This systematic review aims to evaluate the effectiveness of electroacupuncture in treatment of lumbar disc herniation (LDH).Electronic databases of all electroacupuncture for LDH will be searched at PubMed, Cochrane Library, Springer, EMBASE, China National Knowledge Infrastructure (CNKI), Wan-Fang, and Chinese Biological Medical disc, (CBM) from inception to February 29, 2020, with language restricted in Chinese and English. The primary outcome is Japanese Orthopedic Association Scores, a quantification scale for a comprehensive assessment according to patients’ subjects feeling and objective function. Secondary outcomes included visual analogue scale (VAS), Oswestry dysfunction index (ODI), Pittsburgh sleep quality index (PSQI), Self-rating anxiety scale (SAS), self-depression rating scale (SDS), follow-up relapse rate. The systematic review and searches for randomized controlled trials of this therapy for LDH. The Cochrane RevMan V5.3 bias assessment tool is implemented to assess bias risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). Mean difference (MD), standard mean deviation (SMD) and binary data will be used to represent continuous results.This study will provide a comprehensive review and evaluation of the available evidence for the treatment of LDH with this therapy.This study will provide new evidence to evaluate the effectiveness and side effects of electroacupuncture for LDH. Due to the data is not personalized, no formal ethical approval is required. Ever since it occurred, degeneration disc makes LDH easy to be recurrent. LDH has bad influence on people's daily life, work and lifestyle, even leads to long term depression, chronic neurofunction deficit and disability. In recent years, the incidence of LDH has been rising and the onset age has inclined to be younger. The recurrence and complication place a heavy enough burden on both individual and the society. It occurs among those working adults whose age are most under 50 years old and has become a matter of concern about worrying occupational health issue because of the affection of continuation and resumption of employment.Lumbar disc herniation (LDH) refers to a pathological condition as ruptured anulus fibrous or nucleus pulposus beyond the intervertebral disc space due to degeneration disc and exterior pressure.–9 Etiology factors have been investigated in an attempt to understand how LDH produces the symptoms. The prim contributor is degenerative changes of intervertebral disc which is found to increase the press of disc and compresses the nerve root. Inflammation also plays a significant role on the etiology factors which is known to lead to pain. Nucleus pulposus is variety of sequestered antigen, as the herniation occurs, it will be exposed to immune system and leads to immune respond and results in inflammatory pain.–11 Concentration of varieties of chemical, immune and neurogenic inflammatory factors including prostaglandin E2, NO, matrix metalloproteinases, calcitonin generelated peptide, are shown to be higher in the patients with LDH than those of non-herniation controls.–14 Apoptosis mechanism is another contributor according to previous research. Surveys show there are a large number of apoptotic chondrocytes in degenerative lumbar disc tissue, which leads to metabolic disturbance of disc matrix, and makes further promotion of disc degeneration in turn.–17The common signs and symptoms of LDH are low back pain, radicular leg pain, abnormal sensation, degenerated strength of low limber, cauda equina syndrome, and intermittent claudication. Patients reported the primary signs and symptoms are low back pain and radicular leg pain which are also the most suffering throughout the whole process of LDH. Mccracken has found potential and persistent pain stimulates specific tissues and organs, such as the reaction of muscles and nerves, influencing the thinking ability and judgment which makes patients more anxious about pain and trapped in vicious circle. Another research shows that the degree and duration of pain determines anxiety level. Patients are more likely to be sensitive to social stress under both anxiety and pain. The pain-related anxiety has a serious impact on daily life and harms more than the effect the pain itself brings up. It is recognized conclusion that depression is the common psychological symptom of LDH due to the long-term pain. A survey has revealed the incidence of depression in patients with chronic pain ranges from 17.8% to 92.4%. According to the theory of “chronic pain-psychological disorder-chronic pain exacerbation- psychological disorder exacerbation”, patients may have fear of the chronic pain and trapped in the vicious circle. These impacts may cause the patients lose faith of life or even eschew medical treatment. Pain is the leading cause of the psychological changes in patients with LDH and it has mutual influence with anxiety, depression, and fear. Chronic pain leads to negative emotions relieving pain is very important in the treatment of LDH.LDH has forged close ties with anxiety and depression. Pain-related anxiety has a high rate among patients with LDH, it is reported the incidence ranges from 10.6 to 57.4%. There is no consensus to give a recommendation for non-operative or surgical interventions, apart from some cases, symptomatic patients are advised to take consider of surgical treatment if they are not resistant to the severe sciatica or local lumbago. To relieve the pain, surgical treatments performed faster than non-operative ones. However, surgery results in no benefit over a mid-term or long-term follow-ups.–26 Due to the degeneration of lumbar intervertebral disc, recurrent herniation occurs and many patients seek for reoperation following primary surgery.–28 In consideration of the high recurrent rate, most clinic doctors advise patients to accept non-operative treatments if they do not need to take an immediate surgery. Non-operative treatments are, therefore, widely used for LDH. There are numerous non-operative treatments but also a lack of satisfactory for both doctor and patients. Each therapy has advantages and disadvantages. Currently, in addition to those non-operative treatments referred above, some complementary and alternative therapies drew more and more attention to treat LDH.Interventions for LDH are aimed at relieving pain and improving mobility, function and life qualify. The first-line choices for LDH are non-operative treatments which may be consisted of anti-inflammatory medications, physical therapy, education and epidural steroid injection, and others.As one of the complementary and alternative therapies, Traditional Chinese medicine (TCM) therapies play a vital role in preventing and treating many varieties of diseases including LDH. As one of TCM therapies, acupuncture has aroused lots of attraction from all over the world due to its efficiency in the clinical treatment.1.2Qi flowing a circulation through the channels and meridians in the body. Acupuncture corrects the imbalance of the flowing of Qi via a needle inserted into special acupoints along the meridians. Acupuncture has been proved to be efficient in China for more than 2000 years and it had been widely used in treatment of varieties of diseases. Due to the efficiency of pain relief, it has increasingly drawn widespread attention and it was recommended by the World Health Organization since 1980 as an alternative therapy for 43 different disorders. An American survey found that 8 million Americans have been accepted acupuncture therapy in their lifetime and the most common used is for low back pain.–32 According to recent studies, acupuncture can relieve not only pain but also the other symptoms including improving the functional recovery of the whole body. Electroacupuncture is based on acupuncture where a kind of chosen small current passed between pairs of acupuncture needles. The same acupoints are inserted with needles and several pairs of needles can be simultaneously stimulated during the treatment. With the standard operation, electroacupuncture is safe to keep current under control and not beyond the endurance of patients.Acupuncture is one of the key components of TCM therapies in which thin needles are inserted into the body. It is developed and practiced in ancient China dating from Shang Dynasty (1600–1100 BC). Acupuncture is based on TCM theory in which health is deemed as keeping balance of energy that is called 1.3Qi stagnation and blood stasis, external trauma or deficiency of Qi and blood, which all result in obstruction of Qi and blood flowing in the meridians. The principle of TCM treatment is to promote the circulation of Qi and blood of which relieving pain, activating the Qi stagnation and removing blood stasis, improving function. Electroacupuncture corrects the imbalance of the meridians through regulating Qi and blood prolonged stimulation on the acupoints from special devices. Some modern medicine surveys found that LDH is treated by electroacupuncture may be through improving local microcirculation, adjusting the abnormal ultra-structure of nerve cell, regulating the immune system, decreasing the level of inflammatory cytokines, influencing the speed of nerve conduction velocity.–37 Even there are many studies about how electroacupuncture works on LDH and some researchers came up with a variety of hypothesis but no consensus has been reached, leaving the main mechanism still remaining unclear.According to TCM theory, LDH is caused by 1.4To develop treatment recommendations, we systematically evaluated the efficacy and safety of electroacupuncture for LDH.22.1 The review will be conducted in accordance with the PRISMA guidelines and follows the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.–40 If we refine the procedures described in this protocol, we will update the record in the PROSPERO and disclose them in future publications related to this study.PROSPERO registration number is CRD42020151213. This protocol report was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines.2.22.2.1In order to evaluate the efficacy of electroacupuncture in the treatment of LDH, this paper only reviewed the randomized controlled trial (RCT) between electroacupuncture and the control group, including drug therapy, no treatment, placebo, diet and physical therapy, etc. In addition, both Chinese and English publications are restricted languages to this review. All RCT that are not subject to publication state constraints will be included. If the experiment shows that the phrase is random and the blind method is not restricted, it will be regarded as a random study. Animal mechanism studies, case reports, self-controlled, non-randomized controlled trials, random crossover studies, and quasi-randomized trials will be excluded.2.2.2–43Regardless of gender, age, ethnicity, education and economic status, patients with LDH who meet the diagnostic criteria.2.2.3The experimental group should be treated with electroacupuncture and acupoints used according to TCM nomenclature. The types of seed used and the duration of treatment will be unlimited. Electroacupuncture combined with other conventional therapy should be excluded.The following treatment comparisons will be investigated:1.Electroacupuncture compared with no treatment;2.Electroacupuncture compared with placebo or sham treatment;3.Electroacupuncture compared with other active therapies;4.Electroacupuncture in addition to active therapy compared with the same active therapy.We will assess and compare the electroacupuncture according to how the acupuncturists have been trained and educated, on their clinical experience, on total numbers of electroacupuncture sessions, and on the treatment duration and frequency, etc.2.2.4–46 The system review will be performed independently.The primary outcome of this review was body function which is preferentially extracted from Japanese Orthopedic Association Scores. Secondary outcomes include visual analogue scale (VAS), Oswestry disability index (ODI), self-rating anxiety scale (SAS), self-rating depression scale (SDS), Pittsburgh sleep quality index (PSQI), recurrence rate during the follow-up period, and adverse events.2.3Our systematic review will search all RCTs of electroacupuncture for LDH electronically, regardless of publication status and language, by February 29, 2020. Databases include: PubMed, EMBASE, Springer, Web of Science, Cochrane Library, WHO International Clinical Trials Registry Platform (ICTRP), Traditional Chinese Medicine databases (TCMD), China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP) and Wan-Fang database. Other sources, including reference lists of identified publications and meeting minutes, will also be searched.2.4The search strategy will be followed the PRISMA guidelines. The key search terms are (“chronic low back pain” OR “back pain” OR “lumbar pain” OR “lumbago” OR “leg pain” OR “sciatica” OR “low limb pain”) AND  AND (“randomized”). The search strategy will be adapted to different databases demands. Search strategy in PubMed is shown in Table 2.52.5.1Prior to literature retrieval, all reviewers are trained to ensure a basic understanding of the background and purpose of the review. In the literature screening process, we will use EndNote software (V.X8) document management software. The 2 comment author (GLZ and LG) will be in strict accordance with the inclusion criteria, independent screen all retrieval research, read the title, abstract and key words in the literature, and determine which meet the inclusion criteria. We will obtain the full text of all relevant studies for further evaluation. Excluded studies will be documented and explained. If there is a disagreement in the selection process, it will be discussed by the 2 authors (GLZ and LG) and the third author (LXZ) and arbitrated if necessary. If necessary, we will contact the trial author for clarification. The primary selection process is shown in a PRISMA flow chart Fig. .2.5.2The authors will extract data independently from the selected report or study and fill out the data extraction form. We will obtain data on general information, participants, methods, interventions, outcomes, results, adverse events, conflicts of interest, ethical recognition, and other information. For publications with insufficient or ambiguous data, we will attempt to obtain information from the corresponding authors by e-mail or telephone. Any differences will be resolved through discussions between the 2 authors, and further differences will be arbitrated by the third author (LXZ).2.5.3The authors (QZ and YY) will use the Cochrane Collaboration's bias risk assessment tool to assess the risk of bias in all included studies. We will assess the risk of bias in the following areas: sequence generation, assignment sequence hiding, the blindness of participants and staff, and result evaluators, incomplete outcome data, selective outcome reporting, and other sources of bias. This review uses L, U, and H as the key to these assessments, where L (low) indicates a lower risk of bias, U (unclear) indicates that the risk of bias is uncertain, and H (high) indicates a higher risk of bias. If inconsistent results appear, the final decisions will be made by the third author (LXZ). Information on the risk of biased assessments included in the study is summarized in tabular form and the results and impacts are critically discussed. If the information is ambiguous, we will try to contact the author. For repeated publications, we only select the original text.2.5.4Data analysis and quantitative data synthesis will be performed using RevMan V.5.3. For continuous data, if there is no heterogeneity, we will use mean difference (MD) or standard MD (SMD) to measure the therapeutic effect of 95% confidence interval (CI). If significant heterogeneity is found, a random effects model will be used. For dichotomous data, we will use the 95% CI risk ratio (RR) for analysis.2.5.5We will include data from parallel group design studies for meta-analysis. Only the first phase of the data will be included in the random crossover trial. In these trials, participants were randomly divided into 2 intervention groups and individual measurements for each outcome of each participant were collected and analyzed.2.5.6If the primary result has missing or incomplete data, we will contact the author of the communication to obtain the missing data. If it is never available, exclude the experiment from the analysis.2.5.7We will use the Review Manager to assess efficacy and publication bias . The forest map is used to illustrate the relative strength of the effect. The funnel plot is used to illustrate the bias because the number of trials exceeds 10. If a significant difference is detected, a random effects model will be used.2.5.8We will use a funnel plot to detect report bias. If more than 10 trials are included, the funnel plot will be used to assess the reported bias. If the funnel plot is found to be asymmetrical, analyze the cause using Egger method. We will include all eligible trials regardless of the quality of the method.2.5.9We will use RevMan for all statistical analysis. If considerable heterogeneity is observed, a 95% CI random effects model will be used to analyze the combined effect estimates. Subgroup analysis will be performed with careful consideration of each subgroup if necessary.2.5.10There is no presubgroup plan. Subgroup analysis was performed based on control interventions and different outcomes.2.5.11Based on sample size, heterogeneity quality, and statistical models (random or fixed-effect models), we will perform sensitivity analysis.2.5.12The quality of evidence for all outcomes will be judged by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group approach. Bias risk, consistency, directness, precision, publication bias, are aspects of our assessment. High, medium, low or very low represents the 4 levels of evaluation.3–50 therefore it has been prevalent over the last few decades to reduce the need for surgery.LDH is a common spinal disorder for physician visits in the United States. It is the main contributor to low back pain and sciatica due to the displacement of disc, which affects a large population suffering all around the world. Different forms of non-operative treatments should be taken in consideration as priority unless it is in acute stages such as neurological deficit or unendurable pain. As numerous of studies have proved that electroacupuncture is effective, safe, operable, low-cost and promising for LDH,The evaluation of this systematic review will be divided into 4 parts: identification, the inclusion of literature, data extraction, and comprehensive analysis of data. According to the Cochrane method, this study is based on the analysis of clinical RCT evidence at home and abroad, searching and screening the main electronic literature database with evidence-based medical evidence, providing clinicians with more convincing evidence in decision-making, to better guide clinical treatment.Conceptualization: Yuquan Shen.Methodology: Xinling Wang, Zhengsong Zhang, Jianjia Liu, Di ZhangSoftware: Leixiao Zhang, Qun Zhou, Shumi Liang, Yu YangSupervision: Guilong Zhang,Validation: Yu Yang,Writing–original draft: G. Zhang, Leixiao Zhang, Liang Gao, Yuquan Shen, Yu YangGuilong Zhang orcid: 0000-0001-7812-8096.


Whether pre-diabetes in the absence of hypertension (HTN) or dyslipidemia (DLP) is a risk factor for occurrence of major adverse cardiovascular events (MACE) is not fully established. We investigated the effect of impaired fasting glucose (IFG) alone and in combination with HTN, DLP or both on subsequent occurrence of MACE as well as individual MACE components.This longitudinal population-based study included 11,374 inhabitants of Northeastern Iran. The participants were free of any cardiovascular disease at baseline and were followed yearly from 2010 to 2017. Cox proportional hazard models were fitted to measure the hazard of IFG alone or in combination with HTN and DLP on occurrence of MACE as the primary endpoint.Four hundred thirty-seven MACE were recorded during 6.2 ± 0.1 years follow up. IFG alone compared to normal fasting glucose (NFG) was not associated with an increase in occurrence of MACE . However, combination of IFG and HTN  or HTN + DLP  significantly increased the risk for MACE. Moreover, IFG + DM with or without HTN, DLP, or both was also associated with an increase in the incidence of MACE.IFG, per se, does not appear to increase hazard of MACE. However, IFG with HTN or HTN + DLP conferred a significant hazard for MACE in an incremental manner. Moreover, IFG without HTN, adjusted for DLP, can be associated with an increase in the risk for CVD- death. Pre-diabetes (pre-DM) is often taken as a warning sign. Individuals with pre-DM have a glycemic state that is higher than normal but not high enough to be classified as type 2 diabetes (T2DM). The pre-diabetes state is characterized by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or HbA1c of 39 mmol/mol 5.7%) to 46 mmol/mol (6.4%) . Con. Con8]. Therefore, we conducted a study using data from Golestan Cohort Study (GCS) to investigate whether pre-diabetes in the absence of HTN or DLP is a risk factor for occurrence of major adverse cardiovascular events (MACE) as well as its individual components. We also examined the risk for MACE conferred by diabetes in the presence or absence of HTN or DLP. We further did the analysis in which patients with IFG and DM are considered together in comparison with patients with NFG.We extracted data from GCS a community-based prospective cohort study that was launched in Northeastern Iran . The priBaseline data were collected during an interview by a trained general physician, either in the local language (Turkmen) or in the national formal language (Persian), depending on the participant’s preference. Questions were asked about the age, residence area , smoking status, alcohol consumption, history of any heart disease, or any kind of cancer. Height, weight, waist and hip circumference were measured using standard methods, and body mass index (BMI) was calculated. BP was measured twice, with a 10-min interval, from both arms in the sitting position using Richter auscultator sphygmomanometers. A trained technician collected Blood samples (10 ml). In the urban area, the samples were immediately processed in the central laboratory at the Golestan Cohort Study Center. In the rural areas, blood samples were kept in refrigerators (+4C), until they were transferred in cooling boxes to the central laboratory; the maximum duration between blood collection and final processing was 8 h. FBS, triglyceride (TG), cholesterol, and high density lipoprotein (HDL) were measured enzymatically in all individuals .Participants were followed up by annual phone calls from their date of recruitment until the first occurrence of any CVD event, death from any cause, or end of the study (March 2017). Each cohort member was also instructed at the time of enrollment to contact the team in case of certain conditions such as hospitalization or development of a new major disease. These contacts were registered and subsequently followed by a staff member. In case a death, cancer or any CVD event was reported, the GCS team visited the participant’s home and the medical centers in which any major diagnostic or therapeutic procedures were done. The team collected all clinical reports, pathology reports and hospital records. Follow-up assessed at the end of the Golestan study was successful for over 99% of the study participants. If a death was identified, a general practitioner visited the home of the deceased. Causes of death were ascertained through verbal interview and investigation of medical documents . Using tIFG was diagnosed when a participant did not have DM, but had an FBS of 5.6 to < 7.0 mmol/L, according to the American Diabetes Association criteria (ADA) . DM was The primary outcome in the current analysis was the first occurrence of any component of the 3-point MACE defined as non-fatal myocardial infarction (MI), non-fatal stroke, and CVD death. CVD death composed of death due to coronary heart disease, stroke, or heart failure.p < 0.05 was considered statistically significant.Data are presented as means (SE) and numbers (percentage). In all cases, final analysis was based on presence or absence of a risk factor (or factors) in the DM, IFG, and NGT groups using fully adjusted models. Student t-test and Pearson χ2 (or Fisher Exact) tests were used to compare continuous and categorical variables, respectively. Risk analysis was conducted in patients with IFG, and Poisson regression model was used to identify predictors of MACE . Regarding the time to event for MACE and its components, Kaplan-Meyer method was used to estimate the survival probabilities, and Cox proportional hazard models were fitted to measure the hazard ratios. Statistical analyses were performed with Stata software for Windows version 13.0. Values of In this study, we included 11,374 participants from the Northern provinces of Iran who were free of any CVD events at the time of recruitment. Among the cohort 1543 (13.6%) individuals had DM, 2410 (21.2%) had IFG, and 7421 (65.3%) had normal fasting glucose (NFG).p < 007, all). Moreover, the comparison between NFG and IFG showed a significantly higher prevalence of HTN  and DLP  in IFG group. Moreover, compared to NFG group, the IFG group were older and had a significantly higher level of BMI, WC, SBP, DBP, TG, cholesterol, and LDL . Participants with IFG were more likely to use a statin medication than did the NFG group .Baseline characteristics of the study population are demonstrated in Table Over a mean follow up of 6.2 (± 0.1) years, 437 MACE  were reported. CVD death comprised of 155 fatal MI, 101 fatal strokes, and 27 deaths due to heart failure.Table p > 0.05 for all comparisons). Moreover, DM even in the absence of HTN and DLP significantly decreased the MACE free survival   Fig. .Fig. 1TWe next examined the effect of IFG with HTN, DLP, or both HTN + DLP on the occurrence of individual components of MACE in detail. Table The results indicated that IFG in the presence or absence of HTN did not increase the risk for non-fatal MI compared to NFG in the absence of HTN  and , respectively. However, IFG in the presence of HTN significantly increased the risk for non-fatal stroke  and CVD-death . Moreover, IFG in the absence of HTN, adjusted for DLP, did significantly increase the risk for CVD-death . Furthermore, DM in the absence or presence of HTN significantly increased the risk for non-fatal stroke  and , respectively. IFG + DM in the presence of HTN was also associated with an increase in the risk for non-fatal stroke . In addition, DM in the absence or presence of HTN significantly increased the risk for CVD- death  and , respectively. The results also indicated a significant increase in the risk for CVD- death in IFG + DM in the absence or presence of HTN  and , respectively . Moreover, DM in the absence or presence of DLP significantly increased the risk for CVD- death  and , respectively. IFG + DM in the absence or presence of DLP was also significantly associated with an increase in the risk for CVD-death  and , respectively (Supplementary Table The major findings of the present study on composite CVD outcomes (MACE) in a group of individuals with IFG are that IFG, per se, in the absence of HTN and DLP is not associated with an increase in the risk for MACE. In contrast, IFG in the presence of HTN or HTN + DLP is associated with an incremental and significant increase in the risk for MACE. Further analyses regarding the impact of IFG in the presence of HTN, DLP, or HTN + DLP on the individual components of MACE demonstrated that IFG in the presence of HTN or HTN + DLP incrementally increases the risk for non-fatal stroke and CVD-death. Additionally, the combination of IFG with DLP is associated with an increase in the risk for CVD-death. As expected, DM in the absence or presence of HTN, DLP, or both is significantly associated with an increase in the risk for MACE. Moreover, pooled analysis of IFG + DM shows dysglycemic status compared with normoglycemic condition increases the risk for MACE even in the absence of other CV risk factors such as HTN and DLP.Whether pre-DM, per se, is an independent risk factor for CVD has been a matter of debate. In the current study, IFG in the absence of other CV risk factors did not increase the risk for composite end-point of MACE. However, IFG in the absence of HTN, adjusted for DLP, significantly increased the risk for CVD- death. Likewise, other longitudinal population-based studies, also did not find any association between pre-DM alone and CVD risk , 15. MorIt is generally agreed that individuals with pre-diabetes or T2DM have higher than normal CV risk factors. This is probably due to the fact that T2DM and pre-DM share common underlying pathophysiologic disturbances such as insulin resistance , 10, 24.Aggregation of CV risk factors in individuals with pre-DM is known to place them at higher risk for CV events . In the DLP, characterized by elevated TG, low concentration of HDL, and an increased number of small dense LDL, plays a critical role in acceleration of atherosclerosis and is reported as an important independent risk factor for CVD . SeveralWith regard to the addition of both HTN + DLP to IFG, the present analyses showed an incremental increase in the occurrence of composite end-point of MACE. Although addition of DLP to IFG did not increase the risk for MACE, co-existence of DLP + HTN increased the risk for MACE even more than addition of HTN alone to IFG. Our findings support the results of previous studies showing that the risk of CV events associated with co-existence of HTN and DLP, labeled as “lipitation”, is greater than the sum of the CV risks for HTN and DLP alone . The intConsidering the effect of IFG combined with CV risk factors on the individual components of MACE, we found that IFG in the absence of HTN, adjusting for DLP, significantly increased the risk for CVD-death. Addition of HTN, or HTN + DLP to IFG was associated with an incremental increase in the risk for non-fatal stroke and CVD-death. In addition, IFG combined with DLP alone significantly increased the risk for CVD- death. The reason why IFG in the absence of HTN, but not in the absence of both HTN and DLP did increase the risk for CVD-death might be explained by the confounding effect of medications such as statin that has been previously shown to be independently associated with a decrease in the risk for CVD mortality .As expected DM either alone or in combination with HTN, DLP, or HTN + DLP significantly increased the risk for composite end-pint of MACE as well as the individual components of non-fatal stroke and CVD- death. However, addition of HTN, DLP, or HTN+ DLP to DM did not increase the risk for non-fatal MI. These inconclusive findings could be due to the small number of events in each group. In addition, further use of statin might protect participants with DM who also have HTN, DLP, or HTN + DLP from some individual CV events.Moreover, dysglycemia (IFG + DM) either alone or combined with HTN, DLP, or HTN+ DLP was associated with an increase in the risk for MACE. This finding highlighted the fact that high glucose level of any degree might have a significant adverse effect on CV outcomes.This study has several strengths. This study investigated the impact of IFG alone or combined with other well-established CV risk factors such as HTN, DLP, or HTN + DLP, on the occurrence of MACE. We included an adequately large number of participants without any known CVD at baseline and the study had 99% follow-up of participants. In addition, we adjusted for multiple confounding factors including most of the traditional CVD risk factors. Finally, the occurrence of individual CV outcomes, including non-fatal MI, non-fatal stroke, and CVD-death, was assessed. Weaknesses include the fact that, due to non-availability of 2 h post-prandial blood glucose, the effect of only IFG as a component of pre-diabetes could be examined. Although evidence shows that IFG is useful for screening of pre-diabetes in the general population, use of IGT and HbA1C might be stronger predictors of cardiovascular events , 40. FinIn summary, although IFG, per se, did not increase the risk for MACE, the association of IFG with HTN or HTN+ DLP conferred a significant risk for composite end-point of MACE and some individual components such as non-fatal stroke and CVD- death in an incremental manner. Moreover, IFG alone in the absence of HTN, adjusted for DLP, significantly increased the risk for CVD- death. These findings support the idea that emphasis should be placed on identification and treatment of multiple CV risk factors in people with pre-diabetes.Additional file 1 Supplementary Table 1 Cox models predicting components of MACE according to glycemic status and HTN. Supplementary Table 2 Cox regression models predicting individual components of MACE according to glycemic status and DLP


We aimed to evaluate sleep and sleep-related physiological parameters (heart rate variability and glucose dynamics) among evacuees by experimentally recreating the sleep environment of evacuation shelters and cars. Nine healthy young male subjects participated in this study. Two interventions, modeling the sleep environments of evacuation shelters  and car seats , were compared with sleep at home . Physiological data were measured using portable two-channel electroencephalogram and electrooculogram monitoring systems, wearable heart rate sensors, and flash glucose monitors. Wake after sleep onset (WASO) and stage shift were greater in both intervention trials than the control trial, while rapid-eye movement (REM) latency and non-rapid eye movement (NREM) 1 were longer and REM duration was shorter in the evacuation shelter trial than the control trial. Glucose dynamics and power at low frequency (LF.p) of heart rate variability were higher in the car trial than in the control trial. It was confirmed that sleep environment was important to maintain sleep, and affected glucose dynamics and heart rate variability in the experimental situation. Japan has long suffered from a variety of natural disasters, including strong earthquakes and destructive typhoons, due to its geographical characteristics . In receHealth maintenance following disasters is an important issue in health policy. Factors including decreased access to medical care, reduced physical exercise, and dietary change at evacuation sites are involved in worsening health conditions ,7. AlthoSleep disturbance is a risk factor for metabolic syndrome, hypertension, and cerebro-cardiovascular diseases . InsuffiTo our knowledge, no previous study has investigated sleep and physiological responses  focusing on the sleep environment of evacuation shelters or cars. Our hypotheses were that the sleep environment of the evacuation shelter and/or car would worsen sleep quality, increase sympathetic nerve activity, and attenuate parasympathetic nerve activity during sleep, and/or insulin sensitivity would decrease and glucose levels rise. Thus, the aim of the present study was to evaluate sleep and sleep-related physiological parameters by experimentally recreating the sleep environment of evacuation shelters and cars.2; Pittsburgh Sleep Quality Index score (PSQI): 5.1 ± 2.3; and Morningness-Eveningness Questionnaire score: 46.3 ± 8.8) participated in the present study. Exclusion criteria included food allergies, smoking, chronic diseases, shift worker, planned long-distance jet travel during the study period, self-reported sleep problems, and regular use of medications. This study was approved by the Local Ethics Committee of Hiroshima University, and all subjects provided written informed consent to participate.Nine male Japanese young subjects  and another assuming the sleep environment of a car seat , compared with sleep at home . To familiarize the subjects with the process of sleeping with a simple electroencephalograph and to confirm the reproducibility of sleep in the control trial, a home trial was performed before both intervention trials , top. WeIn the evacuation shelter trial, two cardboard boxes (thickness 8 mm) and one disaster rescue blanket  were laid on the laboratory floor, and two disaster rescue blankets were used as comforters. Pillows were brought and used from the home. In the car trial, a car seat with a seat back (backrest) fixed at an angle of 45° from the floor was placed in the laboratory, and two rescue blankets were used as comforters. Subjects took off their shoes and went to bed with their feet down , bottom.During this period, the ambient temperature and relative humidity of the subject’s bedroom and the climate in the bed (near the chest and near the feet) were recorded every 2 min using a data logger .Sleep was recorded using portable two-channel electroencephalogram (EEG) and electrooculogram (EOG) monitoring systems , and sleep stages were manually scored according to the standard criteria  by a sleThe R-R intervals were measured by electrocardiogram (ECG) signals using wearable heart rate sensors . The R-R data were separated consecutively every 5 min and compared with the sleep stage. Following this, if at least one awakening was included in the 5-min note, it was defined as “awake”. If no awakening was included, a stage with a high percentage was adopted. Sleep stages were categorized as NREM sleep or REM sleep. We calculated mean RR, low frequency (LF) , high frequency (HF) , and LF/HF ratio  in NREM, REM, and whole sleep. Note that the HF and LF power were divided by total power (HF.p and LF.p).Glucose levels were continuously measured every 15 min using a flash glucose monitor  inserted into the subject’s upper arm. The system is factory calibrated, which eliminates the need for daily calibration during the 14-day wear time. We computed the sleeping glucose level at bedtime as the average 8-h sleeping time, the fasting glucose level as the average 30-min before waking up, and mean indices of meal excursions as glucose rise to peak (ΔG) . We alsot-tests were performed. One-way analysis of variance (ANOVA) was used to evaluate the effect of interventions on sleep stages and glucose indices. Two-way ANOVA was used to evaluate the effect of interventions on heart rate variability and glucose dynamics, but these interactions were not considered because they were similar to those of the predictor variables. In the analyses of heart rate variability, trial and sleep stage (REM/NREM) were set as predictor variables. In the analysis of glucose dynamics, trial and sleeping time course (hours) were set as predictor variables. As post-hoc test, multiple comparisons using Dunnett’s test were conducted. The false discovery rate (FDR) was investigated by calculating the q-value, that is, FDR analogs of p values, with the R package QVALUE  for LF.p. Post hoc tests showed that LF.p was higher in the car trial than in the control trial  = 132.995, p < 0.001, ηp2 = 0.672 for HF.p; F = 21.035, p < 0.001, ηp2 = 0.220 for LF/HF ratio] while no significant main effect of trials .The average values of heart rate variability during sleep are shown in ol trial . There wp < 0.05, ηp2 = 0.010, q = 0.085] and time course . Post hoc tests showed that glucose dynamics were higher in the car trial than in the control trial  the subjects were not experiencing stress and/or anxiety about the disaster in this experiment; and (ii) the subjects were healthy young adults whose desire for sleep was higher than in other age groups. Thus, the sleep of middle-aged and older people, one-third of whom have sleep problems , might bWhile there was no difference in SWS among the intervention and control trials, stage shift had increased in the intervention trials. The subjects had restricted body movement and could not turn over in the driver’s seat during the intervention trials. In the car trial, the seat was set as low as possible in accordance with a previous study, which suggested that the seat should be let down because a smaller angle is more effective for sleep . FurtherHeart rate variability is commonly used as a marker of cardiac autonomic nervous system activity. During NREM sleep, activity of the parasympathetic nerves was predominant, inducing a decrease in heart rate. During REM sleep, there is a large fluctuation in heart rate due to autonomic nervous system irregularity ,28. WhilThere were no differences between the control trials and intervention trials in the fasting glucose levels and average value of ΔG, while glucose dynamics were higher in the car trial than in the control trial. An association between sleeping time and blood glucose levels has been reported in previous studies. An animal study showed that sleep deprivation of just one day may alter liver function involved in blood glucose and insulin control, increasing the risk of developing type 2 diabetes . A humanSleep is also associated with hunger hormones; insufficient sleep results in a decrease in leptin levels (appetite-suppressing hormone) and an increase in ghrelin levels (appetite-enhancing hormone) the following day . In the This study has some limitations. First, although the hardness and narrowness of the bedding could have reproduced the conditions of sleeping in an evacuation shelter or a car, there is no denying that the temperature and humidity might have been quite different from those in an actual gymnasium or car. Moreover, we could not limit the movements of the legs and body position changes in the car trial or induce claustrophobia. Second, we targeted healthy young men in the present study, but the subjects might have included individuals with sleep problems , as suggested by their PSQI scores and bedtimes. Further studies targeting women and the elderly are also needed. Third, the sample size of the present study was small; thus, the results might have been underestimated due to a lack of statistical power.Sleep environments in an evacuation shelter and car were reproduced experimentally in the present study to compare them with sleep at home. Additionally, the effects on sleep, autonomic nervous activity, and glucose dynamics were examined. As a result, WASO and stage shift were found to have increased in both intervention trials compared with the control trial, while REM latency and NREM 1 were longer and REM duration was shorter in the evacuation shelter trial than the control trial. Glucose dynamics and power at low frequency (LF.p) of heart rate variability were higher in the car trial than in the control trial. It was confirmed that sleep environment was important to maintaining sleep and affected glucose dynamics and heart rate variability in the experimental situation. Improvements in the sleep environment under evacuation are needed that might contribute to the prevention of cardiovascular diseases and disaster-related deaths.


Background and Objectives: Gambling disorder (GD) is a recurrent and persistent problematic gambling behavior that impairs multiple areas of an individual's life. GD can persist through two modes: online or offline. This study aims to compare sociodemographic, clinical, and psychological characteristics between treatment-seeking online and offline gamblers and analyze the effect of the gambling mode (online or offline) on anxiety, depression, impulsivity, and debts.Methods: Seventy-nine treatment-seeking gamblers , who were simultaneously receiving treatment at a specialized Pathological Gambling and Behavioral Addictions Unit, participated in this study. The sample was divided into two subsamples: online  and offline ; the characteristics of these two groups were compared and analyzed using Chi-Square test (χ2), t-Test or Mann–Whitney U-test (p < 0.05). Multiple linear regression analyses were performed to determine the effects of gambling mode on significant variables (lack of premeditation and debts).Results: The online sample with a mean age of 29.4 years mainly chose to engage in sports betting  and showed a higher lack of premeditation levels  than the offline sample. In addition, the online sample was younger with respect to their onset to gambling  and the beginning of their gambling problems  compared to the offline sample. Online gambling increased the levels of lack of premeditation by an average of 5.43 points compared to offline gambling (p < 0.05). Accumulated debts of the online sample were lower  than those of the offline sample . However, the interaction between age and gambling mode revealed that online gamblers increased their debt amounts with age at an average increase of €2,726.33 per year compared to offline gamblers (p < 0.05). No significant influence of gambling mode was found on GD severity, anxiety, and depression levels.Conclusions: Gambling mode has a significant relationship with lack of premeditation—a component of impulsivity—and accumulation of debts in treatment-seeking people with GD; however, no relationship was found with the rest of the variables analyzed. Future research with larger samples is needed to confirm these findings. Gambling disorder (GD) has been defined as a recurrent and persistent gambling behavior that deteriorates multiple areas of an individual's life and generates significant emotional distress . Such maModern technology has led to the unprecedented development and expansion of gambling activities, primarily through online gambling. Recently, there has been an increase in the number of online gamblers in Spain. According to the Directorate General for the Regulation of Gambling (DGOJ), an organization that regulates gambling nationwide in Spain, 83.46% of those who gambled online ranged between 18 and 45 years in 2018 , 8. GambGD has often been associated with impulsive behavior and it is considered a risk factor in its etiology . ImpulsiIn addition to impulsive behavior, GD is often related to higher stress, anxiety, depression , 22, GD To the best of our knowledge, there are few studies that have focused on sociodemographic, clinical, and psychopathological differences between samples of online and offline pathological gamblers. In recent years, there has been a growing interest in the study of GD, especially since the expansion of the online gambling industry and increase in the number of online gamblers.Previous studies have shown significant differences in sociodemographic variables, such as age and education level, with respect to the gambling mode , 27. StuWith respect to impulsivity variables, strategic gamblers have shown a higher lack of perseverance levels than non-strategic gamblers . HoweverGiven the context of and increasing number people indulging in online gambling and its addictive component, the objective of the present study was to explore and compare sociodemographic, clinical, and psychopathological variables between two treatment-seeking samples of persons with GD and estimate the effect of gambling mode on GD severity, anxiety, depression, impulsivity, and accumulated debts. We hypothesized higher GD severity, impulsivity, accumulated debts, anxiety, and depression levels in online gamblers compared to offline gamblers. Considering that online gambling is more harmful than offline gambling, we expected to be able to estimate the effect of gambling mode on the variables under study. Additionally, given that most online samples indulged in sports betting, we wanted to explore its effect on online gamblers.The participants were pathological gamblers, who were treated together in the Pathological Gambling and Behavioral Addictions Unit of the Ramon y Cajal University Hospital , between January 2019 and March 2020. The inclusion criteria were a diagnosis of GD according to DSM-5 criteria and over 18 years of age. Comorbidity with intellectual disability; history of substance abuse/dependence; diagnosis of schizophrenia, or other psychotic disorders, major depression, or bipolar disorder, as well as severe organic and/or neurological pathology including history of traumatic brain injury, or epilepsy were set as exclusion criteria. The initial sample consisted of 102 patients, 23 of which were excluded because of comorbidities; thus, the final sample comprised of 79 patients. The total sample was divided into online (inclusion criteria: gambling predominantly or exclusively online) and offline (inclusion criteria: gambling predominantly or exclusively offline) gamblers. Finally in our sample all the players included in the offline sample played exclusively offline, none of them had any problems with the online game.This is a self-report questionnaire developed to identify the presence of GD according to DSM-5 . It has It is a screening instrument that is used in many studies as a measure of severity of gambling activity. It has 20-item, which a total scores range from 0 to 20. The cutoff point was 5 or more, indicating a probable pathological gambler , 35. ThiPG-YBOCS measures the severity and change in GD symptoms over a recent time interval . This is a 10-item scale, divided into two subscales (gambling thoughts or urges and gambling related behavior) and an overall symptom severity score. The total scores range from 0 to 40 . It is aThis questionnaire evaluates anxiety as a state  and as a trait (more stable condition). It comprises of 40 items divided into two subscales: trait and state, with Likert-type responses from 0 to 3. The total score for each subscale ranges from 0 to 60. There is no cut-off point . This stThis questionnaire measures the severity of depression in adults and adolescents aged 13 and older. It comprises of 21 items. The total score ranges from 0 to 63 points. The following cut-off points were established: 0–13, minimal depression; 14–19, mild depression; 20–28, moderate depression; and 29–63, severe depression , 39. ThiThis scale measures five personality dimensions that contribute to impulsive behavior: negative urgency (tendency to lose control under negative emotions), positive urgency (tendency to lose control under positive emotions), sensation seeking (predisposition to try new and stimulating activities), lack of premeditation (tendency to make decisions without considering their consequences), and lack of perseverance (inability to maintain the level of effort needed during a demanding task). It has 59 items, which are scored using a Likert-type scale , 40. Thiad hoc questionnaire. All variables were systematically collected from the participants.Data about sociodemographic variables such as age, gender, marital status, educational level, and employment were collected. Furthermore, gambling mode and type, onset of gambling activity, onset of GD, GD progression, and accumulated debts were registered using a standardized This study was approved by the Ethics Committee of the Ramon y Cajal University Hospital and was in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent for their participation in the study. There was no monetary compensation for their participation.ad hoc questionnaire .All the assessment procedures were conducted in a single session where patients completed the self-report questionnaires , participated in a structured face-to-face clinical interview, and answered a standardized n = 29) and offline gambling sample (n = 50). Sociodemographic, clinical, and gambling characteristics  were explored. Qualitative variables were assessed by absolute and relative frequency and differences between samples were assessed using the chi-square test (χ2). Continuous variables were assessed using mean and standard deviation (SD) in variables with normal distribution, or median and interquartile range (IQR) in non-normal distribution variables; differences between samples were explored using a t-test or Mann–Whitney U-test, respectively. All contrasts were bilateral, with a significance level of p < 0.05.The total sample was divided into two groups for the initial analysis: online gambling sample . Due to significant differences between participants' age in the online and offline groups, all models were adjusted for age. The method to introduce variables in models was stepwise and was completed from the beginning. As both age and gambling mode had significant effects on accumulated debt, the interaction effect was studied to assess the effect of gambling mode on different ages. Statistical analyses were carried out using SPSS (Version 26) and STATA (Version 16.1 for Windows).p < 0.05) between the online  and offline  sample. In addition, the results reported a significant difference (p < 0.05) in the gambling type between the online  and offline  gambling samples. Lastly, significant differences were detected in one of the impulsivity components, namely, lack of premeditation levels as per the scores of the UPPS-P subscales . No other significant differences were found in any variables.p < 0.05), where online gamblers were on average 7.43 years younger than offline gamblers at the onset of gambling activity. At the onset of GD (p < 0.05), online gamblers were on average 8.89 years younger compared to the offline gamblers.p = 0.604), DSM-5 total criteria (p = 0.959), SOGS total (p = 0.417), PG-YBOCS total (p = 0.653), BDI-II (p = 0.756), STAI-state (p = 0.632), and STAI-trait (p = 0.631).No statistically significant differences between the groups were found for GD progression (Estimation results of linear regression models are showed in p < 0.05). Online gambling increased the levels of lack of premeditation by an average of 5.43 points compared to offline gambling.Model 1 contains the effect of gambling mode on the lack of premeditation. Online gambling, as the main effect on lack of premeditation, was an explanatory variable (p < 0.05).Model 2 shows the effect of lack of premeditation in online gambling, controlling for sports betting and age. Only online gambling had a significant effect on lack of premeditation which increased on average 4.48 points compared to offline gambling (p < 0.05). The interaction effect between age and gambling mode showed that online gamblers' amount of debt increases with age, with an average increase of €2,726.33 per year compared to offline gamblers.Model 3 displays the effect of online gambling and sports betting on accumulated debts (only in patients with debts), and the interaction effect between gambling mode and age. Gambling mode had a significant main effect on accumulated debts  seeking treatment for GD. The main hypothesis was that online and offline gambler profiles would be different and that online gamblers would present higher GD severity, impulsivity, anxiety and depression levels, and accumulated debts than offline gamblers.The results of this study showed that there are significant age differences between the online sample, (M = 29.4 years) compared to the offline sample M = 46.8 years). This can be attributed to the legalization of online gambling, which has led to an increase in the number of pathological gamblers, especially among young adults. Of the online gamblers in Spain, 34.41% are between 26 and 35 years . Therefore, no correction methods were employed for the multiple comparisons to avoid losing the statistical power and increasing the type II error. Another limitation of this study is the underrepresentation of women; thus, gender differences could not be explored. Exploring impulsivity and lack of premeditation through a single measure is also a limitation; therefore, future research should include a more comprehensive assessment, which also includes a non-gambling control sample. In addition, this study was not specifically designed to explore the interaction between the mode and type of gambling; thus, its analysis can only be considered preliminary.In conclusion, the results obtained in our study suggest that the gambling mode (online or offline) could be related to impulsivity and accumulated debts in treatment-seeking people with GD. Thus, online gambling was associated with higher levels of lack of premeditation and lower accumulated debts. However, the amount of debt of online gamblers increases with age increases as compared to offline gamblers.No influence of gambling mode was found on GD severity, anxiety and depression levels, or other components of impulsivity, such as negative and positive urgency, sensation-seeking, or lack of perseverance.Future researchers should increase the sample size, including subsamples of online, offline, and mixed gamblers (gambling both online and offline), who might show differentiated clinical and psychological characteristics, and with adequate gender representation. The design of future studies should also include a greater representation of the different types of gambling within each gambling mode (online vs. offline) to specifically explore the interaction between these two variables in GD. Finally, future research might be able to help design psychotherapeutic treatment programs that are more adjusted to patients' needs. It would be interesting to devise treatment programs that place special emphasis on the lack of premeditation to achieve greater control over one's own behavior as well as a reduction in the harmful effects caused by gambling, such as the amount of accumulated debts among people with GD.angela.ibanez@uah.es.The datasets generated for this article are not readily available because they belong to the hospital database and are not available for public access in order to protect patient confidentiality and in accordance with the informed consent signed by the patients. Requests to access the datasets should be directed to Angela Ibáñez, The studies involving human participants were reviewed and approved by Ethics Committee of the Ramon and Cajal University Hospital. The patients/participants provided their written informed consent to participate in this study.AI outlined the conceptualization. IL-T, LL-Q, and AI were responsible for organizing the fieldwork and took part in the data analyses and contributed to the interpretation of the results. IL-T and LL-Q were responsible for the preparation and checks of the data. IL-T drafted the initial version of the manuscript. All authors revised the manuscript for important intellectual content and approved the final manuscript.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.


A significant difference in respiratory rate diminution is found in favor of the Godoy group in comparison with the control group (p = 0.020). A significant difference is found in favor of the Godoy group in systolic blood pressure decrease (p = 0.015) even in pressure pain threshold (p < 0.05). MLD decreases systolic blood pressure in healthy participants. However, it does not produce any changes in other physiologic outcomes maintaining physiologic values, which may suggest the safety of the technique in patients suffering from other pathologies.The aim of this study is to describe the short-term effects of manual lymph drainage (MLD) isolated in supraclavicular area in healthy subjects. A 4-week cross-sectional, double-blinded randomized clinical trial was conducted. Participants: 24 healthy participants between 18 and 30 years old were recruited from Universidad Europea de Madrid from December 2018 to September 2019. A total of four groups were studied: control, placebo, Vodder, and Godoy. The order of the interventions was randomized. Resting Heart Rate and Oxygen Saturation, blood pressure, pressure pain threshold of trapezius muscle, respiratory rate, range of active cervical movements were measured before and after every intervention. All the participants fulfilled four different interventions with a one-week-wash-out period. No statistically significant differences were found between groups in descriptive data; neither in saturation of oxygen, diastolic blood pressure and cervical range of motion. Significant differences were found in favor of Vodder ( Manual lymphatic drainage (MLD) is a very light, rhythmic and superficial massage technique focused on increasing the activity of the lymphatic system, as well as reducing the consistency of the edema and its volume using manual techniques on the skin ,2. MLD iMLD techniques have been described as effective over edema-volume and pain reduction ,5,6, lymThe autonomic nervous system maintains homeostasis through the coordinated action of sympathetic and parasympathetic systems . In the Different methods of MLD techniques, as superficial, slow and rhythmic techniques, described changes on the cardiac and respiratory parameters  on the nervous, cardiovascular, respiratory and musculoskeletal systems compared with a placebo maneuver and control group. Concealed allocation was achieved by having randomization performed by an external researcher, using a closed envelope given to each participant; nobody could see it but the interventor.A total of four groups were established. One control group and three groups of intervention were defined: Godoy’s MLD, Vodder MLD and placebo. Each participant was randomly assigned to one of the four groups. As a cross over design, each participant served as its own control. The participant did not know the group assignment, nor the therapy received each day; the blinded evaluator did not know about the intervention performed on the participant. The order of the four interventions was randomized, considering a 1-week washout period in between. Each participant’s allocation was placed in a sealed-numbered envelope that was kept at an off-site location. After a participant had been randomized, an independent coordinator gave the therapist the envelope which contained the blinded information about the group allocation and the order of the interventions.Of 30 initial candidates, 24 of them meet the inclusion criteria and do not meet the exclusion criteria. A total of 24 healthy students  were recruited and followed up on the four interventions programmed by protocol from December 2018 to September 2019. Participants were eligible for the study if they (a) were healthy participants between 18 and 30 years old (b) physiotherapy students, (c) who had never studied or been treated with MLD and (d) who agreed to participate voluntarily and signed the informed consent. Exclusion criteria were: (a) neurological diseases, (b) cardiovascular system diseases, (c) respiratory diseases, (d) systemic diseases (e) infection, (f) trauma history or chronic pain, (g) unstable medical or psychiatric illness or medication use, (h) subjects who use drugs in the last 6 months.All the participants were asked not to perform intense physical exercise 24 h before the intervention, as well as not to take caffeine, or smoke at least 30 min before their participation (intervention or measures). Environmental conditions such as temperature or visual and acoustic stimuli were maintained constant during the treatments . The intClinicalTrials.gov ID: NCT03709407.The study was conducted in accordance with the rules of the Declaration of Helsinki. The protocol was approved by the Commission of Research of Health Sciences of the European University of Madrid CIPI/029/17 and Research Ethics Committee of the Prince of Asturias University Hospital OE 31/2018, and it was also registered at All the variables were collected before and after each intervention according to the following protocol. All measuring devices were calibrated and validated previously.(1)Initial assessment :The participant was lying in the supine position for 10 min . After tSubsequently, the participants seats relaxed in a chair, with his feet on the floor parallel and his back supported . Blood p(2)Treatment Procedures:A trained physiotherapist, (10 years’ experience in MLD technique and as a university professor) used specialized hand movements in a range of different sequences at 20–30 stimuli per min for 15 min. The maneuvers were performed as very light, completely pain-free, rhythmical translational movements of the skin in the same direction from lateral to medial close to the supraclavicular fossa. The participants were lying in the supine position and the physiotherapist at the head of the treatment table. In order to maintain consistency, different maneuvers procedure were applied in the same standardized protocols , using t(3)Post-intervention assessment-evaluation:After the corresponding intervention was completed, the participant remained in a supine position to measure the post-intervention variables, all except active CROM, BP and PPT that were performed afterwards in the sitting position as described in the initial assessment. The previous parameter assessment protocol was followed at this moment. When the measurements were completed, the participants were told to carry out their normal daily activity. However, they were informed of the possible side effects of the technique during 30 min after the intervention . Finally, participants were asked about the appearance of symptoms during a period of 30 min post-intervention.p < 0.05 was accepted to be statistically significance level. All the data were analyzed using IBM SPSS 24.0 statistical package for Windows .Quantitative variables are shown by median (Md) and interquartile range (IQR) when non-parametric condition is defined, otherwise they are shown by mean (M) and standard deviation (SD). The mean values and frequencies of the parameters were assessed by descriptive statistics. For comparing groups, the Mann–Whitney U test was used. To analyze the differences before and after treatment for each group, the Wilcoxon test was used. A p = 0.026). A 5-point-cardiac-rate-reduction is found in Vodder group. A statistically significant difference in respiratory rate diminution is found in favor to Godoy group in comparison with control group (p = 0.020).Overall, no differences are found among all the groups after each intervention  in saturation of oxygen, diastolic blood pressure and CROM, neither on age nor sex . Statistp = 0.007) in comparison with all groups . A statistically significant difference is found in favor to Godoy group in systolic blood pressure decrease in comparison with Vodder group (p = 0.015).Vodder group shows a significant increase in systolic blood pressure (p = 0.024): the control group reduces significantly the side bending cervical range of movement. In addition, a statistically significant difference is found in favor of the Godoy group in comparison with placebo group (p = 0.053) in PPT.No statistically significant differences are found between groups in CROM on flex-extension, side bending or rotation movements. However, a statistically significant difference was found between the control group and the Godoy group . There is controversy in the evaluation of this value, depending on the basal state of the participant  and the intensity of the stimulation) referred by some authors ,54, mighAs a limitation, the sample size makes us consider these results with caution and should be confirmed by further investigations with direct physiologic measurements, in pathologic subjects to value the effect and security of the techniques. Even the composition of the sample, healthy university students, could make a rapid compensation of the changes produced, so it makes it difficult to assess the effect of the technique in other participants. Even the basal parameters, as they were non-pathological, were not susceptible to relevant modifications.Our study opens new researching lines for future projects even in pathologies where an autonomic nervous system implication exists, as these techniques are considered safe also in non-healthy subjects. In addition, the fact that these techniques are safe, makes physical therapists confident with them, and opens future research lines. MLD decreases systolic blood pressure in healthy participants. However, it does not produce any changes in other physiologic outcomes, such as cardiovascular or respiratory, which may suggest the safety of the technique in patients suffering from other pathologies. No effects were found in musculoskeletal system. Future studies, in a pathologic sample, such as diabetes or Hypertension should be conducted.


Malnutrition among under-five children is one of the major causes of death in low-income countries. Accordingly, health sectors in developing countries are providing renewed attention to the status of children's nutrition. This study sought to explore the trends and identify the determinants of underweight Ethiopian under-five children across time. Z-score less than -2) and “not underweight” . Logistic regression was used for each survey to detect significant determinants of underweight, while multivariate decomposition was used to determine the trends and identified the child, maternal, and household characteristics that are associated with underweight.  The data in the study was obtained from the 2000, 2005, 2011, and 2016 Ethiopian Demographic and Health Surveys (EDHS). The study involved 27564 under-five children across Ethiopian regions. The status of underweight is determined using weight for age. This anthropometric index has been categorized as “underweight”  in 2016 EDHS. Children whose mother's age is below 20 ) were more likely to be underweight compared with children whose mother's age is above 45. Children whose mothers had no education and primary education only  were more likely underweight compared to children whose mothers had higher education.  Children's age, birth weight, mother's education status, and children's gender were the most common significant factors of underweight. The prevalence of underweight among under-five children declined over time which leads to an achievement in terms of meeting millennium development goals and nutritional targets. Government and concerned stakeholders should work to maintain this achievement for further reduction of underweight among under-five children. Malnutrition among under-five children is a major global public health problem affecting –3 morbidChildhood malnutrition is most prevalent in developing countries . It is tA community-based cross-sectional study among under-five children in western Nepal indicated that underweight in these children declined from 43% in 2001 to 27% in 2016. The study further indicated that compared to children aged less than 24, children older than 24 months were more likely to be underweight. Besides, determinants such as drinking water purification practices, growth, age of children, mother's perception of family size at birth, and growth monitoring are significantly associated with childhood underweight . In a stA cross-sectional study that involved children aged 0-24 months in West Ethiopia revealed that the prevalence of underweight among children under 0-12 months and 0-24 months was 15.1% and 8.9%, respectively . On the Though several studies –17 have This study used data from national, population-based, cross-sectional survey EDHS 2000, 2005, 2011, and 2016, a worldwide project funded by the United States Agency for International Development to collect nationally representative demographic and health data on women and young children. The DHS utilized a multistage stratified cluster sampling in which sample households are selected within clusters (enumeration areas). In the selected households, measurements of height and weight were taken from children 0-59 months, women of 15-49 years, and men of 15-59 years .Z-score values and computed as [Z-score) and anthropometric index of child i, respectively. whereas U and δ are the median and standard deviation of the reference population, respectively. This anthropometric index has been categorized as “underweight” (Z-score less than -2) and “not underweight” . In this sense, a child that belongs to the “not underweight” category might be normal weight, overweight, or obese. However, in Ethiopian context, most reports indicated extremely low proportion of overweight and obese [A total of 27564 under-five children were screened for their weight-to-age measurement. Of these, 8590 were screened in 2000, 2920 in 2005, 7217 in 2011, and 8837 in 2016. EDHS granted permission to access data through the project title “Trends and Determinants of Underweight” among under-five children in Ethiopia. Nutritional status is a composite index of underweight (weight-for-age), stunting (height-for-age), and wasting (weight-for-height) , 20. Thend obese .Independent variables include household characteristics , maternal characteristics , and child characteristics  and child caring practices (exclusive breastfeeding).i, j = 2000, 2005, 2010, and 2016, ΔY is the difference in mean prediction of underweight between year i and year j, given that of different characteristics X.The outcome variable was coded as a binary variable  = 0), and the data analysis was performed using STATA 14. The data analysis part includes three important stages. First, descriptive statistics and trends were analyzed in selected recoded background variables among all births in the five years preceding each survey. Second, binary logistic regression analysis was carried out to identify factors associated with underweight in children. Third, to understand the extent to which each selected covariate contributed to the observed trend in underweight prevalence, multivariate decomposition procedures were implemented. This multivariate decomposition provides a way to analyze differences in the outcome between two groups or, as in this case, between two points of time (like 2000 and 2016 survey years). The decomposition procedure divides the total decline in underweight into two portions: the portion that can be attributed to the change in composition or the prevalence of a set of indicators (referred to as the endowments portion) and the portion that can be attributed to the change in the effect of these indicators (referred to as the coefficient portion) . The forβ is the estimated regression coefficients.Xi − Xj)βi represents the difference due to endowment between the ith and jth years.(Xj(βi − βj) represents the difference due to coefficients between the ith and jth years.In 2000, 41% of children were underweight and this declined to 24% in 2016. This shows a persistent decline of children underweight from 2000 to 2016. However, in 2005, the proportion of households with poorer economic status was 24.7% and increased to 30.4% in 2016. Unfortunately, in 2000, the data of the household related to socioeconomic status was not recorded. Among the total study participants, the number of underweight is higher in males than in females for all survey periods (2000-2016). Majority of the children (higher than 30%) were born within the birth interval of 24 to 35 months, and the gap increased with the increase in the survey periods.In 2000 and 2016, 92.8% and 93.3% of under-five children, respectively, were born from the rural area. Percentage of mothers with primary education increased over the survey periods, and the proportion of women with currently working status is increased from time to time.The EDHS in 2005, 2011, and 2016 showed that the highest proportion of women had the poorest socioeconomic status. About 20% of all the households were below the middle wealth group and did not vary a great deal during the period. The percentage of households with piped drinking water decreased during the study period, from 2.8 percent in 2005 to 0.8 percent in 2016 .The multivariable analysis showed that in the last two EDHS data, male rather than female children were more likely to be underweight . Similarly, according to the 2016 EDHS, children born from a household of poor socioeconomic status were more likely to be underweight rather than under-five children from a family with rich socioeconomic status . More generally, in 2016, children's gender, mothers' age, and educational status and birth types have significant association with underweight in children. In all the four surveys children's age was significantly associated with underweight, and the odds of having overweight increased with increase in the age of children.The multivariate decomposition of the analysis see  identifiThe underweight among under-five children declined by 19.5 points between the surveys of 2000 and 2016. Moreover, the underweight among under-five children declined by 9.95 and 5.01 between 2005 and 2016 and 2011 and 2016 EDHS, respectively.Childhood malnutrition is a major problem in developing nations including Ethiopia. In the present study, we looked at the effects of socioeconomic factors on childhood underweight and its trend in Ethiopia using data from four cross-sectional EDHS datasets. First, the association of each child's maternal and household characteristics with underweight was identified through logistic regression. Second, the maternal and household characteristic's coefficient difference among 2000, 2005, 2011, and 2016 EDHS was determined using multivariate decomposition analysis.In the country, for the last two decades, it is estimated that approximately 41% in 2000 and 24% in 2016 of children were underweight, respectively; this promising result may be due to the great effects of the government of the country and different stakeholders to create an awareness of the nutritional status of mothers and their child feeding practices, improvements of sanitations, and the like. The improvement of sanitation, feeding practice improvements and education of parents have an impact to minimize the child underweight status and this result is consistent with the study conducted in different countries , 24. TheIt was also found that under-five children from poor economic status households were more vulnerable to underweight ) which is in line with . Moreove, 226) whIn the 2005 EDHS of this study, breastfeeding had a significant association with underweight that is in line with a study in West Ethiopia  and in cThis research study has strength over other cross-sectional studies that involved children at a single point of time because it is incorporating children from four  EDHS consecutive periods.According to DHS, data is collected once per five years. Thus, the data of underweight in this study are considered only once per five years, in 2000, 2005, 2011, and 2016, four successive surveys. Hence, it is doubtful if there are lots of up and down trends within the five-year interval. Moreover, this study involved only children aged under five.Children's age, birth weight, mother's education status, and children gender were the most common significant factors of underweight. The prevalence of underweight in under-five children declined from 41% in 2000 to 24% in 2016, and the effect of child, mother, and household characteristics differed significantly overtime. Thus, over the last two decades, many developing countries including Ethiopia have made remarkable progress in reducing underweight in under-five children. This reduction leads to an achievement in terms of meeting nutrition targets and millennium development goals which were used as an input for policymakers to update their strategy and designing strategies to improve the nutritional status of children in Ethiopia. The government and concerned stakeholders should work to maintain this achievement for further reduction of underweights among under-five children.


The prevalence of cardiometabolic risk factors has increased in Slovakian adolescents as a result of serious lifestyle changes. This cross-sectional study aimed to assess the prevalence of insulin resistance (IR) and the associations with cardiometabolic and selected lifestyle risk factors in a sample of Slovak adolescents. In total, 2629 adolescents  aged between 14 and 18 years were examined in the study. Anthropometric parameters, blood pressure (BP), and resting heart rate were measured; fasting venous blood samples were analyzed; and homeostasis model assessment (HOMA)-insulin resistance (IR) was calculated. For statistical data processing, the methods of descriptive and analytical statistics for normal and skewed distribution of variables were used. The mean HOMA-IR was 2.45 ± 1.91, without a significant sex differences. IR (cut-off point for HOMA-IR = 3.16) was detected in 18.6% of adolescents . IR was strongly associated with overweight/obesity  and with almost all monitored cardiometabolic factors, except for total cholesterol (TC) and systolic BP in females. The multivariate model selected variables such as low level of physical fitness, insufficient physical activity, breakfast skipping, a small number of daily meals, frequent consumption of sweetened beverages, and low educational level of fathers as significant risk factors of IR in adolescents. Recognizing the main lifestyle risk factors and early IR identification is important in terms of the performance of preventive strategies. Weight reduction, regular physical activity, and healthy eating habits can improve insulin sensitivity and decrease the incidence of metabolic syndrome, type 2 diabetes, and cardiovascular disease (CVD). Cardiovascular diseases (CVDs) are one of the most serious problems related not only to health but also to the social and economic situation in all developed countries of the contemporary world , and thiCVDs are often considered to be diseases of the elderly, but many epidemiological studies have shown early stages of the atherosclerotic process in childhood and adolescence . At thisInsulin resistance (IR) can be defined as a condition in which peripheral tissues do not respond sufficiently to insulin, which gradually leads to impaired glucose tolerance and later to the development of type 2 diabetes. Insulin resistance can also be considered as a separate risk factor for CVD and is associated with other metabolic diseases. Insulin resistance is a central risk factor for metabolic syndrome (MetS) and stimulates the development of other cardiometabolic risk factors such as dyslipidemia, arterial hypertension, hyperglycemia, and other pathological conditions of the organism. One of the first IR warning signals is the proliferation of adipose tissue as an important endocrine organ, especially in the waist area . Thus, IMetabolic syndrome is a phenomenon of modern society . It is cAlthough MetS was originally described in adults and was not known in children before 1980, the clustering of cardiometabolic risk factors begins at a young age and, currently, the same metabolic diseases found in adults can be found in 13% of normal-weight children and 38% of children with obesity ,10. EarlMetS prevalence in children is lower than in adults, estimated at 2–9.4%, but it is higher in children and adolescents with obesity 12.4–44.2%) .4–44.2% ,14.In 2007, the International Diabetes Federation (IDF) presented the definition of MetS in children and adolescents . It provIn the last few decades, many interventional studies have gained a wealth of new knowledge about foods and nutrients that positively or adversely affect the cardiovascular system not only in adults  but alsoPhysical inactivity doubtless belongs to CVD risk factors. Insufficient physical activity is also significantly associated with the development of MetS and is probably a decisive factor in IR development . IncreasSleep has an essential role in growth, maturation, and good health during childhood and adolescence . HoweverThis cross-sectional study aimed at determining the prevalence of IR in adolescents and its relationship with obesity and other cardiometabolic and selected lifestyle risk factors, as well as selected factors of personal and family history in males and females. These indicators are of great importance for CVD prevention in adolescents and young adults.The analyzed sample of adolescents was selected from the project “The Support of Cardiometabolic Health in the Secondary Schools in the Bratislava Self-governing Region” , which was conducted at secondary schools within the Bratislava Self-governing Region . The project was approved by the Ethics Commission of the Bratislava Self-Governing Region. All procedures were according to the ethical standards, as laid down in the 1964 Declaration of Helsinki and its later amendments. From all legal representatives of children, written informed consent was obtained before being enrolled in the study. Participation in the study was fully voluntary and anonymous, with no explicit incentives provided for participation. All participants were informed about the significance and the course of individual measurement and examination procedures.From all of the students enrolled in high schools in the Bratislava Self-Governing Region , 4382 adolescents  aged 11–19 years participated in this project (22.9%). Students < 14 and >18 years were excluded. Selection criteria were age  and complete anthropometric, blood sample, and blood pressure (BP) examinations. An exclusion criterion was the presence of any illness (acute and/or chronic). The final selected and evaluated sample consisted of 2629 adolescents aged 14–18 years with a mean age of 17.1 ± 1.04 years: 1205 boys (45.8%) and 1424 girls (54.2%). The basic characteristics of the adolescents and sex differences are shown in Basic anthropometric measurements, focused on overweight/obesity and abdominal obesity , were performed by trained staff directly at schools. Body fat content and weight were measured using a digital body composition scale (OMRON BF510) with an accuracy of 100 g. The subject stood in light clothing on metal electrodes with bare feet, their palms firmly gripping handles with electrodes, and their hands were freely lowered . The body fat percentage measurement was based on the bioelectrical impedance method. The body height was measured using a stadiometer (TANITA LEICESTER) on a horizontal floor surface with an accuracy of a whole millimeter . Body mass index was calculated; overweight and obesity was evaluated according to the percentile curves from the 6th National Anthropometric Survey on physical development of children and youth in the Slovak Republic in the year 2001 . Subjectcrista iliaca anterior superior and the lowest rib (with accuracy to the whole millimeter) and evaluated according to the IDF consensus for defining MetS in children and adolescents [Waist circumference was measured using a flexible non-elastic tape in an expiration position directly on the skin in the horizontal plane at half the distance between the lescents . From thBlood pressure and resting heart rate (HR) were measured using an automated digital device, OMRON M-6 COMFORT, under standard conditions on the right arm (after a minimum of 10 min of sitting with back supported and legs on the floor). Before the examination, subjects did not eat or smoke for 2 h. The average values of BP and HR from the 2nd and the 3rd measurements (with a 5-min break between measurements) were calculated. BP values at the age of <18 years were classified using percentile values of systolic and diastolic BP according to age, height, and sex ,36 and, A sampling of overnight fasting venous blood for laboratory examination was performed by qualified nurses under the physician’s guidance and standard biochemical analyses were performed by a central certified laboratory. At the central laboratory, standard blood chemistry analyses , high-density lipoprotein cholesterol (HDL-C) plasma levels, concentrations of high-sensitive C-reactive protein (hsCRP)) were performed . Low-density lipoprotein cholesterol (LDL-C) level was calculated via the Friedewald equation; atherogenic index of plasma (AIP) = log(TG/HDL-C)  and , leisure-time physical activity (frequency and duration per week), sleeping duration and sedentary activities duration  on working days and weekends, psychosocial factors , and nutrition and dietary habits: number and regularity of daily meals , frequency of food groups’ consumption per week . In this study, we recorded the consumption of only sweetened beverages. In the questionnaire designed for parents, we focused on the adolescent birth weight and the breastfeeding duration, the current weight of the parents, and their highest educational level. Multiple response options were dichotomized (desirable/acceptable vs. risky) for multivariate logistic regression. t-test and Mann–Whitney U-test, categorical data were compared using contingency tables and chi-square test. The relationship between IR and each of all of the cardiometabolic factors , lifestyle factors , and selected data on personal and family history  was tested using bivariate analysis, which resulted in crude odds ratios at the 95% confidence interval.For statistical data processing, the methods of descriptive statistics for normal  and skewed distribution of variables  were used. Relationships between continuous variables were assessed using a two-sample p-values < 0.05 were considered as statistically significant. In the case of multivariate logistic regression, collinear variables were excluded . All variables were entered into a general logistic backward stepwise regression model and the elimination method was used to remove non-significant predictors from the model in 16 steps. The stepwise approach is useful because it reduces the number of predictors, reducing the multicollinearity problem, and it is one of the ways to resolve overfitting. The statistical packages Epi InfoTM software, version 7.1.5.0, Atlanta, GA, USA, and SPSS, version 24  were applied.Multivariate logistic regression models were used as well , which resulted in adjusted odds ratios at the 95% confidence interval; The basic sample characteristics, sex differences, and risk marker prevalence are shown in p < 0.001) but, according to body fat content, females had a significantly higher prevalence of overweight . The abdominal obesity according to the IDF criteria [p < 0.001).According to BMI, males had a significantly higher prevalence of overweight/obesity , and for girls it was 10.5 ± 4.1 (in the range of weak fitness), Selected lifestyle and eating habit characteristics are given in p = 0.147), the median of HOMA-IR increases significantly regarding the overweight and obesity prevalence . Mean HOMA-IR values were higher in 14- to 17-year-old males and in 18-year-old females and had a declining trend in both sexes . Insulinevalence . The IR p < 0.001). All of them were in the range of overweight/obesity. In the overweight/obesity group (n = 696), the MetS prevalence was 5.5% .In the whole sample (n = 2629), 38 (1.4%) adolescents met the IDF criteria for the MetS diagnosis  and AIP  were observed, and with all anthropometric parameters, especially waist circumference  and WHtR . Bivariate analysis showed highly significant associations of IR with each of all observed cardiometabolic factors in boys. This was similar in the case of girls, except for TC level and systolic BP. Among the metabolic parameters, in both sexes, the closest relationships of HOMA-IR with the TG level , body fat content , and WHtR  in males and non-HDL-cholesterol , triglycerides , body fat content , and WHtR  in females were statistically significant among the variables associated with IR in adolescents in multivariate logistic regression analyses . Multivariate logistic regression confirmed a significant association of IR with a higher educational level of mothers and with a higher current weight of both parents in males, and with a lower educational level of fathers in females . The same cut-off value was used by authors in Košice (Slovakia) in a group of 224 high school students with an average age of 18 years, and they found only a 13.9% prevalence of IR [In our sample, almost one fifth of adolescents, 18.6% (19.8% of boys and 17.6% of girls), had a risk of IR without significant sex differences in average HOMA-IR values . The HELENA study, conducted in a large sample of adolescents aged 12.5–17.5 years from six European cities, found that females experienced more stress than males , which iSleep is an important factor for normal growth and development during childhood and adolescence  and is rAnother lifestyle factor that can directly or indirectly affect insulin sensitivity is physical activity. Several studies have found that increased physical effort increases insulin sensitivity in overweight adolescents, even when there is no change in body weight or body fat content . SedentaSmoking is an important risky behavior in adolescents worldwide, with potential adverse health effects. It is assumed that early smoking onset age is an important public health issue, but there are controversial outcomes regarding the health consequences of adolescents . KelishaOne of the main causes of obesity, IR, and MetS is generally considered to be related to food choices and eating habits. It is even assumed that there is some connection between sleep deprivation and food choice, i.e., that people with sleep deprivation more often tend to choose unhealthy foods high in energy and fat content . BreakfaFamily history, ethnicity, prenatal and postnatal nutrition, obesity, pubescence, eating habits, and sedentary lifestyle may affect insulin sensitivity in the pediatric population . It is aThe strength of our study is in a large sample of adolescents and young adults and the ability to examine a wide variety of cardiometabolic and selected lifestyle risk factors, as well as selected factors of personal and family history in males and females. These indicators are of great importance for CVD prevention in adolescents and young adults. Our study is limited by its cross-sectional design, which does not determine cause-and-effect relationships between different variables. This method is often used to make inferences about possible relationships or to gather preliminary data to support further research and experimentation. The generalizability of our findings to the wider population may be limited as well. The other limitations are mentioned in the discussion. In our study, a relatively high incidence of IR  without significant sex differences was found in a large sample of adolescents in the Slovakian capital self-governing region. In both sexes, the highly significant associations of IR with overweight/obesity, specifically with abdominal obesity expressed as WHtR, were confirmed. Regarding plasma lipids, triglyceride levels had the closest association with IR. When it comes to lifestyle factors, a highly significant relationship of IR with insufficient physical activity and low physical fitness in both sexes was found, but we were unable to confirm the impact of daily sedentary activity duration. Skipping breakfast, a low number of meals per day , and frequent consumption of sweetened beverages showed significant relationships with IR regarding dietary habits. Our study also found an important association of parents’ body weight and parental educational level  with the development of IR in adolescents. On the other hand, we cannot confirm the impact of low birth weight and/or breastfeeding duration on IR in adolescents.