ES = 0.3, p = 0.003), knee extension ), peak expiratory flow , and sports activity  after three months. E-training had no effect on HrQoL but did on muscle strength, lung function, and physical activity. It is a promising and feasible approach to facilitate large-scale, yet individual, training support.Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical activity, and fatigue. This is a randomised, controlled trial with a wait-list control group. Data were collected at baseline, after three and six months, and analysed using a hybrid linear model. One-hundred twenty-six pwMS participated in the home-based aerobic (1×/week) and strength training (2×/week) intervention that was supervised and documented via an internet-platform. The intervention group received e-training for six months, and the control group received e-training after a three months waiting period. Significant differences between the groups were only observed for muscle strength (knee flexion (effect size  In the past, persons with multiple sclerosis (pwMS) were advised against physical activity ; howevern = 18, 10 in the intervention group, eight in the control group), and after six months to a total of 39% (n = 49).One-hundred twenty-six participants were randomised consecutively . After tp = 0.01). No differences were found for HrQoL (p = 0.462), fatigue (p = 0.407), aerobic fitness (p = 0.864), forced vital capacity (p = 0.929), knee extension (p = 0.594), knee flexion (p = 0.164), trunk extension (p = 0.988), trunk flexion (p = 0.825), and the sport score (p = 0.568).SD = 2.72). A total of 8548 physical activities were recorded in the online activity journal. Apart from the strength training sessions, the most frequent entries were: cycling (n = 984), Nordic walking (n = 780), walking the dog (n = 605), running/jogging (n = 459), gym (n = 381), swimming (n = 333), walking (n = 209), and cross-trainer (n = 110). Regarding the frequency of use, 73% of participants in the intervention group documented at least 80% of the prescribed strength training sessions (two per week) during the first three months. A reduction in frequency of training gradually started after four weeks. In months 4–6, only 36% of participants documented at least 80% of the prescribed sessions.Over the course of the study, a total of 3639 strength training sessions with feedback on 21,566 individual training exercises were documented via the participant interface. A training plan contained 5.9 strength-building exercises on average. Regarding HrQoL, no significant time effects within the groups or interaction effects were detectable in either the first or second phase of the study . This hoThere were also no significant effects for fatigue after three months, but in the second phase of the study the intervention group recorded a significant increase in fatigue.The intervention group recorded significant increases in muscle strength after three months with a medium effect size for knee extension and knee flexion, which, in both cases were also significant in comparison with the control group. Significant increases in trunk flexion were recorded after three months for both the intervention group and the control group, which did not differ significantly between the groups. There was no change in trunk extension for either group in the first phase of the study, and in the second phase only the intervention group showed a significant increase in strength.No significant changes were measurable for aerobic capacity, or static lung volume in either group. There was a significant increase in peak expiratory flow in the intervention group after thrree months of training, which was also significant in comparison with the control group.The intervention group recorded a highly significant increase in sports activities (Baecke sports score) after three months, while this increase became apparent in the control group in the second phase of the study, after training had begun.The e-training intervention as applied in this study could not influence the primary outcome HrQoL or fatigue, but secondary outcomes, such as muscle strength of the lower extremities, lung function and, especially, physical activity, improved significantly.Effects of physical exercise training on HrQoL for pwMS have been demonstrated in two meta-analyses ,7, but aTwo review articles concluded that physical exercise training can improve fatigue ,11. HoweES = 0.27) [n = 31 as against n = 18).Isometric maximum strength of the knee extensors was increased by 9% and that of the knee flexors by 13% after three months of training. The effect sizes for leg strength gains accomplished in this study correspond well to the mean effect size of strength training in pwMS that was determined in a recent meta-analysis (mean  = 0.27) . This ca2 mL/(kg·min) (VO2peak) of up to 10% of the measurement value is possible and realistic for pwMS [No effects on aerobic capacity could be achieved. A training-induced increase in Peak oxygen consumption in Ofor pwMS . ReasonsNevertheless, the peak expiratory flow could be significantly increased as a result of the training. The baseline values of peak expiratory flow were approximately 84% of the norm, which may indicate a weakness of the respiratory musculature that occurs in pwMS at an early stage of the disease . The reaPhysical activity improved significantly in both groups, corresponding with the respective start of the internet-supported training. The recorded mean change of about one point of the sport score corresponds to approximately 60 to 90 min of additional regular, moderately-intensive sports activity per week. This approximately meets the amount of prescribed exercise sessions of about 2–3 per week.Compliance and frequency of use are key aspects in the evaluation of internet-based interventions and deserve thorough analysis, as it is through this that the prescribed dosage of the intervention is determined. The frequency of use was higher than for most internet-based interventions . This coThe presented study did not exploit the full potential of internet-based interventions and leaves room for improvement. An increase in the frequency of use and compliance, and a reduction in the dropout rate might be achieved by an increased level of support  or a strAlthough a number of measures were taken to prevent bias , we were not able to blind participants. Double-blinding is hardly possible in rehabilitation or training studies.Another major disadvantage of the applied e-training platform is the lack of direct supervision. No cameras, motion detection systems, or other objective methods of observing the training were used. Non-functional execution of the exercises and faulty or incorrect training documentation are, therefore, not precluded.Due to recruitment strategies, the sample was probably more active and predisposed to sports than average  and onlyApproval for the study was given by the ethics committee of the medical faculty of the Friedrich-Alexander-University Erlangen-Nürnberg . The study was performed in two study centres and used a two-arm, randomised, controlled design with a wait-list control group and assessments at baseline, and after three and six months. The main effects of the e-training were assessed in the primary analysis after three months, by comparison of intervention to control conditions. To detect potential long-term effects, the intervention group received the e-training for another three months. The wait-list control group received no intervention for the first three months, and then three months of e-training. Both study centres applied identical and standardized procedures for assessment and intervention.Recruitment was carried out via contact lists from previous studies, press announcements in local newspapers, and websites of multiple sclerosis societies.Criteria for inclusion were diagnosed multiple sclerosis, an Expanded Disability Status Scale (EDSS) score of less than or equal to 4.0, not less than four weeks of clinical stability prior to inclusion in the study, and access to the internet. Criteria for exclusion were primary progressive multiple sclerosis and clinically-relevant cardiological, internal, or orthopaedic contraindications to exercise, which were assessed by the patients’ attending physicians.2peak, cut-off value 30) as a measure of fitness. Allocation was carried out after the baseline data collection by entering the stratification criteria into an urn randomization program . Thereby, allocation was concealed at the time of assessment.The randomisation was stratified according to the EDSS  and maximum oxygen uptake  . The totMaximum isometric muscle strength was tested with the M3 Diagnos machine . After a five-minute warm-up on a bicycle ergometer at 40 watts and familiarization  with the procedure, subjects were instructed to increase muscle contraction strength over a period of 1–2 s and then sustain maximum contraction for 5 s. Two repetitions with a rest interval of one minute were carried out. Peak torque values were calculated by the M3 Diagnosis software  and determined as the highest attained torque during one attempt. The best out of two attempts was recorded.2peak) was determined by the Master Screen CPX System during a spiroergometry on a bicycle ergometer  at 70–80 revolutions per minute.Forced vital capacity and peak expiratory flow were tested with the Master Screen CPX System  to evaluate lung function. After familiarization, the value of the best of two test attempts was taken. As a marker of endurance capacity, peak oxygen uptake  with one-to-one support for each participant. The trainers were exercise therapists and/or physical therapists with experience in the prevention and rehabilitation setting with different indications including multiple sclerosis. These therapists were additionally trained with regard to all study and prescription processes. Exercises were delivered with detailed descriptions and pictures in PDF documents. Training support and communication took place asynchronously  via a messaging service in the software and, when required, by email and telephone. No special equipment was necessary except an elastic exercise band or a large gymnastic ball. The number of sets and repetitions to be completed for each exercise were prescribed individually for each participant and training session, and were dependent on fitness levels. Training intensity was regulated by the participant’s subjective, perceived exertion, which was rated between 6 and 20 on the Borg Scale . This scIn addition to the strength training, endurance training was to be carried out once a week. Based on the spiroergometric evaluation, recommendations regarding the intensity of jogging, walking, cycling, and swimming were made . The form of activity for the endurance training was freely selected, duration (between 10–60 min) was adjusted to individual fitness levels. In contrast to the strength training, the endurance training was, however, not systematically progressed after the initial recommendation of training parameters. A more detailed intervention description is available on the clinicaltrials.gov entry  for the Compliance with the e-training was recorded electronically via the documentation function of the training software.f(V) = 0.25), and two groups and two measurements (within-between interaction) yielded n = 128. Taking into account a drop-out rate of approximately 35%, the required sample size was n = 172.A sample size calculation determining a significance level of 0.05, statistical power of 0.8, medium effect size  and both intervention groups as fixed effects, and the intercept and slope as random effects. Primary analysis was at T1, after three months’ intervention, against the control group. Changes in the measured values were treated and analysed individually for each time period. In this connection, changes in the groups with respect to the value of the previous measurement were determined and tested for statistical significance both within the group (time effect) and in a comparison of the groups (interaction group × time). Through this procedure, differences arising at the previous measurement  were statistically controlled. Grouping by time effects, though, were only calculated for the primary analysis at T1, since this comparison is not meaningful for T2. Furthermore, all outcomes were adjusted according to the baseline value of the EDSS. All available observations were included in the analysis as randomised (full information likelihood), there was no imputation of missing data. The results are therefore not biased by a missing at random (MAR) assumption. Effect sizes were calculated for time effects and for group × time interactions (Cohen’s d) and interpreted as large (>0.8), medium (0.5–0.8) or small (0.2–0.5) effects.Internet-based exercise interventions can lead to improvements in physical activity levels and physical function outcomes in persons with multiple sclerosis. This e-training intervention had no effect on health-related quality of life but is a promising and feasible approach to facilitate individually-tailored training support, considering the large sample size and significant effects on muscle strength, lung function, and sports activities. Reduction of compliance over time is a shortcoming, especially of internet-based studies, and needs to be explored and systematically counteracted in further studies. To improve adherence and health-related quality of life, social support could to be an important factor to be considered in future exercise interventions.


Dangguixu-san (DS), a herbal extract, is widely used in Korean medicine for the treatment of traumatic ecchymosis and pain by promoting blood circulation and relieving blood stasis. However, the effects of DS on ankle sprain have not been evaluated in a randomized clinical trial. Here, we describe the protocol for a randomized controlled trial that will evaluate the efficacy and safety of DS for the treatment of ankle sprain.Ankle sprain is a common musculoskeletal injury. In Korean medicine, blood stasis is thought to be the main cause of pain and swelling in patients with ankle sprain. n = 48) with acute lateral ankle sprain (ALAS) that occurred within 72 h before enrollment will be randomly assigned to a DS (n = 24) or a placebo (n = 24) group. Both groups will receive acupuncture treatment once a day for 5 days a week (excluding Saturday and Sunday) and the trial medication (DS/placebo capsule) three times a day for seven consecutive days. The primary outcome measure will be pain relief evaluated using a Visual Analog Scale (VAS). Secondary outcome measures will include Foot and Ankle Outcome Scores (FAOS), edema, European Quality of Life Five-Dimension-Five-Level Scale (EQ-5D-5 L) scores, and the number of recurrent ankle sprains. VAS, FAOS, edema, and EQ-5D-5 L scores will be recorded before, at the end of, and at 4 weeks after treatment completion. EQ-5D-5 L scores will be additionally recorded at 26 weeks after treatment completion. The number of recurrent ankle sprains will be recorded at 4, 8, 12, and 26 weeks after treatment completion.In this randomized, double-blinded, placebo-controlled, parallel-arm clinical trial with a 1:1 allocation ratio, participants .cris.nih.go.kr, registration number: The online version of this article (10.1186/s13063-018-2571-1) contains supplementary material, which is available to authorized users. Ankle sprain is one of the more common musculoskeletal injuries and is associated with a high prevalence of persistent problems that lead to an increased burden of chronic health issues in the community –5. The aHuangdi’s Inner Classic. Generally, blood stasis is a significant pathological product of blood stagnation [EoHyeol in Korean, Yu Xue in Chinese, and Oketsu in Japanese [Blood stasis is an important pathological concept in traditional East Asian medicine (TEAM) since it was first documented in agnation , 15. Bloagnation . Accordiagnation , 18. ThiJapanese .Dangguixu-san (DS), which is composed of Angelicae gigantis radix, Paeoniae radix rubra, Linderae radix, Cyperi rhizoma, Sappan lignum, Carthami flos, Persicae semen, Cinnamomum cassia, and Glycyrrhizae radix, promotes blood circulation and relieves blood stasis; therefore, it is the most frequently prescribed herbal formula for the treatment of traumatic ecchymosis and pain [Dangkwisoo-san in Korean and Tokishusan in Japanese [In Korean medicine, because it is considered that pain and swelling associated with ankle sprain could be caused by blood stasis, activation of blood circulation is the main treatment principle for ankle sprain , 21. In and pain  and is rand pain . This foJapanese , 27.Acupuncture is one of the more commonly used therapeutic modalities for painful conditions in complementary and alternative medicine, including Korean medicine . A surveAlthough DS is used for the treatment of ankle sprain in Korean medicine, evidence regarding its efficacy is insufficient. Therefore, we designed a randomized, double-blinded, placebo-controlled, parallel-arm clinical trial for investigating the efficacy and safety of DS for the treatment of ankle sprain. The results of this study are expected to provide evidence regarding the usefulness of DS for the treatment of ankle sprain.The objective of this study is to compare the efficacy of DS treatment combined with acupuncture with that of placebo combined with acupuncture for pain reduction in patients with acute lateral ankle sprain (ALAS) in order to investigate the efficacy of DS for the treatment of ankle sprain.Our null hypothesis is that the pain control effects of DS are not superior to those of placebo in patients with ALAS.n = 24) or a placebo (n = 24) group. Patients in both groups will receive acupuncture treatment once a day for 5 days a week (excluding Saturday and Sunday) and the trial medication (DS/placebo capsule) three times a day for seven consecutive days. The primary outcome measure will be pain relief evaluated using a Visual Analog Scale (VAS). The secondary outcome measures will be Foot and Ankle Outcome Scores (FAOS), edema, European Quality of Life Five-Dimension-Five-Level Scale (EQ-5D-5 L) scores, and the number of recurrent ankle sprains. VAS, FAOS, edema, and EQ-5D-5 L scores will be assessed before, at the end of, and at 4 weeks after treatment completion. EQ-5D-5 L scores will be additionally recorded at 26 weeks after treatment completion. The number of recurrent ankle sprains will be recorded at 4, 8, 12, and 26 weeks after treatment completion.The present study design is in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and Consolidated Standards Of Reporting Trials (CONSORT) 2010 guidelines , 32 . The trial has been registered at cris.nih.go.kr . The study design is summarized in Table Participants will be recruited at Semyung University Korean Medicine Hospital in Chungju, Republic of Korea. The study will be advertised through local newspapers, the Internet, and posters in communities and hospitals. Participants will be provided with an explanation about the study by the clinical research coordinator (CRC) and will be requested to voluntarily sign an informed consent before participation. The CRC will continuously monitor the medical condition of the enrolled participants to ensure adherence to the intervention protocols.i.e., negative anterior drawer and talar tilt test results), little or no hemorrhaging, no point tenderness, decreased total ankle motion by ≤ 5°, and a swelling of ≤ 0.5 cm. Patients with some loss of function, positive anterior drawer test findings , negative talar tilt test findings , hemorrhaging, point tenderness, decreased total ankle motion by > 5° but < 10°, and a swelling of > 0.5 cm but < 2.0 cm will be diagnosed with grade II ALAS [Patients aged older than 19 years who have sustained a grade I or grade II ALAS within 72 h before enrollment and are willing to voluntarily sign an informed consent form will be considered for enrollment. A grade I ankle sprain will be diagnosed when there is no loss of function or ligament laxity ; motor or sensory disturbance due to nervous system disorders in the same leg; pregnancy or breastfeeding; medication with drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), pain relievers, or steroids for pain relief from the time of trauma to participation in the clinical trial (excluding the use of adherent inflammatory pain relievers on the day of screening); impaired hepatic  or renal  function; ineligibility for participation in the trial because of a history of gastrointestinal diseases that might affect the absorption of the trial medication, as judged by the principal investigator (PI); genetic conditions such as galactose intolerance, Lapp lactase deficiency, and glucose-galactose malabsorption; a history of hypersensitivity to the components of the trial medication; and participation in other clinical trials within 4 weeks of screening for the present study or concurrent participation in other clinical trials.Subjects with a poor general condition and those who are not fit for acupuncture or DS treatment will be excluded. Other exclusion criteria are as follows: fracture confirmed on x-rays or grade III ankle sprain  ; a histoThis study has been approved by the Institutional Review Board (IRB) of Semyung University Korean Medicine Hospital in Chungju. The purpose and potential risks of this clinical trial will be fully explained to the participants and their families. All participants will be asked to provide written informed consent before participation.http://www.randomization.com) and randomly allocated to one of the two study groups (n = 24 each). The serial number codes will be inserted into opaque envelopes that will be sealed and stored in a double-locked cabinet.After the acquisition of written informed consent and completion of baseline measurements, the 48 enrolled participants will be assigned serial numbers generated using a randomization tool  and the trial medication (DS/placebo capsule) three times a day for seven consecutive days. Treatment will be administered by Korean medicine physicians with 6 years of formal university training in Korean medicine, a licence to administer treatment, and at least 1 year of clinical experience. To ensure strict adherence to the study protocol, the physicians will receive training together and employ the same techniques.All participants will receive acupuncture at the ST36, ST41, BL60, BL62, KI3, KI6, GB39, and GB40 points on the affected side . Only stThe trial medications will include DS and placebo capsules, which will be identical in appearance, taste, and smell. The DS formulation composed of granular extracts of nine herbal substances, will be a gray-brown powder contained in a 0.6-g pink capsule Fig. . The plaAngelicae gigantics radix, 0.42 g of Paeoniae radix rubra, 0.42 g of Linderae radix, 0.42 g of Cyperi rhizoma, 0.42 g of Sappan lignum, 0.33 g of Carthami flos, 0.29 g of Persicae semen, 0.25 g of Cinnamomum cassia, and 0.21 g of Glycyrrhizae radix are added to the extractor. The mixture is extracted with 8–10 volumes of purified water at 80–100 °C for 3–4 h. The extract is filtered (100 mesh), concentrated under reduced pressure at ≤ 60 °C, and dried to obtain 350 mg of a granular extract. Then, 45 mg of lactose hydrate, 100 mg of corn starch, and 5 mg of magnesium stearate are mixed into the granular extract, and the mixture is converted into granules, dried, crushed, and filled into capsules.The manufacturing process for the DS capsules is as follows. First, 0.63 g of Capsules will be sourced from Kyungjin Pharmaceutical Co., Ltd. ). The medication will be dispensed as 0.6-g capsules packed in sealed boxes containing a 1-week dose.Between the preintervention period and 4 weeks after treatment completion, participants will not be allowed to take the following drugs: NSAIDS, pain relievers, steroids, or adherent inflammatory pain relievers; drugs containing potassium, licorice, glycyrrhizic acid, furosemide, ethacrynic acid, or trichloromethazine; and drugs containing any of the main ingredients of DS. Participants will be asked to return their medication boxes to allow enumeration of leftover capsules and for monitoring participant adherence.VAS, FAOS, edema, and EQ-5D-5 L scores will be assessed before, at the end of, and at 4 weeks after treatment completion. EQ-5D-5 L scores will be additionally recorded at 26 weeks after treatment completion. The number of recurrent ankle sprains will be recorded at 4, 8, 12, and 26 weeks after treatment completion.Because the objective of this study is to investigate the efficacy of DS therapy for pain relief in patients with ALAS, changes in the pain severity (measured using VAS) will be considered as the primary outcome. The VAS will be a 10-cm straight line marked at each end with the anchor labels “no pain” and “pain as bad as it could be” . PatientSecondary outcomes will include changes in FAOS, edema, EQ-5D-5 L scores, and the number of recurrent ankle sprains. The FAOS is a self-administered questionnaire specific to feet and ankles. It is designed to assess week-to-week changes in symptoms and function after foot and ankle injuries and comprises five subscales: pain (nine items), other symptoms (seven items), activities of daily living (17 items), sports and recreational activities (five items), and foot-and-ankle-related quality of life (four items). The subscales are scored separately using a Likert response format, with higher scores indicating higher levels of function .Edema will be measured in centimeters using the figure-of-eight method. A measurement tape will be applied across the following landmarks in a figure-of-eight fashion: navicular tuberosity, distal tip of the lateral malleolus, distal tip of the medial malleolus, and base of the fifth metatarsal. The resulting value will be compared with the corresponding value for the healthy ankle .The European Quality of Life Five-Dimension Scale (EQ-5D) is a generic instrument for assessment of health-related quality of life. It is based on a descriptive system that defines health in terms of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three response categories: no, some, or extreme problems. The EQ-5D-5 L, which will be used in this study, is a new version of the EQ-5D that includes five levels of severity in each of the existing five EQ-5D dimensions .Recurrent ankle sprain will be defined as ankle sprain occurring as a result of participation in sports or other daily activities and causing one or more of the following: discontinuation of the sports activity, inability to fully participate in the next planned sports activity, inability to go to work/school the following day, and the requirement of medical attention  .AEs are undesirable and unintentional signs, symptoms, or diseases that appear during or after treatment in a clinical trial. The participants in this study will be required to voluntarily report any AEs. All AEs that occur during the trial will be documented. Adverse events that might occur in this study include skin irritation, urticaria, itching, anorexia, stomach discomfort, diarrhea, nausea, vomiting, pseudoaldosteronism, and hypokalemia. The CRC will record all AEs in detail, including the time and date of occurrence, degree of severity, any measures related to the treatment of the AE, and any potentially causal relationship between the treatment and the AE, and report all AEs to the PI and relevant IRB. In case of serious AEs (SAEs), defined as those causing severe disability or malfunction, appropriate measures will be taken and the incident will be immediately reported to the PI and relevant IRB. In case an AE occurs because of the clinical trial, participants will notify the CRC and PI and will be compensated by the “Clinical Trial Compensation.”This protocol has been reviewed and revised several times by experts on acupuncture, herbal medicine, orthopedics, statistics, and methodology. Before the trial, all researchers will be requested to attend a series of training sessions, which will ensure that the personnel involved fully understand the trial protocol and standard operating procedures (SOPs) that will be employed during the study. The Data Monitoring Committee will be composed of the PI and CRC. The clinical trial will be monitored by a clinical research associate (CRA), who will check all documents related to the clinical trial, including Case Report Forms (CRFs) and SOPs, and ensure that the clinical trial is conducted in accordance with the prescribed protocols and SOPs. Monitoring will be conducted independent of the PI. In the event that the protocol described herein is revised, the revisions will require approval from the Ministry of Food and Drug Safety and the IRB of Semyung University Korean Medicine Hospital in Chungju.Because of the lack of adequate preliminary studies, we adopted a pilot study design with 24 participants in each group, considering the limited research funds, study period, and recruitment opportunities.t test or Wilcoxon’s rank sum test, while categorical data will be presented as frequencies and percentages and compared using the chi-square or Fisher’s exact test. VAS scores for pain and the secondary outcomes  will be evaluated by RM ANCOVA. Dependent variables will include values measured before, at the end of, and at 4 weeks after treatment completion. Changes in the VAS score from baseline to treatment completion (visit 5) and 4 weeks after treatment completion (visit 6) will be determined by the paired t test. A repeated contrast test will be performed to account for time differences in each group. A P value of < 0.05 will be considered statistically significant. We will perform per-protocol analysis for the assessment of efficacy and a supplementary full analysis set. All statistical analyses will be performed using SPSS version 22.0 .Baseline characteristics will be compared between the two groups. Repeated measures analysis of covariance (RM ANCOVA) will be performed to determine differences between groups, considering the different baseline characteristics (covariance). Continuous data will be presented as means and standard deviations and compared using the independent i.e., < 80% compliance with the protocol, incidence of SAEs, reluctance to continue the trial, incomplete data that could influence the trial, large error in protocol or significant deviation in implementation, and decision to terminate trial participation by the PI or IRB) will be excluded. Missing values will be implemented by multiple imputations. In addition, differences between subjects who complete the study and dropouts will be statistically analyzed to determine whether any particular factor is significantly associated with participation dropout. Interim analyses will not be performed.Data for subjects who meet the dropout criteria  will be stored in a cabinet until the end of the study. Written informed consent for the publication of individual details and accompanying images will be obtained from the participants.The design of this study, including the treatment and evaluation schedules, is based on the designs of several acupuncture studies for ankle sprain .There is good evidence to support the usefulness of immobilization and, occasionally, surgical correction for the management of grade III ankle sprain. However, clinical standards for the acute management of grade I and grade II ankle sprain are not well defined . TherefoWe will use VAS scores for pain as the primary outcome measure and FAOS, edema, EQ-5D-5 L scores, and the number of recurrences as secondary outcomes in order to evaluate the efficacy of DS for relieving pain and swelling, aiding the recovery of ankle function, improving quality of life, and decreasing the number of recurrences in patients with ALAS.This study has some limitations. First, there is concern that the short treatment period planned for minimizing the dropout rate could affect the results of this study. Second, because preliminary data for determining the sample size is inadequate, we designed this trial as a single-center pilot study. Third, in previous studies –44, recuNevertheless, the results of this study are expected to provide preliminary evidence regarding the usefulness and acceptability of DS treatment for the treatment of grade I and grade II ankle sprain and serve as a basis for further research.We will report the final data to the Ministry of Health and Welfare through the Korea Health Industry Development Institute. We will also publish the results after study completion.This trial is ongoing. Enrollment and trial procedures are expected to be complete by the end of May 2019.Additional file 1:SPIRIT Checklist. (DOCX 367 kb)


Neisseria meningitidis is rare. We hereby describe the second case of an arthroplasty infected with Neisseria meningitidis that responded favourably to prosthesis retention with surgical debridement, in combination with antibiotics treatment. Primary meningococcal meningitis is an infrequent but known disease. However, the infection of a prosthetic joint with Neisseria meningitidis is a Gram-negative, facultative, aerobic, or anaerobic diplococcus. It was isolated for the first time by Anton Weischselbaum in 1887 in the cerebrospinal fluid of a meningitis patient [ N. meningitidis can cause extremely severe diseases, such as meningitis and life-threatening sepsis, as well as the asymptomatic colonization of the nasopharynx in approximately 10% of the population during endemic periods of infection [ N. meningitidis is a rare but known disease. However, as far as we know, there is only one published case report of an arthroplasty infected with Neisseria meningitidis [nfection . It rarenfection . Primaryngitidis . We hereThe duration and form of administration of antibiotic agents in these infections are based on expert opinions. The traditional recommendation duration of total postdebridement antibiotic treatment of 6 to maximal 12 weeks or the duration of its initial parental part (2–4 weeks) is discussed in favour of an oral antibiotic treatment from the start . N. meningitidis serogroup B ), with an intermediate sensitivity to penicillin (minimum inhibitory concentration (MIC): 0,25 microg/ml by E-test ) and sensitivity to cefotaxime ) and ciprofloxacin  according to the CLSI guidelines [ N. meningitidis was identified by growth on chocolate agar and blood agar, and by utilization of enriched media ). Blood cultures were negatives ). The procedure included arthroscopic debridement with implant retention because of individual patient circumstances and acute onset of symptoms in the setting of a well-fixed prosthesis without a sinus tract and antibiotics and 2 grams ceftriaxone administered intravenously every 24 hours over a 3-week period, followed by oral administration of 750 mg ciprofloxacin every 12 hours over the total 12-week study period. No recurrence has been observed during a two-year follow-up. The Department of Preventive Medicine and Public Health was notified of the case and the recommendations on prophylaxis and treatment of possible carriers were followed, and the patient was vaccinated with meningococcal vaccines following this episode [A 78-year-old Caucasian female patient with dislipemia, stable ischemic cardiopathology, degenerative aortic and mitral valves, and generalized osteoarthritis arrived at the Emergency Department of Hospital Punta de Europa, Algeciras, Spain, a 328-bed general hospital, with a chief complaint of pain in her left knee. The patient had undergone a total left knee arthroplasty 7 months before due to a severe functional limitation secondary to osteoarthritis. Seven days before admission and while experiencing symptoms of pharyngitis, she had an accident at home and suffered a sprain in her left ankle. The patient complained of pain and swelling in the above joint that radiated towards her left knee. Within days of the accident, the patient reported a gradual reduction in the symptoms in her ankle but an increase of pain in her knee. She started complaining of intense pain, functional impairment, redness, and increase of local temperature but without evidence of skin rash. The presence of intra-articular fluid was confirmed in the operated knee. There were no other affected joints or presence of skin lesions. Main analytical data were as follows: leukocytes: 13.6 × 109/L with 80% granulocytes; haemoglobin: 11.8 g/dL; platelets: 486 × 109/L; immunoglobulin levels in serum were normal. An arthrocentesis was performed and it yielded an amber-coloured fluid with 9.9 × 109/L (67% polymorphonuclear), glucose: 97 mg/dL, proteins: 4.2 g/dL, and LDH: 1866 U/L. No crystals were observed. The joint fluid culture was positive forInfection is the most feared complication after an arthroplasty and has proven to be the cause for a notable rate of morbidity and a nonnegligible rate of mortality . There aIn his article, Aslam et al.  include  Staphylococcus aureus, Streptococcus spp., and Gram-negative bacilli, although the proportions vary depending on the series [The most frequently isolated bacteria in prosthetic joint infections are:e series . Neisseria meningitidis. The first one, acute meningococcemia, is a severe condition that occurs within the context of a sepsis, a septic shock, or meningitis. Although rarer, bacteraemia adopts a less aggressive clinical course, such as chronic meningococcemia, indistinguishable from chronic gonococcemia, which is a rare infection characterized by intermittent fever episodes, maculopapular rash, and arthralgia; it can also adopt the form of transient meningococcemia, characterized by fever and unspecified rash over a 2–5-day evolution period where presence of N. meningitidis in the blood usually comes as an unexpected finding [Three clinical syndromes have been described in association to the bloodstream infection with finding . N. meningitidis to infect prosthetic joints shall depend upon the affinity for the osteoarticular tissue, the type of prosthesis employed, and the residual joint tissue. The frequency of arthritis complicating acute meningococcal disease in adults ranges from 4 to 50%. Schaad [Besides, the ability of. Schaad  describeBoth the case described by Vikram et al.  and the  N. meningitidis are capable of producing biofilm. This favours its persistence in the nasopharynx and seems to play an important role in the process of colonization and the carrier status (in this case the pharyngitis seven days before admission was the probable entry site but was not confirmed). Nonetheless, the role of biofilm-forming strains in the different clinical syndromes associated with the meningococcal disease is still to be determined.Biofilm formation plays a crucial role in the ability of germs to colonize nonbiological surfaces. Both encapsulated and nonencapsulated forms of N. meningitidis serogroup Y in an 80-year-old female patient. This patient's prosthesis had been placed 3 years before and, as in the case hereby presented, it did not have any distinctive clinical feature. The management included prosthesis retention and a 6-week course of i.v. ceftriaxone.To our knowledge, this is the second reported case of primary meningococcal arthritis in a prosthetic joint. The previous case, published in 2001, described the infection of a total knee prosthesis by N. meningitidis is very rare and limited to a very reduced number of endocarditis on prosthetic valves [ N. meningitidis is a germ that has low affinity for the joint tissue and, although capable of producing biofilm in order to survive in the surface secretions of the nasopharynx, it has very limited capacity to cause infections in abiotic surfaces, and here lies the exceptional significance of the case hereby presented.In both cases, the most likely route of entry for the germ into the joint was the haematogenous route, although the presence of this germ in blood could never be confirmed. The case presented was probably favoured by a minor local trauma. Besides, the infection of other types of nonarticular prosthetic grafts withc valves , 15. The


It has been shown that inflammation and oxidative stress are important factors in postoperative atrial fibrillation (POAF). Angiotensin converting enzyme (ACE) and apelin have a close relationship with inflammation and oxidative stress. The effect of ACE and apelin on POAF after off-pump coronary artery bypass grafting (OPCABG) remains a question. The concentrations of serum ACE, angiotensin II (Ang II), apelin, bradykinin (BK), malondialdehyde (MDA), and C reactive protein (CRP) were measured in the perioperative period of OPCABG. The levels of serum ACE in the POAF group were higher than in the no POAF group both preoperatively and postoperatively. Apelin in the POAF group was lower than in the no POAF group. There was a correlation between serum ACE and apelin. Postoperatively, CRP and MDA in the POAF group were higher than in the no POAF group; however, there was no difference before the operation. Preoperative ACE and apelin were both significant and independent risk factors for POAF. In conclusion, the high ACE and low apelin preoperatively led to CRP and MDA being increased postoperatively, which was probably associated with POAF after OPCABG. Apelin may be a new predictor for POAF. Postoperative atrial fibrillation (POAF) is a common postoperative complication following coronary artery bypass grafting (CABG), which occurs in approximately 13% to 40% of patients . POAF, aNCT02807532).A retrospective case-controlled clinical trial was carried out. This clinical trial has been registered at ClinicalTrials.gov , serious heart failure (EF < 0.30), refusal to cooperate with specimen collection and laboratory examination, ongoing participation in other clinical trials, and being unable to provide informed consent due to mental disorders or language barriers.The concentrations of serum ACE, Ang II, apelin, BK, and MDA were measured using an enzyme linked immune sorbent assay (ELISA) and CRP was measured using immunoturbidimetry in the peripheral blood from 508 consecutive patients with a sinus rhythm in the perioperative period of OPCABG. Preoperative peripheral blood was obtained at 06:00-07:00 the morning after admission before the operation. Postoperative peripheral blood was obtained at 06:00-07:00 the morning after the operation. Both carried were out on an empty stomach.The patient's ECG in the intensive care unit (ICU) was continuously monitored for 48 hours after the operation. A standard 12-lead ECG was then recorded once per day after the patient returned to the general ward; ECGs were continuously monitored after any sign of clinical deterioration  until the POAF was converted. The above were measured for 7 days after the operation . POAF was defined as a classical AF waveform lasting more than 1 minute.t-test. Categorical variables were reported as frequency and percentage. Comparisons between groups were analyzed with a chi-squared test, correction chi-squared test, or Fisher's exact test. The continuous variables with an abnormal distribution were analyzed using the Mann–Whitney U test. Comparisons of data before and after the operation were evaluated using a paired t-test. The correlation between the 2 data sets was analyzed with bivariate correlation analysis. Independent risk factor analysis was used for univariate and multivariate logistic regression analysis. The factors where P < 0.1 were included in a multivariate logistic regression analysis as more factors were considered. P < 0.05 was considered significant in all comparisons.All statistical calculations were carried out using SPSS 18.0 software . Continuous variables were reported as the mean ± standard deviation. Continuous variables with a normal distribution were analyzed with an independent P = 0.036), smoking (P = 0.044), left atrial diameters , left ventricle end-diastolic volume , and statins (P = 0.002).A total of 508 cases of OPCABG patients were included in this study. The incidence rate of POAF was 21.26% (108/508). The clinical characteristics of the patient groups in the POAF group and no POAF group are listed in P = 0.001 and P = 0.033, resp.). The levels of serum apelin in the POAF group were lower than the no POAF group both preoperatively and postoperatively . The levels of serum Ang II and BK showed no difference between the groups both preoperatively and postoperatively. The levels of CRP and serum MDA in the POAF group were higher than the no POAF group postoperatively , but it showed no difference between the groups preoperatively. All the above results are listed in P < 0.001) and postoperatively  and postoperatively , pre-apelin, smoking, LDL, statins, EF, LAD, and LVEDV were significant and independent risk factors for POAF preoperatively  which was the boundary value. The logistic regression analysis was subsequently carried out.P < 0.001; Data comparisons between preoperative and postoperative levels showed that the levels of serum ACE, Ang II, apelin, and BK were not statistically significantly different in the entire sample, the POAF group, and the no POAF group. The levels of CRP and serum MDA postoperatively were higher than preoperatively  is a hormone system that is involved in the regulation of the plasma sodium concentration and arterial blood pressure. It is an important control system in the human body. Several studies have shown that ACE and Ang II, as the major characters of RAAS, participate in the pathological process of POAF , 17–19. Apelin is an endogenous ligand of the G-protein coupled receptor APJ, and it exhibits homology to angiotensin II. The signaling system stimulated by apelin regulates many physiological functions and pathological processes . It is kThe relationships between POAF, ACE, Ang II, BK, and apelin are unknown. The aim of this study was to investigate this question. We measured the level of ACE, Ang II, apelin, BK, CRP, and MDA preoperatively and postoperatively in the POAF group and no POAF group. The conclusions were as follows.First, the levels of serum ACE and apelin were significantly different between the POAF group and no POAF group both preoperatively and postoperatively, but the levels of serum Ang II and BK showed no difference. These data suggest that the predominant downstream effectors of ACE, Ang II, and BK may have little influence on the pathological processes of OPCABG-POAF. Perhaps this is the reason for ACEI not having a significant preventive effect on POAF. The OPCABG operation may not affect Ang II. Raised Ang II after persistent and permanent AF may be caused by myocardial fibrosis.Second, there was a correlation between serum ACE and apelin preoperative and postoperative levels. At the same time, ACE and apelin were both significant and independent risk factors for POAF preoperatively. The results showed that ACE and apelin/APJ perhaps not only play important roles in OPCABG-POAF but also work together. It is known that ACE and ACE2 have a negative correlation in the human body. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardiovascular protective peptide . The incThird, we found that the influence of the operation on the level of ACE, Ang II, apelin, and BK was not obvious. The difference between preoperation and post-AF levels that has been shown in many studies may be due to POAF itself and may have nothing to do with OPCABG surgery. The higher level of ACE and the lower level of apelin preoperatively were the risk factors for POAF and were not changed after the operation. CRP and MDA are classical detection indices for inflammation and oxidative stress , 23, 24.In conclusion, we observed the changes and differences in levels of ACE, apelin, inflammation, and oxidative stress may be the biological reasons for POAF from this study. Higher serum ACE levels were perhaps a risk factor for POAF and higher serum apelin levels were perhaps a protection factor. Apelin may be a new predictor for POAF. The potential value of this information should be further evaluated in larger, prospective, multicenter studies.


In addition to being an established complicating factor for myocardial infarction (MI), recent studies have revealed that atrial fibrillation (AF) increased risk of MI. This study is to evaluate the risk of MI associated with AF in a nationwide population based cohort. We examine the association between AF and incident MI in 497,366 adults from the Korean National Health Insurance Service database, who were free of AF and MI at baseline. AF group  was compared with propensity matched no-AF group . Over 4.2 years of follow up, 137 MI events occurred. AF was associated with 3-fold increased risk of MI  in both men  and women . The risk of AF-associated MI was higher in patients free of hypertension, diabetes, ischemic stroke, and dyslipidemia at baseline. The cumulative incidence of AF-associated MI was lower in patients on anticoagulant and statin therapies. Our finding suggests that AF complications beyond stoke should extend to total mortality to include MI. Patients with AF have 5 times the risk of stroke and double the risk of mortality compared with those without AF4. AF has known to complicate acute myocardial infarction (MI)5. In addition to being an established complicating factor for MI, recent studies have revealed that AF increased the risk of MI7. In the Atherosclerosis Risk in Communities (ARIC) study, AF was associated with an increased risk of non-ST segment elevation MI (NSTEMI)6. In a recent study performed by Soliman et al.7, AF was associated with a 70% increased risk of incident MI. However, these results are yet to be validated in a nationwide population based cohort and the mechanisms explaining these associations are not fully understood.The significance of atrial fibrillation (AF) as a major public health problem comes from its increasing prevalence and strong association with morbidity and mortalityThus, we examined the association between AF and MI by analyzing a recently developed Korean National Health Insurance Service–national sample cohort (NHIS-NSC) database, which includes over five hundred thousand individuals. In addition, the beneficial effects of the commonly prescribed medications for AF patients on the occurrence of MI have not been elucidated. Herein, we also analyzed the association of medications with incident MI in AF patients.8. As all individuals in South Korea are enrolled in the NHIS, this database represents the entire Korean population9. This is a semi-dynamic cohort database; the cohort has been followed up to either the time of the participant’s disqualification of health services due to death or emigration or the end of the study period. The database contains eligibility and demographic information regarding health insurance and medical aid beneficiaries, medical bill details, diagnostic codes, medical treatment, disease histories, prescription drug used, and personal information for inpatients and outpatient visits.The national health insurance service (NHIS) in Korea is a single-payer program and is mandatory for all residents in South Korea. This retrospective study used the NHIS-NSC 2002–2013 dataset, comprising a random sample of 1,025,340 subjects, which amounted to 2.2% of the entire Korean population in the NHIS in 2002 . Data were produced by the NHIS using a systematic sampling method for the purpose of research. Random sampling was used based on 1,476 stratath revision of the International Classification of Diseases (ICD-10) codes obtained from the Korean National Statistical Office  were reviewed by two physicians. Patients were determined to have AF if documented by ECG. The positive predictive value was 94.1%. The clinical end point was the first occurrence of MI during follow up. MI cases were identified by ICD-10 codes of I21or I22, and were ascertained when the diagnosis was confirmed by hospitalization or death from MI. To evaluate the accuracy of our definition of MI, we conducted a validation study with medical records of two independent tertiary hospitals from 2006–2013. A total of 4,688 patients were found to have ICD codes of I21 or I22. Data of clinical history, cardiac biomarkers, ECGs and the results of coronary angiography were reviewed by two cardiologists. The positive predictive value was 86.5%.A total of 506,805 patients, who had a health check-up between 2009 and 2013, were enrolled and follow-up data were reviewed until December 2013. AF cases were identified by ICD-10 codes (ICD-10: I48)Medical records of all patients were reviewed from 2002 till 2013 in order to clarify the newly diagnosed AF and MI during the study period. The laboratory and survey questionnaire data of general and life-transition health examinations for all cohort members were merged.11. We attempted to match each patient in the AF cohort with a patient in the control cohort with a similar propensity score, based on nearest-neighbor matching without replacement, using a caliper width equal to 0.05 of the standard deviation of the logit of the propensity score. Pre- and post-match absolute standardized differences were presented as Love Plots12.Of the 8,296 patients with AF, patients who had AF or MI before 2009  and who suffered an MI before AF (n = 25) were excluded. Finally 3,295 patients were enrolled in the AF group. Among those without AF , 494,071 patients were enrolled in the no-AF group after excluding the patients who suffered an MI before 2009 . Given the differences in the baseline characteristics and the risk of cardiovascular diseases between the AF and control groups, we used 1:4 propensity score matching and calculated the propensity score, with predicted probability of AF occurrence conditional on baseline covariates, by multivariable logistic regression  or end-stage renal disease (ESRD), dyslipidemia, ischemic stroke, peripheral artery occlusive disease (PAOD), chronic obstructive pulmonary disease (COPD), history of malignancy, anemia, smoking history, blood pressure, body mass index, waist circumference, body surface area, cholesterol level, serum creatinine, and estimated –glomerular filtration rate (eGFR). Covariates included in propensity matching were the data from baseline examination at the time of health check-up, and the definitions of comorbidities were based on ICD codes. The matching procedure was performed using R packages , including Matchit, RItools, and CEMData were presented as mean ± SD for normally distributed continuous variables and as proportions for categorical variables. Age-adjusted incidence rate of MI per 1000 person-years in patients with and without AF was calculated in the propensity matched population and in the sex subgroup. Person-time for the incidence rate in the AF group was calculated from AF diagnosis to the occurrence of MI or censoring. In the no-AF group, person-time was calculated from baseline to MI occurrence or censoring. Cumulative incidence of MI was plotted using a Kaplan-Meier method, with statistical significance examined using log-rank test by AF status. The risk of MI was assessed using Cox regression analysis. Statistical analysis was performed using SPSS 21.0 statistical software . All p-values were two tailed, and values less than 0.05 were considered statistically significant.2DS2-VASc score was 2.6 ± 1.9 in the AF group and 1.2 ± 1.3 in the no-AF group (P < 0.001). Covariates with significant imbalances in the pre-matched cohort which were well balanced after propensity matching are displayed in Table The mean age of matched patients was 63 years  and 58% of the patients were male. Table Aspirin, anticoagulants, statin, digoxin, beta blocking agent (BB), and calcium channel blocker (CCB) were more frequently prescribed in the AF group than in the no-AF group; aspirin , anticoagulant , statin , digoxin , BB , and CCB .Over 4.2 years of follow up, 137 incident MI events occurred. Figure The age-adjusted incidence rate of MI among participants was higher in those with AF than in those without AF (4.42 vs 1.42 per 1000 person-years), with an incidence rate ratio (IRR) of 3.12 . In a sex stratified analysis, the higher age-adjusted MI IRRs by AF status was observed in women  compared with men  , 3.12; 95% CI, 2.23–4.37, p < 0.001] was an independent risk factor for MI. Other risk factors were hypertension , diabetes , HF , CKD or ESRD  and dyslipidemia   AF was significantly associated with increased risk of incident MI. (2) Association between AF and the risk of MI did not differ by sex. (3) The risk of AF associated incident MI was higher in patients free of hypertension, diabetes, ischemic stroke, and dyslipidemia. (4) The incidence of AF associated incident MI was lower in patients on anticoagulant and statin therapies.15.In this study, AF was associated with 3-fold increased risk of MI, even after the risk factors and potential confounders for MI were included in the matching. These findings were in accordance with the recently reported several studies which showed AF as an independent risk factor for MI15, it were not observed in this study. Previously, it was reported that women were less likely to receive warfarin than men17 and this may be the possible explanation for gender difference of MI14. However, in our study, use of anticoagulant did not differ between sex and this, in part, may contribute to the similar risk of MI between men and women.Contrary to recent studies which showed gender difference in the association between AF and MI19. In contrast, recent studies showed that patients with AF without cardiovascular co-morbidities had an increased risk of cardiovascular events and mortality20. These interactions suggest that shared underlying risk factors are not the only mechanisms explaining the association between AF and MI. There are plausible explanations for why AF patients with less co-morbidity were predisposed to MI. In patients with established risk factors for MI, AF may contribute less to the occurrence to MI, compared with those who were previously healthy. In our study, anticoagulants showed beneficial effect against AF associated incident MI. Accordingly, embolic events to coronary arteries are another possible explanation. Statin use, and also, is higher in patients with cardiovascular diseases, which may decrease the incident MI. Further study is needed in this regard.Notably, we confirmed that the risk of MI was significantly higher in patients with AF free of overt cardiovascular disease than in subjects without AF. Previous study from Olmsted County revealed that lone AF had a comparable risk of embolic events and mortality to the general population21. Prevention of thrombus formation with anticoagulation, in part, might be an explanation. In our study, the anticoagulants analyzed were direct thrombin inhibitor, factor Xa inhibitors, as well as warfarin, and whether the new oral anticoagulants could have a role in preventing MI in the setting of AF needs to be further investigated.In this analysis stratified by medications after AF diagnosis, the risk of incident MI was less in anticoagulant users. Previously, it was reported that warfarin might have a protective effect against MI23. In accordance with these studies, this study revealed that the risk of AF associated incident MI was less in statin users than in non-users. In a study, association between AF and inflammation has been reported24. The role of inflammation in MI has already been established25. Anti-inflammatory and anti-thrombotic activities of statin may reduce the risk of AF associated incident MI.Clinical trials have already demonstrated a clear beneficial effect of statin for prevention of ischemic heart disease26. The rate control strategy in AF patients is expected to reduce the occurrence of type 2 MI, by reducing the oxygen demand and by increasing the diastolic filling time of coronary arteries. However, the result of this study was not in accordance with this common belief, suggesting that type 2 MI is less likely to be the main mechanism by which AF leads to MI.Type 2 MI can occur due to poorly controlled ventricular response in AF patients27, this result suggests a bidirectional relationship between AF and MI. However, the pathophysiology of AF associated incident MI is complex and incompletely understood. Further research to determine the underlying mechanism with the association of AF and MI is warranted. The prevalence of AF doubles with each additional decade of life28. With an increasing older population, the occurrence of AF itself and AF-associated morbidity and mortality is expected to increase as well. From a preventive perspective, the notion should suggest that AF potentiates the risk of MI.Considering MI as a known risk factor for AF26. We could not analyze the association of AF with different types of MI. Third, even though the NHIS recommends biennial health check-up to all health insurance subscribers, it is not compulsory and there is a possibility that healthier and more educated subjects could have participated in this study. Fourth, potentially uncontrolled covariates may exist because comorbidities included in propensity matching are the data from baseline examination. They may be absent at baseline, but may have developed during the follow-up. Fifth, similar to other studies, considerable confounders may remain although propensity-score matching was well balanced. Despite the limitations, this study is the nation-wide population based observational studies providing the further evidence for a link between AF and MI, and the effects of medications on the occurrence of AF related incident MI.There are several limitations to this study. Although we ascertained AF cases with ECGs as well as ICD codes, it is possible that paroxysmal or asymptomatic AF cases were not detected. Also, we could not analyze paroxysmal, persistent and permanent AF separately. Second, because MI cases were identified by ICD-10 code, data for cardiac markers, ECGs, and coronary angiography were not available, which could have provided further information about the type of MIAF is associated with an increased risk of MI in the nationwide cohort study of Korean population. The association between AF and MI did not differ by sex and higher in patients free of cardiovascular diseases at baseline. Anticoagulants and statin showed beneficial effects against MI in AF patients. Our finding suggests that AF complications beyond stroke should extend to total mortality to include MI.Supplementary information


We performed a multiple logistic regression analysis to identify the factors associated with HT, DM, or DL. Older age and a higher body mass index were significant factors associated with HT. Older age, female sex, a higher body mass index, advanced liver fibrosis, and the NASH type of FLD  were significant factors associated with DM. Finally, the NASH type of FLD  was the only significant factor associated with DL. Thus, the associations of NASH with DM and DL were stronger than those of ASH with DM and DL. In the management of FLD subjects, controlling DM and DL is particularly important for NASH subjects.Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are representative types of fatty liver disease (FLD) and have similar histologic features. In this study, we aimed to compare the associations of the two FLD types with hypertension (HT), diabetes mellitus (DM), and dyslipidemia (DL). A nationwide survey investigating FLD status included 753 Japanese subjects  with biopsy-proven ASH ( Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are two major types of fatty liver disease (FLD) . Many stIn a previous study based on a nationwide survey of FLD status, we reported some differences in the associations of AFL and NAFL with HT, DM, and DL: the association of AFL with HT was stronger than that of NAFL with HT and the association of NAFL with DL was stronger than that of AFL with DL . Based oFor the second nationwide survey, we send a questionnaire to 101 hospitals where gastroenterologists affiliated with the Japanese Society of Gastroenterology worked and had participated in the first nationwide survey. Using the answers to the questionnaire, we collected data on subjects with biopsy-proven ASH or NASH (including progressive fibrosis and cirrhosis) who visited the hospitals between 2009 and 2011. The questionnaire collected information on patients' age; sex; body mass index (BMI); laboratory test values; drinking history; the presence or absence of HT, DM, and DL; and histopathological findings of the liver. All the patients gave informed consent at the time of liver biopsy. This study was conducted in accordance with the guidelines of the Declaration of Helsinki.The gastroenterologists who answered the questionnaire diagnosed ALD based on the criteria defined by the Alcohol and Liver Research Group of the Ministry of Education   and diagThe criteria for HT defined by the Japanese Society of Hypertension guidelines for the management of hypertension include a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg . The criU test and the chi-square test were used for continuous variables and categorical variables, respectively. We performed a multiple logistic regression analysis to identify the factors associated with HT, DM, or DL. The potential factors were age (per year), sex, BMI (<25 kg/m2 versus 25 to 30 kg/m2 or >30 kg/m2), liver fibrosis stage (F1/F2 versus F3/F4), and FLD type. Following a univariate analysis, we conducted a multivariate analysis using all the above potential factors. A P value of <0.05 was considered statistically significant. We performed all analyses using the STATA version 13.1 software program .Continuous variables were expressed as medians . The Mann–Whitney Sixty-five (64.4%) of the 101 hospitals answered the questionnaire, providing data for 760 FLD subjects (172 ASH and 588 NASH). We excluded 7 NASH subjects because of missing data related to the presence or absence of HT, DM, and DL. Consequently, we enrolled 753 subjects . 2, advanced liver fibrosis, and the NASH type of FLD were significantly associated with DM. The multivariate analysis identified the same factors as the univariate analysis , we found that the association of AFL with HT was stronger than that of NAFL with HT and the association of NAFL with DL was stronger than that of AFL with DL . Our twoWe believe that the findings of this study are applicable in clinical practice. Our results were obtained from analyses of clinical and histologic data, whereas there are clinical data-derived indices for the histologic stage of FLD. For example, the aspartate aminotransferase/platelet ratio index (APRI) , the fibOur results may be linked to some differences in outcomes between ALD and NAFLD subjects. Few studies have directly compared the outcomes of ALD and NAFLD subjects. A recent cohort study, however, found that survival rates for ALD subjects were relatively low compared with those for NAFLD subjects . Most stThe present study of ASH and NASH subjects identified the factors associated with HT, DM, and DL. Older age and a higher BMI were associated with HT, consistent with the results of previous studies , 29. In 2 were associated with DM, results consistent with those of systematic analyses [2. The present study, which included subjects with biopsy-proven ASH or NASH, found that advanced liver fibrosis was another factor associated with DM. This result agrees with those from studies examining the association of advanced liver fibrosis with DM [Older age and a BMI of >30 kg/m with DM , 32. Fur with DM . Accumul with DM . A possi with DM , 36. UnfOur current and previous studies on the status of FLD revealed that NAFLD, irrespective of its histologic stage, is more strongly associated with DL than ALD is. A recent review investigating risk factors for CVD in subjects with chronic liver disease with various etiologies showed the following serum lipid profiles for ALD and NAFLD: among most ALD patients, serum LDL cholesterol levels, HDL cholesterol levels, and triglyceride levels are unaltered, increased, and increased, respectively, and among most NAFLD patients, serum LDL cholesterol levels, HDL cholesterol levels, and triglyceride levels are increased, decreased, and increased, respectively . HoweverThe present study has some limitations. First, this was a cross-sectional study; the design of which cannot prove the causality of the associations. Second, the present study used only Japanese subjects, which may hamper the generalizability of the findings. Third, patient selection bias might have affected the results because each gastroenterologist made the decision regarding the need for a liver biopsy in clinical practice. Fourth, no data on smoking were included in this study, which might have influenced our results. Many studies have examined the causal relationship between smoking and HT, DM, or DL, and some have demonstrated a positive relationship between smoking and DM . It is pIn conclusion, the present study suggests that the associations of NASH with DM and DL are stronger than those of ASH with DM and DL. These findings imply that NASH patients have more CVD risk factors than ASH subjects do. To improve the outcomes of FLD patients, it is pivotal to control both the risk factors and FLD per se. Our results indicate that NASH patients in particular require such control to prevent CVD.


The incidence of prostate cancer among Taean County residents has increased since the HSOS.The Hebei Spirit oil spill (HSOS) occurred in the Republic of Korea on 7 December 2007. We aimed to describe the cancer incidence trend in Taean County before and after the oil spill. Five major cancers and leukemia were analyzed. Cancer incidence data were obtained from the Korean National Cancer Center. We compared the standardized incidence rates in Taean with those observed nationwide and selected three coastal areas. Joinpoint regression analysis was used to examine the trends in the average annual percent change and perform comparisons. The incidence rate of prostate cancer increased from 2007 to 2009 at an annual average of 39.3% : −25.9, 161.8), 13.5% , and 15.6% , respectively, in Taean, nationwide, and in the coastal areas. The incidence of leukemia among women increased at an annual average of 9.5%  in Taean and 0.6%  nationwide; the rate decreased by 1.9%  in the coastal areas. The trends between Taean County and the coastal areas differed only for prostate cancer ( The Hebei Spirit oil spill (HSOS) occurred in the western coastal area of the Korean peninsula on 7 December 2007 , and wasa]pyrene, as group 1 human carcinogens, and benz[a]anthracene, dibenzanthracene, chrysene, naphthalene, bezo[b]fluoranthene, bezo[k]fluoranthene, and indenopyrene as group 2 human carcinogens [The spilled oil contained volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), and heavy metals . Crude ocinogens ,5.The HSOS continues to affect Taean County residents and clean-up workers, with the effects manifesting as various adverse health events across Korea, including acute-stage physical ,6,7,8,9 While oil spills have occurred across the world, studies on the associated mid- and long-term health effects have been reported only in three countries: Spain (Prestige oil spill), the USA  were selected for analysis. The five major cancers for Korean men are those of the stomach (C16), lung (C33−C34), colon (C18−C20), liver (C22), and prostate (C61); and those for Korean women are thyroid (C73), breast (C50), colon (C18−C20), stomach (C16), and lung (C33−C34) cancers . Data onThe age-standardized incidence rate (SIR) was calculated using the mid-year Korean registration population in 2000 as the standard population. This method uses the same formula for the regional cancer incidence rate as that used in the Korean Statistical Information Service (KOSIS) . Data onTo compare the SIRs between Taean or the HSOS-exposure areas in Taean and Korea as a whole or the coastal areas, the five- or six-year incidence rates and incidence rate ratios (IRRs) were calculated for 1999−2003, 2004−2008, and 2009−2014. To obtain the 95% confidence interval (CI), the standard error (SE) for the five-year or six-year incidence rate was calculated using a formula proposed by Boyle and Parkin . AdditioTo examine the cancer incidence trend in the areas, joinpoint regression analysis was performed. A model selection and average annual percent change (AAPC) comparison test were performed using the Monte Carlo permutation method  through This study was approved by the Institutional Review Board of Dankook University Hospital, Cheonan, Korea . According to the Privacy Protect Act in Korea, informed consent is not required for the use of anonymized national statistics datasets.p = 0.0004) but not in all cancers, excluding thyroid cancer and leukemia among women.In this study, we found that the incidence rate of prostate cancer has increased in Taean since 2007 and is higher than that observed in other coastal areas, in 2009−2014. Furthermore, the incidence rates were higher in the high-exposure areas than in the low-exposure areas. Additionally, the APC of the incidence rates in Taean was higher than that observed nationwide and in the coastal areas . However, as cancer can develop as late as 10 years after exposure, it may be difficult to conclude that the cancer developed because of exposure to the oil spill. In Taean, a coal-fired power plant has been in existence since 1995 ; it is lIn Korea, the prostate cancer incidence rate has increased since 1999 when the cancer database was set up . AccordiIn Taean, especially in the high-exposure areas, residents have a low SES  and the We found that the incidence of leukemia among female Taean residents had increased and was higher than in the other coastal areas and nationwide, in 2009−2014. The incidence rates were higher in the high-exposure areas than the low-exposure areas. However, the IRR was not significantly high because leukemia is not a common disease and also due to the fact that Taean has a small population. Conversely, in men, the leukemia incidence rate decreased in Taean and was lower in the high-exposure areas than the low-exposure areas in 2009−2014. Additionally, the incidence rate  was higher among women (7.3) than men (4.7) in 2009–2014 in Taean, but was higher among men than women in the coastal areas, at 5.8, 4.1, 4.9, and 3.9, among Korean men, Korean women, men in coastal areas, and women in coastal areas, respectively . In thisIn this study, we selected comparison areas that are similar to Taean in terms of their characteristics, such as the predominance of the farming, fishing, and tourism industries ,55, and In this study, when we compared the cancer incidence rate, excluding that of thyroid cancer, between Taean and Korea as a whole, we found that the incidence rate tended to increase in Taean during all the periods, but not nationwide, since 2011. We excluded thyroid cancer from the analysis because of the potential detection bias associated with thyroid cancer in Korea. Enhanced accessibility to low-cost diagnostic procedures is reported to have increased the incidence of thyroid cancers with carcinomas smaller than 1 cm in size in Korea .We could not investigate the obvious association between oil exposure and cancer incidence in this study. Although we could not identify the reason for the rapid increase in the incidence rate, we found that the incidence rate of prostate cancer was higher among Taean residents than those living in the other coastal areas; the incidence rates were higher in the high-exposure areas, especially after the HSOS. Additionally, we could not prove the aforementioned association because ours is an ecological study. However, our study participants were all Taean residents, and the reliability and validity of our data are high as we used national data. We did not adjust for confounding factors, such as smoking habit, alcohol consumption, exercise status, SES, health status, and family history, or consider exposure factors, such as the duration of clean-up work and frequency of visits to the oil spill site except for the exposure in the living area. Our study period was not long enough for the cancer incidence after exposure to be analyzed. Therefore, studies with a longer follow-up period are needed. Advanced analyses such as age-period-cohort analyses may provide additional clues pertaining to oil spill exposure and cancer development. Despite these limitations, however, this is the first long-term follow-up study to examine the cancer incidence trend according to oil spill exposure using a national cancer registry of all residents exposed to the oil spill. The incidence rate of prostate cancer and burden of the disease have been increasing in Korea  and worlAfter the HSOS, an increased incidence rate of cancer was observed among Taean residents, particularly in terms of prostate cancer. Studies with a longer follow-up are needed to accurately identify the association between cancer incidence and oil spill in residents.


Traditional neuropsychological measurement of cognitive processing speed with tasks such as the Symbol Search and Coding subsets of the WAIS-IV, consistently show decline with advancing age. This is potentially problematic with populations where deficits in motor performance are expected, i.e., in aging or stroke populations. Thus, the aim of the current study was to explore the contribution of hand motor speed to traditional paper-and-pencil measures of processing speed and to a simple computer-customized non-motor perception decision task, the Inspection Time (IT) task. Participants were 67 young university students aged between 18 and 29 , and 40 older adults aged between 40 and 81  primarily with a similar education profile. As expected, results indicated that age group differences were highly significant on the motor dexterity, Symbol Search and Coding tasks. However, no significant differences or correlations were seen between age groups and the simple visual perception IT task. Furthermore, controlling for motor dexterity did not remove significant age-group differences on the paper-and-pencil measures. This demonstrates that although much of past research into cognitive decline with age is confounded by use of motor reaction times as the operational measure, significant age differences in cognitive processing also exist on more complex tasks. The implications of the results are crucial in the realm of aging research, and caution against the use of traditional WAIS tasks with a clinical population where motor speed may be compromised, as in stroke. Cognitive processing speed when defined as the ability to process information rapidly, is closely related to the ability to perform higher-order cognitive tasks  are confounded by motor speed in young and older adults. It was hypothesized that younger adults would outperform older adults on the Symbol Search and Coding tasks but not the IT task, and not when controlling for motor dexterity. It was also hypothesized that the Symbol Search and Coding tasks would be significantly correlated with motor dexterity .M age = 19.6, age range: 18–29), and 40 healthy older adults . The young adult group predominantly consisted of first year Psychology students, who received course credit, while the older adult group were predominantly recruited through personal networks or recruited through the University of the Third Age (U3A), and received a $20 Coles-Myer voucher. Exclusion criteria included previous diagnosis of a neurological disorder and the inability to understand and speak English with basic competence. A demographic questionnaire elicited information on age, lifestyle status, and education level. A measure of general negative affect: The Depression Anxiety and Stress Scale  with a pencil. Performance was measured as the number of symbols accurately identified in 2 min. In healthy adults, raw scores on Symbol Search have been shown to decline by more than 50% between the ages of 25 and 65  the appropriate symbol in a box underneath a digit (one-to-nine), using a key at the top of the page containing digits and their corresponding symbols. Performance is based on the number of pairs correctly copied in 2 min.www.Vpixx.com). Stimuli were presented on an Apple eMac Computer running at 89 Hz screen refresh rate. Across the trials, a fixation cross was presented for a random duration between 700 and 1,000 ms, followed by a blank screen for 50 ms, then the target stimulus was presented at variable exposure times beginning at 1 s, immediately followed by a mask, presented for 500 ms. These exposure times were not altered between the various age groups. Target stimulus was either a fish, truck, or butterfly  aimed at exploring performance on dependent measures between age-groups while controlling for motor dexterity. An independent samples t-test on IT performance between age-groups was also conducted to explore performance between young and older adults on all dependent measures. To explore the relationship between the Symbol Search and Coding with motor dexterity, correlation analyses were conducted between Pegboard scores and Symbol Search and Coding tasks. A second analysis was then conducted after splitting participants into three age groups, namely, young adults aged 18–29 (N = 67), middle-aged adults aged 40–59 (N = 9), and older adults aged 61–81 (N = 31). Though we acknowledge that the small numbers in the middle-aged group is a limitation to an ANOVA, analyses were conducted to determine whether any absence of significance using two age groups was due to the nine participants in the intermediate age-group .An independent samples Given the various levels of education within the sample, an ANOVA was conducted to determine whether performance on dependent measures  were significantly different between participants “highest level of completed education” within young and older adults. See Table t-test was conducted to determine whether there were differences in performance on any dependent measures within each age group across genders.Given the uneven spread of genders within our sample , an independent samples M difference = 11.66, t(38) = 2.478 p = 0.018. See Table Results revealed no significant differences on any dependent measure between genders in the younger group. However, results demonstrated significant difference for Coding performance between genders for the older adults showing that males outperformed females, Table Sample size, means, standard deviations and range for each of the variables by age-group are shown in Table Correlational analyses were performed to investigate the strength, direction and significance of associations between age and dependent measures of motor dexterity and processing speed. Results revealed significant moderate to strong positive correlations with increasing age and scores on all three conditions of the Pegboard, indicating age-related motor dexterity decline. Significant strong negative correlations were also demonstrated between increasing age and scores on the Symbol Search and Coding tasks, indicating a slower processing speed as age increases. A significant weak correlation was also exhibited between increasing age and higher scores on the IT, indicating that a longer stimulus exposure duration was required to identify a visual stimulus as age increased.Correlational analyses were performed to investigate the strength, direction and significance of associations between the Pegboard and measures of processing speed, namely, Symbol Search, Coding, and IT. Results demonstrated significant positive correlations between each condition of the Pegboard and both paper-and pencil measures of Processing speed, i.e., the Symbol Search and Coding. This indicated that better motor dexterity was associated with a faster processing speed, as measured by the Symbol Search and Coding. Contrary to this, there was no significant relationship between any condition of the Pegboard and performance scores on the IT, indicating that motor dexterity is unlikely to impede or improve performance on the IT. A full correlation table of all measures is shown in Table t-test was conducted to compare performance on dependent measures between younger and older adults. Significant age-group differences were found for mean scores on all paper-and-pencil measures, namely, Symbol Search and Coding, as well as on all Pegboard tasks. However, significant age group differences were not demonstrated for performance on psychophysical measure of processing speed, i.e., the IT task.An Independent-samples t-tests are shown in Table The results of the independent-samples F = 27.751, p < 0.01, partial η2 = 0.211 and on Coding scores F = 52.464, p < 0.01, partial η2 = 0.335, and thus, there were still significant differences on paper-and-pencil task scores  between young and older adults, even when controlling for motor dexterity.An ANCOVA was conducted to explore the relationship between age and outcome on processing speed measures  while controlling for motor dexterity of the dominant hand, given that participants used their dominant hand to complete the paper-and-pencil tasks used in the current study. Despite controlling for motor dexterity, age still had a large significant effect on Symbol Search scores r = −0.466) and age and Coding scores (r = −0.573). However, controlling for motor dexterity had little impact on the strength of the relationship between age and IT scores (r = 0.190). See Table An inspection of zero order correlation revealed that controlling for motor dexterity influenced the strength of the relationship between age and Symbol Search scores ( r = −0.53. HoweveN = 67), middle-aged adults aged 40–59 (N = 9), and older adults aged 61–81 (N = 31). An ANOVA was conducted to assess mean differences in performance on dependent measures by age-group. Results demonstrated significant age-group differences for mean scores on all paper-and-pencil measures , as well as on all conditions of the Pegboard task. However, significant age-group differences were not demonstrated for performance on the IT task. These results coincide with results found with the sample divided into two age groups . Results of the ANOVA are shown in Table To ensure that the nine participants aged between 40 and 59 did not bias results when using only two age groups, analyses were run using three age groups. Specifically, the sample was divided into young adults aged 18–29  = 2.485 p = 0.019. See Table Results revealed no significant differences on any dependent measure between genders in the younger group, as well as in the middle-aged group. However, results again demonstrated significant differences in Coding performance between genders for the older adults with males outperforming females, 12.46, t2 = 2.485 F = 13.748, p < 0.01, partial η2 = 0.344 and on Coding scores F = 26.009, p < 0.01, partial η2 = 0.459, and thus, there were still significant differences on paper-and-pencil task scores  between young, middle-aged, and older adults, even when controlling for motor dexterity. Results of the ANCOVA are presented in Table An ANCOVA was conducted to explore the relationship between age and outcome on processing speed measures  while controlling for motor dexterity of the dominant hand. Despite controlling for motor dexterity, age still had a large significant effect on Symbol Search scores F1, 6 = 13.74The most important findings of this study are that although motor reaction times were correlated with age, decline in cognitive processing speed across the lifespan is not fully/completely explained by motor performance. This is the case whether using traditional paper-and-pencil measures from the WAIS-IV; or IT, a non-motor measure of visual perceptual processing speed.As expected, significant age group differences were demonstrated on the Symbol Search and Coding tasks but not on the Inspection Time task. Declines in performance on the Symbol Search and Coding demonstrated in the current study are in line with the body of evidence referenced earlier that indicates processing speed declines with age , La Trobe University.SC initiated the project, designed the outline and content and has contributed to the writing. DE has contributed to most of the writing, and developed the first and final draft of the manuscript. KM has contributed to some of the writing. DE, KM, and DC largely contributed to participant recruitment, data collection and data analysis. AB developed the modified Inspection Time task, and provided clear protocols on how to conduct the task with participants. AB also ran practice trials using the task with all researchers, which in turn assisted in data collection.The project has been approved by La Trobe University Human Ethics Committee (UHEC), approval number S15/19. All funding has been provided by La Trobe University, School of Psychology and Public Health, Department of Psychology and Counselling.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. The reviewer JH and handling Editor declared their shared aý liation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.