervention THI scores between the two groups .Three studies , 25, 26 I2 = 0%, P = 0.53), so a fixed effects model was utilized. The results showed a significant difference in 1-month post-intervention THI scores between the two groups  . The results showed a significant difference in 6-month post-intervention THI scores between the two groups  . The results exhibited a statistically significant difference in the mean change in THI scores at 1 month post intervention between the two groups .Three studies , 22, 24 I2 = 0%, P = 0.87). The results showed that there was a significant difference in the mean change in THI scores 6 months post intervention between the two groups .Two studies , 22 evalP = 0.02). Nonsignificant differences in other outcomes were found between the two groups  . The results showed a nonsignificant difference in the incidence of adverse events between the rTMS and sham-rTMS groups  .Visual inspection of funnel plots was adopted in this evaluation Fig. . Egger᾽sIn this study, we reported the results of a systematic review and meta-analysis of 29 selected RCTs showing that rTMS can effectively ameliorate chronic tinnitus. To ensure reliable conclusions, we retrieved, reviewed, and summarized previously published studies on rTMS for the treatment of chronic tinnitus, which had high quality and showed good compliance in patients, to answer various clinical questions about the efficacy and safety of this treatment. Overall, our results suggested that rTMS is effective for the treatment of chronic tinnitus. Subgroup analyses showed that rTMS started to exert its efficacy at 1 week and continued to be effective 6 months after treatment. In addition, rTMS is a safe option, as serious adverse events were evenly distributed between participants randomly assigned to the rTMS and sham rTMS groups. Of all included studies, 93.10% stimulated the auditory cortex as a predominant stimulation site, wherein 77.78% stimulated the left auditory cortex, regardless of which ear was affected. There is strong evidence that the left primary auditory cortex is a potential target for the 1-Hz-rTMS treatment of tinnitus in pilot studies . This exThere is a high level of heterogeneity in tinnitus in the population. Although many clinical studies involving various treatments for tinnitus have been conducted, there is a lack of widespread agreement on its efficacy in reducing tinnitus loudness and the impacts of tinnitus, which might be attributed to the low level of evidence that cannot be used to verify the effects . This poCompared with previous meta-analyses associated with rTMS and tinnitus, our study has the following advantages. First, we performed a series of assessments for the included studies to ensure the high reliability of our conclusions, including publication of the protocol, detailed and predefined sensitivity, comprehensive assessments for risks of systematic and random errors, and assessments for the quality of evidence. Second, most of the studies were single- or double-blind studies with a relatively high level of evidence, which increased the reliability of the results. Third, the rationality and reliability of our meta-analysis have been prudently and significantly improved in that the overall comprehensive estimation has been performed based on a large sample size. Additionally, sufficient sensitivity analyses and the assessment of publication bias were carried out to ensure the stability of this meta-analysis. Fourth, we conducted a quantitative analysis of the safety of rTMS for the treatment of chronic tinnitus.In addition, some limitations of our study must be acknowledged. First, despite the inclusion of recent large randomized trials, the limited number of enrolled subjects in our meta-analysis limits more accurate analyses, and some results were nonsignificant, which might be attributed to the nature of the population receiving rTMS. Second, this study only analysed English-language references, which leads to lost data from those in other languages. Third, although Egger᾽s and Begg᾽s analyses showed no publication bias in our meta-analysis, because of the limited number of studies included in this analysis, the possibility of false negatives cannot be excluded.In summary, our systematic review and meta-analysis confirms the efficacy of rTMS and shows satisfactory safety in patients with chronic tinnitus. However, its safety needs to be verified in large-sample studies. Restrained by the insufficient number of eligible studies and the nature of the target population, more proposals to encourage large-sample, multi-centre, randomized double-blind trials are needed for further verification.