title
stringlengths 1
1.19k
| keywords
stringlengths 0
668
| concept
stringlengths 0
909
| paragraph
stringlengths 0
61.8k
| PMID
stringlengths 10
11
|
|---|---|---|---|---|
16S rRNA gene sequencing processing. | We quality controlled dereplicated 16S sequences without primers and denoised them into amplicon sequence variants (ASVs) using the R package DADA2 (v1.20.0) using the pooled settings for denoising and chimera removal ( | PMC10294643 |
||
Estimation of microbial beta diversity. | We calculated weighted UniFrac distances to obtain the pairwise beta diversity, which we further evaluated by the adonis2 function using the R package vegan to test the significance with 999 permutations ( | PMC10294643 |
||
Estimation of microbial alpha diversity. | REGRESSION | We used the R package DivNet to estimate Shannon diversity using ecological network regression models. We employed the function “betta” ( | PMC10294643 |
|
Source tracking of microbiota. | To estimate the sources of the infant microbiota at different body sites, we performed bacterial source tracking using FEAST ( | PMC10294643 |
||
Differential abundance analysis. | We used ANCOM to search for differentiated bacterial taxa by randomization group ( | PMC10294643 |
||
Data availability. | Sequencing reads were deposited in the Sequence Read Archive (SRA) under Inclusion and exclusion criteria for the clinical trial. Download | PMC10294643 |
||
ACKNOWLEDGMENTS | INFECTIOUS DISEASES, LUNG, ALLERGY, BLOOD, HEART | We acknowledge Quest Diagnostics for their support of this study (maternal screening labs). Study data were collected and managed using REDCap electronic data capture tools hosted at the Inova Health System.Funding was provided by National Institute of Allergy and Infectious Diseases of the National Institutes of Health under the Intramural Research Program (S.K.H.); National Heart, Lung, and Blood Institute of the National Institutes of Health, K01HL141589 (N.T.M.); Inova Health System Seed Grant (S.K.H.); Canadian Institute for Advanced Research (CIFAR; M.G.D.B.); EMCH Fund, Rutgers University (M.G.D.B.); and C&D Fund, Rutgers University (M.G.D.B.).We thank Kristy and Roger Crombie for their generous philanthropic donation toward this project in loving memory of their daughter Anna Charlotte.We thank the Inova Foundation and its donors, including Steve Smith and Christine Luckscheiter, for support of this project.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Conceptualization, N.T.M., M.G.D.B., and S.K.H.; Methodology, N.T.M., S.L., L.J.A., M.G.D.B., and S.K.H.; Investigation, N.T.M., M.K.D., H.S., J.W., S.L., V.D., L.J.A., M.J.B., T.K., A.A.S., M.G.D.B., and S.K.H.; Data Curation, S.L., V.D., A.A.S., and S.K.H.; Visualization, H.S., J.W., and M.K.D.; Funding acquisition, N.T.M., M.G.D.B., and S.K.H.; Project administration, S.L. and S.K.H.; Supervision, N.T.M., M.G.D.B., and S.K.H.; Writing – original draft, N.T.M., M.G.D.B., and S.K.H.; Writing – review & editing, N.T.M., M.K.D., H.S., J.W., S.L., V.D., L.J.A., M.J.B., T.K., A.A.S., M.G.D.B., and S.K.H.M.G.D.B. has intellectual property on NYU patent U.S. Patent 10357521. N.T.M. is on the scientific advisory board of Tiny Health Inc. No other authors have competing interests to declare.This article is a direct contribution from Maria Gloria Dominguez Bello, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Seth Bordenstein, Pennsylvania State University, and Omry Koren, Bar-Ilan University. | PMC10294643 |
|
REFERENCES | PMC10294643 |
|||
Background | INFLUENZA | The morbidity of influenza in children increased rapidly in decade. Reduning injection (RDN), a small but fine Chinese herbal formula, has antipyretic, antiviral, anti-inflammatory effects. We intend to evaluate the efficacy and safety of RDN for the influenza in children versus Oseltamivir, explore the possible antiviral mechanism of RDN and provide evidence-based medical evidence for rational clinical drug usage. | PMC10357598 |
|
Method | fever | DISEASE, SECONDARY, INFLUENZA | We design a randomized, double-blind, double-dummy, parallel control of positive drug, multi-centre clinical study. According to the formula of mean superiority test, a total of 240 patients with influenza in children will be randomized 1:1 into the experimental group and control group. The experimental group will take RDN and Oseltamivir phosphate granule simulants and the control group will take Oseltamivir phosphate granule and RDN simulants. Each group will be treated for 5 days. The primary outcome measure is temperature recovery time, and the secondary outcome measures include time when the fever begins to subside, time and degree of disease to alleviate, disappearance rate of individual symptoms and so on. We will measure before enrollment and each 24 h after treatment for comparison. | PMC10357598 |
Discussion | INFLUENZA | The study is launched to evaluate the efficacy and safety of RDN for the treatment of influenza in children and to provide an alternative option for influenza in children. | PMC10357598 |
|
Trial registration | This study is registered in ClinicalTrials.gov as NCT04183725, registered on 3 December, 2019. | PMC10357598 |
||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12906-023-04037-1. | PMC10357598 |
||
Keywords | PMC10357598 |
|||
Introduction | fever, Fever | INFLUENZA A, VIRUS, INFLUENZA, INFLUENZA | Influenza, a negative-strand RNA virus of the Orthomyxoviridae family, is classified into influenza A, B and C viruses (IAV, IBV and ICV). Specially, with its “reassortment” of segmented genomes [Fever, occurring in 95% of influenza children, is the most salient sign, 59% of children 3 years has fever 39.0℃ [Reduning (RDN), consisting of Qing Hao ( | PMC10357598 |
Method | PMC10357598 |
|||
Study design | INFLUENZA | This is a randomized, double-blinded, double-dummy, parallel control of positive drug, multi-centre clinical study. The trial will be conducted in ten centers at China and collaborate with hospitals including Children’s Hospital Of Soochow University, Anhui Provincial Children’s Hospital, Qilu Children’s Hospital of Shandong University, Tianjin 4th Centre Hospital, Renmin Hospital of Wuhan University, Hebei Maternity&Child Healthcare Hospital, the Second Affiliated Hospital of Jiaxing University, the First Hospital of Hunan University of Chinese Medicine, Affiliated Hospital of Shanxi University of Traditional Chinese Medicine and one undetermined. The trial obtained ethical approval from Ethics Committee of The First Affiliated Hospital of Henan University of Chinese medicine (approval number: 2019HL-137-01), and will be conducted according to Participants with influenza in Children will undergo a standardized baseline evaluation before treatment. All included participants are randomly divided into two groups: experimental group and control group.The experimental group receives RDN + Oseltamivir phosphate granule simulants and the control group receives Oseltamivir phosphate granules + RDN simulants. After five days of treatment with evaluation every 24 h, the efficacy and safety of two groups will be evaluated. The study design is shown in Fig.
Flow diagram | PMC10357598 |
|
Sample size estimation and randomization | INFLUENZA | Taking time of temperature recovery as clinical main efficacy indicator, we calculate two groups’ sample size using mean superiority test formula. According to data of efficacy evaluation about adult influenza treating with RDN and Oseltamivir in the early stage, the per protocol set (PPS) of time of temperature recovery comes: Oseltamivir is 46.50 ± 1.74(h) and RDN is 30.47 ± 1.69(h); so that δ for 15.35 h, 100 participants will be required for each group, and 200 is the total. If the 20% dropout rate is considered, 240 cases were planned to be observed. We adopt the method of center stratified block randomization in trial: there is 10 centers, 4 segments, each center has 24 cases and each group has 12 cases.Randomization will be used for patient allocation [ | PMC10357598 |
|
Blinding | taste, smell and packaging of the simulant, CRF | ADVERSE EVENTS, CRF, EMERGENCY, BLIND | This is a double-blind (patients and clinicians are blinded) and double-dummy study. A two-stage blind design is adopted. The first stage was the group corresponding to number of each case (such as group A, group B) and the second stage was the intervention corresponding to each group (experimental group or control group).Treatment assignments will not be revealed until the whole process is completed. Emergency letter will be opened by researchers when emergency (such as severe adverse events) or patient needs rescue and must know the treatment had received. Once the blind is broken, the patient with this number will be withdrawn from the trial handling as a dropout case and the researchers should record the reasons in the case report form (CRF). All emergency letters will be returned together with the CRF after the trial for blind review. When the blind codes are leaked or the opening rate of emergency letter exceeds 20%, the double-blind test will declare failure.To achieve blinding, the outer packaging of experimental and control drugs should be identical. Size, color, shape, taste, smell and packaging of the simulant are identical to that of the corresponding medicine by adding artificial pigment [ | PMC10357598 |
Eligibility criteria | The diagnostic criteria will be formulated from epidemiological history, clinical manifestations and laboratory diagnosis according to | PMC10357598 |
||
Inclusion criteria | ;Patients | VIRUS, INFLUENZA |
Patients get influenza within 48 h with positive results of rapid defection for virus antigen.Apart from general influenza symptoms, patients’ temperature before study is over 38℃;Patients’ age is between 2 and 14 years and informed consents (from guardian or patient themselves) is got. | PMC10357598 |
Exclusion criteria | allergic, infections, immunodeficiency, virus infection | INFLUENZA, VIRUS INFECTION, MYCOPLASMA INFECTION, INFECTIONS, IMMUNODEFICIENCY, SEVERE MALNUTRITION |
Patients is not common influenza (severe or critical) or concomitant other respiratory or pulmonary infections;Patients is not virus infection (mycoplasma infection or bacterial infection);Patients’ laboratory examination results such as serum creatinine (SCR), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are exceeded the normal range;Patients has severe malnutrition, immunodeficiency (or taking glucocorticoid) or severe vital organ diseases;Patients with severe infections must be treated with other antiviral drugs;Patients are allergic to the RDN or Oseltamivir phosphate granules;Patients has taken Oseltamivir or other heat-clearing & detoxicating traditional Chinese medicine before study;Patients may cause loss of follow-up such as unstable living environment.Patients with any of the above should be excluded. | PMC10357598 |
Exit criteria | CRF | ADVERSE REACTIONS, CRF, BLIND, COMPLICATIONS | Patients will leave the trial when one of the following criteria is met:
The symptoms of patients get worse after 3 days of medication;Some comorbidities, complications or special physiological changes occur during the test;Patients with poor compliance don’t reach 80% of the prescribed amount should be used in the trial;Cases breaking the blind or opening the blind urgently in the trial;Drugs out of prescribed protocol are used in the trial;Patients who want to quit the trial or refuse to accept prescription and examination have the right to withdraw from the trial according to the provisions of the informed consent. And the reason should be understood and documented possibly.Notice: Whatever reason the cases are dropped out of the trial, the CRF should be kept and transformed into final result using the last result examined, and the efficacy and adverse reactions (ADRs) should be carried out using its full data set. | PMC10357598 |
Suspension criteria | mistakes |
Serious problems about safety occur in the trial;The curative efficacy of drugs is too poor or even ineffective and has no clinical value in the trial;Severe mistakes of clinical trial protocol are founded that is difficult to evaluate the efficacy of the drug; or obvious deviation occur in the progress of implementation and it is difficult to evaluate efficacy of the drug if it continues;The sponsor requests the suspension (such as financial reasons, management reasons, etc.);The administrative department cancels the test. | PMC10357598 |
|
Elimination criteria |
Patients do not meet the inclusion criteria are founded after enrollment;Drugs out of prescribed plan are used in the trial;Cases no medication after enrollment;Cases no evaluation or record about medication. | PMC10357598 |
||
Informed consent | The participants are between 2 ~ 14 years old. After a full explanation by the clinicians, written informed consent from participants (or their parent or legal guardian in the case of children under 16) will be obtained before intervention [ | PMC10357598 |
||
Interventions | All researchers are clinical doctors and they will receive standardized training before starting trial. The experimental drug is RDN and the control drug is Oseltamivir. RDN simulant and Oseltamivir simulant have no active ingredients, the former is intravenous drip with normal saline (NS) or grape sugar (GS) avoiding light and the latter is identical with Oseltamivir’s color, flavor and appearance. The detailed method of administration of two groups is shown in Table
The detailed method of administration of two groups0.5ml/kg/day, maximum is no more than 10ml/day5%GS/0.9%NS diluted 50 ~ 100ml iv drip 30 ~ 40gtt/min q.d.*510ml/day5%GS/0.9%NS diluted 100 ~ 200ml,iv drip, 30 ~ 60gtt/min q.d.*515ml/day5%GS/0.9%NS diluted 200 ~ 250ml,iv drip, 30 ~ 60gtt/min q.d.*520ml/day5%GS/0.9%NS diluted 250ml,iv drip, 30 ~ 60gtt/min q.d.*5
| PMC10357598 |
||
Discontinuation | RECURRENCE | Clinical symptoms and signs have no improvement or aggravation compared with those before enrollment after taking the medicine for 3 days or more. That needs to switch to another treatment and stop the medication. After completing the post-treatment evaluation and related laboratory tests, this case is declared over and this patient is recorded in PPS as invalid and qualified case statistics. When the body temperature of patient returns to normal and the symptoms and signs disappear within 5 days, the drug can be stopped. Follow-up visit is conducted after 24 h. If there is no recurrence, it will be counted as a recovered case. | PMC10357598 |
|
Concomitant | CRF | ADVERSE EVENTS, SECONDARY, CRF | Drugs out of curative plan such as heat-clearing and detoxicating traditional Chinese medicine and oral or intravenous hormone that maybe affect the effect of Oseltamivir shall not be used. When taking antipyretic and analgesic drugs necessarily, the usage and dosage of antipyretic and analgesic drugs are recorded as one of the secondary efficacy evaluation indicators. Concomitant medication is required due to adverse events during the trial, which should be recorded in the CRF in detail. | PMC10357598 |
Follow-up | All included patients will be re-evaluated after five days of treatment to assess the efficacy and safety. Patients whose symptoms worsened will receive a supply of relevant medicine and a written withdrawal schedule. | PMC10357598 |
||
Outcomes | By searching for relevant literature [ | PMC10357598 |
||
Primary outcome measure | Time of temperature recovery.
Definition: time when axillary temperature drops below 37.3℃ without repetition after the first use of the drug.Regulation of axillary temperature recording (Mercury thermometer and body temperature measuring instrument): after the first usage in 24 h, the temperature will be measured in the first 2 h, 4 h, 6 and 8 h; and after 24 h, the temperature will be measured at least 2 times a day. When axillary temperature drops below 37.3℃ without repetition in 24 h, it is the treatment end point. | PMC10357598 |
||
Secondary Outcome measure | fever | DISEASE, INFLUENZA, REMISSION, COMPLICATIONS, INFLUENZA |
In clinical manifestation, we will record such as time point of fever subside, time point of disease alleviate, degree of disease remission and disappearance rate of individual symptoms;In laboratory examination, we will record the rate of negative conversion of Influenza viral;In treatment, we will record the usage and frequency of antipyretic and analgesic drugs;In outcome, we will record the incidence of complications of influenza. | PMC10357598 |
Criteria of comprehensive efficacy | VIRUS, INFLUENZA | Criteria of cure: the curative effect of clinical symptoms reaches the level of cure after finishing medication and the rapid detection for virus antigen of influenza turns negative. All two criteria must be met.Criteria of invalid treatment: the curative effect of clinical symptoms is invalid, aggravated or complicated after the end of the medication and the rapid detection for virus antigen of influenza is still positive. Only one of the above is satisfied, it is considered invalid. | PMC10357598 |
|
Safety assessments | anaphylaxis | ANAPHYLAXIS | All participants will undergo the following laboratory examination. Safety assessments include vital signs, blood routine, urine routine, liver function, kidney function and twelve-lead electrocardiogram (ECG). We will judge anaphylaxis according to Assessment of study endpoints is shown in Table
Measurement items and assessment of study endpointsDrug recycle/medication compliance | PMC10357598 |
Data management | CRF | CRF | CRF will be written by researcher and that will be delivered to the specific data administrators to establish a database after passing the examination of the clinical supervisor. The data on CRF is inputted into the database by two independent data administrator respectively which is reviewed manually, checked by computer, examined blindly, and then is locked for the statistical analysis. | PMC10357598 |
Data statistic and analysis | PMC10357598 |
|||
Data selection | DISEASE | Four datasets will be conducted intention to treat (ITT), full analysis sets (FAS), per protocol set (PPS), and safety analysis set (SS). ITT is conducted for efficacy and AEs. FAS refers to the ideal set of participants who are as close as possible to the principle of intention to treat and is obtained after removing the participants from all the randomization with the least and reasonable method. PPS, a subset of FAS, is a data set generated from disease case set fully compliant with the trial protocol. SS refers to the randomized cases that have taken a tested drug at least once with safety evaluation data after treatment. | PMC10357598 |
|
Statistical method | Data analysis will be performed by professional statisticians using SAS 9.1.3. For measurement data, Group t test or Wilcoxon rank sum test will be used for comparison between groups; for counting data, χ | PMC10357598 |
||
Analysis contents |
List the frequency of cases enrolled, violated and dropped out;List the details of cases of violation, dropout, low compliance, time-window violation, out of protocol drug usage.List the datasets for analysis.Comparability analysis: compare demographic data and other baseline indicators to measure the balance of each group.Effectiveness analysis: FAS and PPS analysis. The study is a multi-center clinical trial, the influence of central effect on efficacy indicators should be considered in the analysis. Measurement data uses covariance analysis which considering the central factor, and count data uses CMH test corrected by the central stratification.Safety analysis: compare the incidence of AE in each group and describe the AE in the trial. Compare the changes of normal/abnormal laboratory indicators before and after the test, and list the details of cases with abnormal/abnormal aggravation before and after the test.Concomitant medication analysis: compare the details of each group and list them down. | PMC10357598 |
||
Quality control | PMC10357598 |
|||
Measures of quality control | Sponsor and researchers will adopt standard operating procedures (SOP) to ensure implementation of quality control and quality assurance systems for clinical trials. We will verify all observations and findings to make sure each conclusion in clinical trial deriving from original data. Meanwhile we will conduct quality control in every stage to acquire reliable and correct data. | PMC10357598 |
||
Training of investigators | Supervisor with each sub-center will conduct clinical trial training for researchers before starting trials. They will know experimental drug’s nature, function, efficacy and safety (including related information before marketing), and any new information about the drug that finding during the trial. | PMC10357598 |
||
Enhancement of compliance of patients | CRF | CRF |
Researchers will conduct informed consent carefully to ensure subjects understand experimental requirements fully and comply to trial. They should know that the sponsor will provide free trial medication, laboratory examination fees and so on.Using dose counting method monitors subjects compliance. Compliance = actual dosage/prescribed dosage × 100%. Good drug compliance: 80 − 120%; poor drug compliance: less than 80% or more than 120%.Researcher should require subjects to bring all drugs when follow-up and record on CRF. Patients with poor efficacy and compliance will strengthen follow-up. | PMC10357598 |
Monitoring of clinical trials | CRF | CRF | The sponsor appoints supervisor. Supervisor will visit trial hospitals on-site regularly to guarantee clinical protocol’s implementation strictly, and check original data to ensure it is identical with CRF. | PMC10357598 |
Audit of clinical trials | CRF | CRF | The drug supervision and administration department and sponsor will entrust inspectors to conduct inspection systematically to ensure the execution of the trial consistent with protocol, and the data reported by the sub-center is identical with CRF or other original records. The audit will be carried out by personnel who is not directly involved in the clinical trial. | PMC10357598 |
Discussion | INFLUENZA | Influenza is getting more and more serious these years and early antiviral treatment can maximize clinical benefits [There are two limitations in the study. One is that children cannot express their discomfort symptoms well; another is the results of clinical symptom record table might have subjective factors. | PMC10357598 |
|
Acknowledgements | The assistance and efforts of every researchers in this trial deserve gratitude. | PMC10357598 |
||
Authors’ contributions | WL | WL and XY conceived the project. WL contributed knowledge of core outcome set development and wrote the protocol. XY provided supervision for all aspects of the project. YS wrote the manuscript. WL and XY reviewed the manuscript. All authors have read and approved the final manuscript. | PMC10357598 |
|
Funding | Z0687 | This trial is supported financially by National Natural Science Foundation of General Program (81973982), National Key R&D Program of China (2018YFC1707400) and Fundamental Research Funds for the Central public welfare research institutes (Z0687). | PMC10357598 |
|
Data Availability | The data will be available when collected. | PMC10357598 |
||
Declarations | PMC10357598 |
|||
Competing interests | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10357598 |
||
Ethics approval and consent to participate | The trial obtained ethical clearance from Ethics Committee of The First Affiliated Hospital of Henan University of Chinese medicine. The participants are between 2 ~ 14 years old, we will comply to the | PMC10357598 |
||
Consent for publication | Not applicable. | PMC10357598 |
||
Trial status | The study is currently at the systematic literature review stage. | PMC10357598 |
||
Abbreviations | Reduning injectionInfluenza-like illnessadverse reactionadverse eventnormal salinegrape sugarelectrocardiogramthe Medical Dictionary for Regulatory Activitiesblood pressureheart ratepulsecase report formper protocol setintention to treatfull analysis setssafety analysis setCochran Mantel Haenszelstandard operating procedure | PMC10357598 |
||
References | PMC10357598 |
|||
Results | PMC10014105 |
|||
Apremilast reduces binge-like drinking behavior and the motivation for ethanol in a genetic risk model of drinking to intoxication. | AUDs | To test whether PDE4 inhibition reduces binge-like alcohol drinking, we administered apremilast to selectively bred “High Drinking in the Dark” (replicate HDID-1 and HDID-2) mice of both sexes prior to measuring limited access drinking using the widely adopted “Drinking in the Dark” (DID) assay (Next, we found that 2 clinically relevant doses of apremilast, 20 and 40 mg/kg (i.p.) reduced binge drinking and BALs (below 80 mg% — the level of intoxication), in female and male HDID-1 mice (AUDs are characterized by a chronic history of harmful drinking. To determine the efficacy of apremilast in reducing chronic alcohol intake, we tested whether 40 mg/kg (i.p.) of apremilast would reduce binge drinking in HDID-1 mice (of both sexes) over a 4-week period, as compared to baseline drinking levels. Here we saw that 40 mg/kg of apremilast reduced chronic binge-like ethanol intake of female and male HDID-1 mice (To determine whether PDE4 inhibition reduces the motivation for alcohol drinking, we next tested the effects of apremilast in inbred HDID-1 (iHDID-1) mice of both sexes during 2 operant ethanol self-administration tasks: (a) operant responding under a progressive ratio (PR) schedule of reinforcement and (b) quinine-adulterated alcohol responding (To ascertain whether apremilast would reduce compulsive-like responding to alcohol (another facet of human alcohol motivation), mice were tested for quinine-adulterated alcohol responding (see timeline in | PMC10014105 |
|
The NAc is a critical site of action for reduction of drinking by apremilast. | Recent evidence suggests that increased expression of PDE4 subtypes, namely PDE4b, is linked to human AUD (Next, we sought to determine how acute treatment with apremilast altered functional activity in NAc D1 MSNs and D2 MSNs, which together comprise greater than 90% of the neurons in the NAc and are the 2 major output pathways of this region. We performed ex vivo whole-cell patch clamp electrophysiology in brain slices from male and female hemizygous Dopaminergic neurotransmission in NAc MSNs is largely mediated through PKA signaling, of which PDE4 is a critical regulator. Nishi et al. demonstrated that the PDE4 inhibitor rolipram increased neuronal excitability in isolated MSNs ( | PMC10014105 |
||
Apremilast reduces dependence-induced escalations in alcohol intake in C57BL/6J mice. | alcohol dependence | To test whether apremilast reduces harmful drinking associated with alcohol dependence, 2 models of dependence-induced escalations in ethanol drinking were used in C57BL/6J mice, an established high-drinking strain from which both methods were developed (Because dependence in individuals with AUD is characterized by chronic harmful drinking, we next sought to test the effects of apremilast in a chronic model of dependence-induced escalations in alcohol drinking ( | PMC10014105 |
|
Individuals with AUD consume fewer drinks per day when treated with apremilast. | nausea and vomiting, DSM-5 | DISORDERS | A phase IIa double-blind, placebo-controlled POC study was conducted with the aim of clinically validating the effect of apremilast on decreasing alcohol intake in preclinical models of AUD. It was hypothesized that individuals with AUD who were treated with apremilast would consume significantly fewer standard drinks (~14 grams of alcohol per drink) per day over an 11-day period of ad libitum drinking than those treated with placebo. To further clarify whether any such effect was a result of reduction in heavy drinking specifically, numbers of heavy drinking days (4+ drinks/day for women, 5+ drinks/day for men) were similarly examined over this same period. Earlier PDE4 inhibitors like rolipram and ibudilast are associated with side effects, particularly nausea and vomiting, that may significantly reduce treatment retention (Study admission criteria specified non–treatment-seeking male and female paid volunteers 18 to 65 years of age with AUD of moderately severe or greater, as defined by the Diagnostic and Statistical Manual for Mental Disorders – Fifth Edition (DSM-5) criteria (The rate of study completion (84%) was equivalent across groups and is detailed in All participants completing the protocol ( | PMC10014105 |
Discussion | ADVERSE EFFECTS | We leveraged gene expression profiles of drinking to intoxication to identify compounds that might be repurposed to reduce excessive alcohol drinking characteristic of AUD. The FDA-approved PDE4 inhibitor apremilast was identified as the most promising target for repurposing, given a lower likelihood of severe PDE4 adverse effects associated with treatment discontinuation than earlier PDE4 inhibitors. We propose it is imperative to test potential therapeutics across multiple drinking paradigms, species, and strains to reduce the number of clinical study failures. The present work determined whether apremilast would reduce harmful alcohol drinking in male and female mice from 4 different strains with high risk for excessive drinking (i.e., selectively bred HDID-1 and 2, inbred HDID-1 mice, and C57BL/6J mice). Strikingly, we found that apremilast reduced excessive drinking across a spectrum of clinically relevant drinking models for binge-like, motivational, compulsive-like, and stress- and non–stress-induced facilitation of dependence-like drinking. Although follow-up testing suggests that apremilast acts through central means (i.e., the NAc), it is possible that either or both central and peripheral actions of apremilast are necessary for reducing harmful drinking. Therefore, future work should address the importance of such central and peripheral mechanisms. In a human POC study, we employed a double-blind, placebo-controlled study in non–treatment-seeking individuals with AUD and found that oral apremilast was robustly effective at reducing the number of daily drinks consumed. PDE4b, a target of apremilast, has been associated with both alcohol and nicotine dependence. We show that a gene identified from a genome-wide association study (Because apremilast works across a spectrum of models, in both sexes of 4 strains of mice (at multiple labs and universities) and importantly, in humans, we sought to determine the neural mechanisms by which PDE4 inhibition reduces harmful drinking. The NAc is a critical brain region for many behaviors and is well studied for its role in alcohol drinking. Structural and molecular changes in the NAc following both acute and chronic ethanol drinking are thought to play a role in further aberrant drinking patterns (The extent to which PDE4 inhibition, and in particular apremilast, alters input to, and output of, subpopulations of MSNs in the NAc helps to identify potential critical neurobiological mechanisms and may in part explain the observed reduction in harmful alcohol drinking across drinking models. Decreased alcohol drinking seen with chemogenetic manipulation of the NAc likely engages different signaling pathways that may be dependent on drinking paradigm, sex, and/or distinct cell types (The above double-blind, placebo-controlled POC study found a large effect of apremilast (90 mg/d) on decreasing drinking relative to placebo in 51 non–treatment-seeking men and women with severe AUD. The observed effect size for apremilast was more than double that reported in a comprehensive meta-analysis of randomized controlled trials of the FDA-approved treatments for AUD, acamprosate and naltrexone (This collaborative set of studies from 6 independent laboratories and universities highlights apremilast as a powerful AUD treatment option and further identifies mechanisms by which apremilast may reduce harmful alcohol drinking. | PMC10014105 |
|
Methods | Further information can be found in | PMC10014105 |
||
Data availability. | The drinking, behavioral, gene expression, and electrophysiological data supporting the findings of this study have been deposited and are available in the Figshare digital repository (10.6084/m9.figshare.14687358). | PMC10014105 |
||
Statistics. | Significance was set at an | PMC10014105 |
||
Study approvals. | For animal studies, all procedures were approved by the local Institutional Animal Care and Use Committee and were conducted in accordance with the NIH | PMC10014105 |
||
Author contributions | RA | Preclinical: ARO, KBG, RA Mangieri, RA Morrisett, AJR, and MFL conceived and performed the preclinical experiments, performed analyses, and wrote the manuscript. EJF, AT, KGT, and HCA performed the preclinical experiments. PM analyzed preclinical data. JCC, MR, and HCB conceived the preclinical experiments and edited the manuscript. Clinical: BJM conceived and conducted the clinical study, interpreted results, and wrote the manuscript. JML analyzed the clinical data, interpreted results, and wrote the manuscript. AB, JB, JM, SQ, FS, and MS conducted the clinical study. TKE and JJM analyzed the physiological data and interpreted results. | PMC10014105 |
|
Supplementary Material | PMC10014105 |
|||
01/19/2023 | In-Press Preview | PMC10014105 |
||
03/15/2023 | Electronic publication | PMC10014105 |
||
Apremilast reduces binge-like drinking behavior and ethanol motivation in mice selectively bred for drinking to intoxication. | ( | PMC10014105 |
||
Apremilast reduces binge-like drinking behavior through increasing excitability of D1, but not D2, MSNs. | ( | PMC10014105 |
||
Apremilast reduces dependence-induced escalations in ethanol drinking in C57BL/6J mice. | ( | PMC10014105 |
||
Apremilast reduces alcohol intake in non–treatment-seeking individuals with an AUD. | ( | PMC10014105 |
||
1. Introduction | obesity, Obesity, hypertension | OBESITY, OBESITY, OBESE, HYPERTENSION, DISEASES | (1) Background: The ‘Living Better’ web-based programme has shown short- and long-term benefits for body composition and psychological variables in obese patients with hypertension by promoting a healthier lifestyle. To further explore the potential of this programme, in this work we aimed to explore the possible effect of the patient’s ‘own doctor’ appearing in the video content of the Living Better intervention. (2) Methods: A total of 132 patients were randomly assigned either to the experimental (EG, The prevalence of obesity has increased nearly threefold over the past few decades, creating a significant burden not only on individuals’ health but also on society as a whole. Obesity has become a global pandemic [The international guidelines specialising in obesity [Several systematic reviews and meta-analyses have examined the use of technology and the internet in treating obesity and hypertension and have found that online interventions promoting healthy lifestyles can effectively improve body weight and/or blood pressure levels [To take this research further, in this current study we aimed to explore the possible effect of the patients’ ‘own doctor’ appearing in all the videos of the Living Better programme. Using video modelling, which involves the demonstration of desired behaviours, outcomes, and attitudes through active visual representations by an actor, is considered an effective way to educate and guide patients through behavioural interventions, even among people with low levels of literacy [Therefore, although to date we are not aware of previous studies that have analysed the possible effect of the audiovisual presence of a therapist (psychologist, doctor, nurse, physiotherapist, or nutritionist, etc.) in online interventions designed to prevent or treat diseases, it is plausible that their presence may improve patients’ motivation to change their eating habits and attitudes towards PA. This change would also bring about a change in lifestyle itself (eating habits and PA levels) and by extension, body composition. Considering all the above, the aim of this present research was to analyse the influence exerted by the identity of the main doctor appearing in the audiovisual content of the Living Better web-based intervention on patients with the obesity–hypertension phenotype in terms of the following variables: body mass index (BMI), PA levels, adherence to the Mediterranean diet, motivation towards PA, motivation to change eating habits, and eating style. We hypothesised that patients who saw their own doctor giving them the indications would attain greater benefits in the different variables analysed than those in the ‘unknown doctor’ control group. | PMC10097159 |
2. Materials and Methods | PMC10097159 |
|||
2.1. Study Design | The present study was a prospective, single-centre, randomised clinical trial that followed the ethical guidelines established in the Declaration of Helsinki and was approved by the Hospital of Sagunto Human Ethics Committee. The trial was registered at ClinicalTrials.gov (NCT04739033) and conducted according to the details outlined in the CONSORT statement [ | PMC10097159 |
||
Eligibility Criteria | hypertension, overweight | HYPERTENSION | Eligible participants were all adults/older adults aged between 18 and 75 years with hypertension and who were overweight (BMI > 24.9 kg/m | PMC10097159 |
2.2. Procedure | obesity, Hypertension | OBESITY, HYPERTENSION, HYPERTENSION | This work took place at the Hospital Universitario de Sagunto (Valencia, Spain) between February and June 2021. All participants from the hospital’s Hypertension and Vascular Risk Unit with the obesity–hypertension phenotype who had not previously participated in the Living Better studies [ | PMC10097159 |
2.3. Intervention | obesity | OBESITY, HYPERTENSION | Living Better is a computerised intervention that is self-administered through the internet. The treatment protocol consists of 9 modules and incorporates psychological strategies that encourage a healthy lifestyle by progressively establishing healthy eating habits and increasing the level of PA, as recommended by international guidelines. A period of 12 weeks was allowed for the completion of the entire programme, during which time the modules were activated weekly or fortnightly. Some of the techniques used were self-monitoring, self-instruction, behavioural recording, stimulus control, self-reinforcement, problem-solving techniques, and homework. In addition, the accompanying web page (designed and hosted by a web-based platform called Wix) offered useful tools such as the ability to download documents online and view multiple videos and had a responsive design that adjusted the site for viewing with mobile devices. More details about the intervention can be found in Baños et al. [The programme content followed by both groups was identical, with the exception that the physician who appeared in the audiovisual material differed between them; the CG patients saw a doctor that they did not know while those assigned to the EG saw their own obesity–hypertension phenotype specialist. Specifically, Living Better contains 32 videos (reaching a total of 52 min) of the presenting doctors’ audiovisual presence. Both the doctors involved in delivering the audiovisual content in this study were specialists in the obesity–hypertension phenotype and vascular risk, regularly engaged in PA, and had a healthy appearance. | PMC10097159 |
2.4. Outcome Measures | The patient’s age, sex, and the number of visits to the specialist were all registered before the randomisation process was implemented. Furthermore, the variables listed below were recorded via the same platform as the intervention programme. | PMC10097159 |
||
2.5. Primary Outcome | Because of the indications of the health authorities and hospital regulations related to the COVID-19 pandemic, the participants were instructed to register their BMI in a pharmacy near their homes. They were also instructed to go to the pharmacy while fasting to avoid the possibility that any food or drink ingested could have influenced their data. Thus, the same person (pharmacist or pharmacy assistant) used an approved device to assess their weight and height; BMI was calculated by dividing patient weight by their height squared (kg/m | PMC10097159 |
||
2.6. Secondary Outcomes | Physical activity levels were evaluated using the abbreviated version of the International Physical Activity Questionnaire (IPAQ short form), which has been validated for use in the Spanish population [Motivation towards physical activity (PA) was evaluated using the validated Spanish version of the Behavioural Regulation in Exercise Questionnaire-2 (BREQ-2; [Eating behaviour was assessed using the Dutch Eating Behaviours Questionnaire (DEBQ; [Finally, at the end of the intervention, the online platform automatically collected the degree of programme completion by each patient (number of modules they had reviewed out of a total of 9). | PMC10097159 |
||
2.7. Statistical Analysis | A sample size of 50 patients per group was required to achieve a statistically significant 0.85-point BMI reduction between the estimated mean and the sampling mean, in line with previous study data [ | PMC10097159 |
||
3. Results | We screened 557 participants in this randomised controlled trial. A total of 425 individuals were not allocated for randomisation because they did not respond to the invitation by postal mail (The results of the two-way ANOVA analyses showed significant time-by-group interaction effects for the intrinsic motivation to change eating habits and amotivation, with large effect sizes (ηp2 ≥ 0.032; After adjusting the ANOVA results for baseline data, the post hoc tests showed higher intrinsic motivation to change eating habits (mean difference of 0.9, 95% CI [0.1, 1.6]; | PMC10097159 |
||
4. Discussion | obesity | OBESITY, HYPERTENSION | This study analysed the influence of the audiovisual presence of patients’ own specialist doctor in an online intervention programme designed to promote a healthy lifestyle, adherence to the Mediterranean diet, motivation to change eating habits, eating behaviour, and motivation towards PA in patients with an obesity–hypertension phenotype. Our results confirmed the positive effects of the Living Better intervention on BMI [Despite the above, it is worth noting that, regardless of which doctor appeared in the audio-visual material, Living Better still achieved Mediterranean dietary eating habits close to the upper limit of the average adherence range (above 8 points), even though the interventions took place during the COVID-19 confinement period. This is especially interesting given that some studies have demonstrated the negative effects the COVID-19 pandemic had on eating habits in general [Regarding PA, as in previous studies [In this current study, the number of losses in the post-intervention assessments was manifestly higher compared to those from the previous studies [The present study had some limitations worth mentioning. Firstly, participants who enrolled in the study had already demonstrated an initial level of motivation towards engaging in an e-health programme, which may have introduced selection bias. Therefore, our findings may only be applicable to individuals with internet access who are similarly interested in e-health interventions [ | PMC10097159 |
5. Conclusions | Our findings suggest that the presence of patients’ own doctor in the audiovisual content of an online intervention programme aimed at promoting a healthy lifestyle did not show significant additional benefits in terms of BMI, levels of physical activity, adherence to the Mediterranean diet, eating behaviour, or motivation towards physical activity among patients with an obesity-hypertension phenotype. However, their presence did improve intrinsic motivation and amotivation related to eating habits. Future studies with multiple doctors per arm and with a larger and more representative sample size should be performed to investigate the short- and long-term impact of the presence of patients’ own doctor in such audiovisual web-based interventions for adults with this phenotype. | PMC10097159 |
||
Author Contributions | M.R.-C., R.M.B., E.R. and J.F.L. conceived this research methodology and wrote/prepared the original draft. P.M.-B. and R.H. were responsible for the methodology. M.R.-C. and J.F.L. conducted a formal analysis. R.M.B., E.R. and J.F.L. managed the investigation. P.M.-B., M.R.-C. and R.H. reviewed and edited the manuscript. R.C., M.D.V. and T.E.-M. were responsible for visualization. All authors have read and agreed to the published version of the manuscript. | PMC10097159 |
||
Institutional Review Board Statement | This study, where human participants were involved, was approved by the Human Research Ethics Committee at the Hospital Universitario de Sagunto and followed the ethical guidelines established in the Declaration of Helsinki. It was also reviewed and approved on 6 June 2019 by the University CEU-Cardenal Herrera Ethics Committee (CEI19/085). The patients/participants provided their written informed consent to participate in this study. | PMC10097159 |
||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10097159 |
||
Data Availability Statement | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10097159 |
||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10097159 |
||
References | PROGRESSION | Progression of the participants through the trial.Pre- and post-differences between the experimental and the control groups in terms of intrinsic motivation (Baseline characteristics of the study participants.Data presented as mean (SD).Results of the 2 × 2 ANOVA tests.Data presented as mean (SD). | PMC10097159 |
|
Objective | This study compared in vitro the anastomosis cleaning efficacy of different irrigant activation techniques at different levels; control group non-activation (NA), passive ultrasonic irrigation (PUI) using Irrisafe, and EDDY sonic activation. | PMC10007824 |
||
Methods | Sixty anastomosis-containing mesial roots of mandibular molars were mounted in resin, sectioned at 2, 4, and 6 mm from the apex. Then reassembled and instrumented in a copper cube. For the irrigation technique roots were randomly divided into 3 groups ( | PMC10007824 |
||
Results | All three irrigation techniques significantly improved anastomosis cleanliness ( | PMC10007824 |
||
Conclusions | Irrigant activation improves anastomosis cleanliness. EDDY was the most efficient in cleaning anastomoses located in the critical apical part of the root canal. | PMC10007824 |
||
Clinical relevance | APICAL PERIODONTITIS | Cleaning and disinfection of the root canal system followed by apical and coronal sealing is the key for healing or prevention of apical periodontitis. Remnants of debris and microorganisms retained within the anastomoses (isthmuses), or other root canal irregularities may lead to persistent apical periodontitis. Proper irrigation and activation are essential for cleaning root canal anastomoses. | PMC10007824 |
Subsets and Splits