Anastomotic leaks (AL) present a significant source of clinical and economic burden on patients undergoing colorectal surgeries. This study was aimed at evaluating the clinical and economic consequences of AL and its risk factors.  A retrospective cohort study was conducted between 2012 and 2013 based on the billing information of 337 patients who underwent low anterior resection (LAR). The outcomes evaluated were the development of AL, use of antibiotics, 30-day readmission and mortality, and total hospital costs, including readmissions and length of stay (LOS). The risk factors for AL, as well as the relationship between AL and clinical outcomes, were analyzed using multivariable Poisson regression. Generalized linear models (GLM) were employed to evaluate the association between AL and continuous outcomes (LOS and costs). p = 0.021), blood transfusion , and cancer diagnosis  were found to be independent predictors of AL. Patients with AL showed higher antibiotic usage , 30-day readmission  and mortality , and longer LOS . Total hospital costs amounted to R$210,105 for patients with AL in comparison with R$34,270 for patients without AL (p < 0.001). In multivariable GLM, the total hospital costs for AL patients were 4.66  times higher than those for patients without AL.  AL was detected in 6.8% of the patients. Emergency surgery (aRR 2.56; 95% CI: 1.15–5.71,  AL leads to worse clinical outcomes and increases hospital costs by 4.66 times. The risk factors for AL were found to be emergency surgery, blood transfusion, and cancer diagnosis. An anastomotic leak (AL) is one of the most serious surgical complications that can develop following colorectal surgery . In two AL has both clinical and economic consequences. Patients with AL have longer hospital length of stay (LOS), larger probability of infection, and higher intensive care unit (ICU) admission, hospital readmission, and mortality rates , 19. AllThe International Study Group of Rectal Cancer proposed a severity grading of AL following anterior rectal resections: grade A consists of the development of an AL treated conservatively, grade B requires invasive treatment but no surgery, and grade C requires reoperation .Although there is information about the clinical and economic burden of AL in the literature, data continues to be scarce, especially in middle-income countries where financial burden poses greater challenges due to the resource constraints in such countries. The objective of this study was to evaluate the clinical and economic burden of AL in LAR in the Brazilian private healthcare system and investigate the risk factors for such outcomes.The dataset of patients who consecutively underwent LAR between January 2012 and December 2013 was reviewed retrospectively. The administrative database of resource utilization from the Brazilian private healthcare system includes admissions, diagnoses, procedures, medications, transfusions, laboratory and imaging tests, the materials used during the patient's hospitalization, and the cost of hospitalization. Approximately 12 million patients—which account for nearly 25% of the total patients in the Brazilian private healthcare system—are included in this administrative database. The tracking of the patients in this database is done based on their health insurance plan codes and not from specific hospitals, which provides reliable follow-up data in the short term, even in cases of readmission into different hospitals.In this study, we excluded patients who did not meet the following eligibility criteria: available age, gender, surgical approach (open or laparoscopic), and the International Classification of Diseases (ICD) code. Moreover, the LAR must have been performed no more than 3 days after the hospital admission.The following variables were evaluated for each patient: age, gender, preoperative chemoradiation, ICD code for admission related to the surgery, surgical approach, extent of surgery , protective stoma, timing of the procedure (emergency versus elective surgery), in-hospital mortality, hospital LOS, ICU admission, 30-day readmission, antibiotic usage, perioperative blood transfusion, occurrence of AL, and hospitalization costs.Antibiotic usage was defined as postoperative exposure to a nonprophylactic antibiotic for over 7 days within 30 days of the index surgery, while perioperative transfusion was defined as the use of red cell concentrate within 30 days of the index surgery. AL was considered to be the combination of three conditions: (1) a reoperation or image-guided percutaneous drainage within 30 days of the index surgery; (2) a sign of a clinical AL investigation with at least one postoperative imaging study, such as computed tomography (CT) scan, abdominal X-ray, or other abdominal exams with intravenous contrast; and (3) a sign of a clinical infection investigation with a blood culture exam within 30 days of the index surgery. Only the patients classified as B and C, according to the International Study Group of Rectal Cancer, were included in the AL group .The economic outcomes considered the total hospitalization costs, including 30-day readmissions. These included the cost of materials, pharmacy, transfusion, laboratory and imaging tests, procedures, therapies, inpatient care, and intensive care.The clinical outcomes were evaluated in terms of both the index surgery admission and any readmission within 30 days. The outcomes that were evaluated and computed in the analysis include in-hospital mortality, hospital LOS, ICU admission, 30-day readmission, antibiotic usage, and AL.t-test, and categorical variables were evaluated using the chi-square test or Fisher's exact test. The variables with a p value < 0.1 were initially considered for the multivariate analysis. Multivariable Poisson regression analysis was used and presented as a risk ratio (RR) with 95% confidence interval (CI) to determine the factors associated with AL. In order to evaluate costs and LOS, a generalized linear model (GLM) was employed, since it is the preferred approach for multivariate analysis of cost data with gamma distribution [p value < 0.05 was considered statistically significant. The statistical analysis was performed using the SPSS .Only cases with no missing values were included in the analysis. Continuous variables were evaluated using Student's ribution . All anaAmong the 1,321 potentially eligible patients, 337 fulfilled the eligibility criteria and were included in the analysis . Throughp = 0.67). The proportion of patients with cancer was higher in patients who developed AL (51.3%) in comparison with those without AL (27.4%) (p = 0.016). There was no difference in the use of chemotherapy and radiotherapy among the groups (p = 1.00 for both comparisons).The demographics and perioperative patients' data are presented in p < 0.001). In the multivariate analysis, including the significant variables (p < 0.05), all the analyzed outcomes remained significantly associated with AL. The largest impact of AL was on the mortality rate, which was found to be 13.49 times higher in AL patients than in patients without AL in the analysis adjusted for age, gender, cancer diagnosis, and timing of surgery (p < 0.001).Some of the major clinical outcomes are presented in The economic outcomes of the patients are displayed in p < 0.001). In the construction of a multivariable GLM model that evaluated the total costs, other possible predictors for costs were considered. Multivisceral resection had a p value = 0.42. Therefore, it did not enter the multivariable model. The variables selected for GLM were AL, age, gender, cancer diagnosis, timing of surgery, protective stoma, and surgical approach. The coefficients in the multivariable GLM analysis are presented in p < 0.001) for AL patients than for patients without AL.In the GLM analysis, the total costs for patients with AL were 6 times higher than those for patients without AL . These results are consistent with some other reports in the literature, although in our cohort, the strength of association was found to be higher. In a New Zealand cohort of 233 patients undergoing LAR for benign and malignant diseases, patients who developed AL had higher 30-day mortality as compared to patients without AL  as well as LOS, which was approximately two times higher in AL patients [The present study showed that AL, after adjustment for possible confounders, increases the risk of antibiotic usage by approximately 70%, the probability of hospital readmission by three times, and hospital LOS by 4.4 times. Additionally, it has a huge impact on mortality, with a relative risk (RR) of 13.46 , and type  of surgery among other variables . The ecoOur analysis of risk factors for AL did not include a large number of possible predictors, considering the limited amount of information that could be derived from the administrative database. A perioperative blood transfusion, the variable with the highest impact, is an indicator of several factors within the surgical procedure and may indicate anemia, intraoperative significant blood loss, or postoperative adverse events. On the other hand, an emergency procedure, a variable that has not been included in many previous studies on the risk factors for AL, is a strong predictor. Finally, cancer diagnosis (predominantly of the colon and rectum) is also an independent risk factor for AL development.Some limitations of our study must be acknowledged. The dataset used for all the analyses was based on the patients' administrative information. This approach carries the risk of bias of other retrospective studies as well as the problems associated with the lack of individual clinical patient information, such as the type of anastomosis and tumor distance from the anal verge. A better adjustment in the multivariable analysis could possibly be achieved with more clinical variables, and the definition of AL could be more precise if data from patients' charts was available, for instance. Also, in our multivariable analysis, especially the ones regarding mortality and AL incidence, the number of events was small, and a more robust analysis would demand larger events per covariable proportion. Furthermore, our present study may have underestimated the AL rate. A study conducted with the Swedish Colorectal Cancer Registry showed that the false-negative rate could constitute almost 30% of the AL diagnosis . The occIn conclusion, AL leads to a heavy burden in LAR procedures from both the clinical and economic perspectives, increasing the hospital costs by 4.66 times. The risk factors identified for the development of AL were emergency surgery, blood transfusion, and cancer diagnosis.


This study investigated the treatment outcomes, and factors affecting the outcomes, of new tuberculosis (TB) patients in Busan, South Korea.We retrospectively analysed the citywide TB registry data  of new TB patients registered in Busan from January 2014 to December 2015.A total of 4732 patients were included in this study . The overall treatment success rate was 83.9% ; 8.0% of patients died, and 3.6% were lost to follow-up. In multivariate analyses, a higher rate of loss to follow-up was associated with foreign nationality, registered as TB-positive at least twice, and being in Q4 (fourth quintile) or Q5 (fifth quintile) of the regional deprivation index. Conversely, a lower rate of loss to follow-up was associated with female gender, smear-positive for pulmonary TB (PTB), and the treatment outcome being reported by a public health centre. Higher mortality was associated with old age (≥ 75 years), smear-positive PTB, treatment outcome being reported by the hospital, and being registered as TB-positive twice. Lower mortality was associated with female gender, treatment outcome being reported by a public health centre or clinic, and Q5 of the regional deprivation index.Treatment outcomes of new TB patients were sub-optimal in Busan. TB control programs should maintain close monitoring and provide greater socioeconomic support to patients at high risk of poor treatment outcomes. Despite efforts to eliminate tuberculosis (TB), the incidence and mortality of TB remain high worldwide. In 2016 alone, there were 10.4 million new TB cases globally, and 1.7 million people died from the disease , and TB The “End TB Strategy” of the World Health Organization (WHO) has set a target to increase the TB treatment success rate to 90% by 2025, and to reduce TB deaths by 95% (compared to 2015) by 2035, to end the global TB epidemic . To faciTo achieve the WHO’s TB targets, South Korea has made many changes to its NTP since 2011. The Korea Centers for Disease Control and Prevention (KCDC) outlined the “New 2020 Plan,” which set a target to cut the TB incidence rate in half by 2020  . SeveralDespite these efforts to improve TB treatment in South Korea, there are limited data regarding recent treatment outcomes of South Korean TB patients and little is known about the effects of the 2011 policy changes. Factors affecting treatment outcomes of South Korean TB patients are not well understood. Most previous studies included only a small number of patients, were conducted in a single institution, or were conducted solely in the private sector –8; thereThis retrospective cohort study was conducted in Busan, which is the second-largest city in South Korea, with a population of 3.5 million in 2015 . Notified TB cases in Busan made up 7.5% of all notified TB cases in South Korea. The incidence rates of total and new TB cases in Busan were 87.6 and 68.6/100,000 population in 2015, respectively . The incAll TB patients registered in Busan from January 2014 to December 2015 were screened for inclusion. Among them, new TB patients were included in the analysis. Patients with rifampin-resistant (RR) or MDR-TB were excluded because the long duration of treatment required for these strains made it difficult to confirm treatment outcomes at the time of data collection. Patients with an unknown treatment history, and whose final diagnosis was changed to a disease other than TB, were also excluded. A patient could be registered more than once if they had been transferred from one institution to another during treatment. In total, 1021 (21.6%) of the patients in our cohort were registered at two or more different institutions. We regarded this patient as one case from the beginning of data extraction.Almost all of the registered TB patients received treatment according to Korean guidelines for TB , i.e. a The present study protocol was reviewed and approved by the Institutional Review Board of Pusan National University Hospital . The requirement for obtaining informed consent was waived by the Institutional Review Board of Pusan National University Hospital because this was a retrospective study of routinely collected monitoring data. The dataset was private and provided by the Department of Health and Hygiene of Busan City. Administrative permission for review and analysis of the patient’s record was obtained from the Department of Health and Hygiene of Busan City. The data were de-identified prior to being analysed.TB is a mandatorily notifiable disease in South Korea. All patients diagnosed with TB are registered with the Korean NTSS, which is a web-based registration system launched in 2000 by the KCDC. The citywide registry data used in the present study were a subset of this Korean NTSS data. The Korean NTSS includes the following information: identification number, age, sex, nationality, address, TB case classification (based on history of previous TB treatment), type of TB (pulmonary TB [PTB] or extrapulmonary TB [EPTB]), type of institution that registered the patient initially, type of institution that reported the final treatment outcome, results of acid fast bacilli (AFB) smear and culture, drug susceptibility test results, and treatment outcome.A flowchart showing the process followed to establish the study cohort of new TB patients registered in Busan in 2014–2015 is presented in Fig. All definitions used in the study were in accordance with WHO definitions . PatientThe Korean NTSS does not record socioeconomic data of patients. Therefore, we used a regional deprivation index. The regional deprivation index is used to estimate the socioeconomic status of an area (town-level by address in our study), and is regarded as an indirect indicator of the socioeconomic status of patients in a given area. The index is the sum of the following nine socioeconomic variables: house environment, educational level, social class of head-of-household and proportion of elderly people, single household, household without a car, non-apartment housing, female-headed household, and divorced or separated household. Higher index values indicate more deprivation, with Q5 (fifth quintile) corresponding to the most severe deprivation, and Q1 (first quintile) to the lowest level of deprivation .p values < 0.05 were accepted as statistically significant.Continuous variables are expressed as means ± standard deviation and categorical variables as percentages. Continuous and categorical variables were compared using ANOVAs and chi-squared tests, respectively. To evaluate the factors affecting treatment outcomes, multivariate logistic regression was performed. Sensitivity analysis was also performed, in which all patients listed as “not evaluated” were assumed to be “lost to follow-up.” All statistical analyses were performed using SAS software . Two-tailed n = 78) of total patients were of foreign nationality. PTB was the most common type of TB , and 38.8% of the PTB patients showed positive smear results. Regarding the notifying institution, the private sector institutions notified over 90% of the study cohort (n = 4262). There was no significant difference in baseline characteristics between 2014 and 2015.A total of 6256 patients were screened during the study period. After application of the criteria outlined above, 4732 patients were included in the study cohort Fig. . BaselinTreatment outcomes are listed in Table Table Table Higher rates of loss to follow-up were seen in patients who were registered in 2015, were foreign nationals, were registered as TB-positive at least twice, or who were classified as Q4 or Q5 in the regional deprivation index. Female gender, smear-positive PTB, and treatment outcome reported by a public health centre were protective against loss to follow-up.Higher mortality was associated with older age (≥ 75 years), diagnosis of PTB , treatment outcome reported by a hospital, and two registrations as TB-positive. On the other hand, lower mortality was associated with female gender, treatment outcome being was reported by a public health centre or clinic, and classification of Q5 in the regional deprivation index.To our knowledge, this is the first large-scale study to investigate the treatment outcomes, and factors affecting outcomes, of new patients with TB in Busan, South Korea. A major strength of our study was that it included a large cohort of TB patients, drawn from the population of a major city. Another strength is that we were able to include patients who transferred to other hospitals within the city, by using patient identification numbers to determine treatment outcomes. The Korean NTSS successfully registered 94.0% of all TB cases in 2014 , so it iDuring the study period, the treatment success rate of new TB patients in Busan was 83.9%, which was similar to that of South Korea as a whole (84.4% for 2014 and 83.8% for 2015) . SeveralTo reduce death from TB, interventions for elderly patients should be prioritised. Elderly patients are more likely to show an atypical presentation of TB, so actively searching for cases would facilitate early diagnosis and timely treatment, which would in turn likely reduce mortality , 29. TheThe number of elderly TB patients is expected to increase in the future, and efforts to reduce mortality of elderly patients may be stymied by the inherent demographic characteristics of this population. In addition, all new patients with TB had low rates of treatment failure which would be difficult to decrease further. Therefore, to achieve WHO targets, a paradigm shift in TB control strategies may be necessary to reduce non-adherence to treatment among patients in Busan. Non-adherence results in serious problems not only for the patients themselves , but also for communities in terms of the spread of infection . In our To improve patient compliance, PPM collaborations should be expanded throughout South Korea, as well as in Busan specifically, to enhance TB control in the private sector. A previous South Korean study showed that PPM collaborations decreased the rate of loss to follow-up in the private sector . For nonThere were several limitations to this study. First, socioeconomic parameters that could affect patient treatment outcomes were not recorded . We used a regional deprivation index as an indirect indicator of socioeconomic status, but it showed inconsistent associations with treatment outcomes. Because the regional deprivation index is based on the data of a given area (town level), not a patient, it might not reflect the socioeconomic status of the individual patient. Also, Busan is one of the most highly developed metropolitan cities in South Korea, so differences in regional deprivation might not be particularly significant. Further, socioeconomic differences may be diluted by free-of-charge hospital visits for TB and relatively easy access to healthcare services for all patients in Busan. Second, we did not include previously treated patients, or those with RR- or MDR-TB in the analyses. These patients are well known as high-risk groups for poor treatment outcomes. Further investigations are needed on these vulnerable populations. Finally, we could not distinguish between TB-related and non-TB related deaths. Although the WHO defines TB death as that occurring during TB treatment, irrespective of cause, knowing the actual cause of death may help to improve TB control programs.Treatment outcomes of new TB patients were found to be sub-optimal in Busan, South Korea. To reduce mortality and loss to follow-up rates, and therefor increase the treatment success rate, TB control programs should involve close monitoring and provide more socioeconomic support to patients at high risk for poor treatment outcomes.


Stroke is the third leading cause of mortality worldwide. One of the factors that affect the occurrence of stroke can be attributed to changes in the levels of trace elements. Accumulating evidence has been shown that magnesium, as an important element, is a new predictor of stroke. We aimed to determine the levels of Mg in ischemic stroke patients in comparison with those having the hemorrhagic type.This study was conducted on 447 stroke patients. Demographic characteristics of patients, stroke severity, and risk factors such as hypertension, ischemic heart disease, diabetes mellitus, and hyperlipidemia were recorded. Stroke was diagnosed based on the neurological examination and neuroimaging findings e.g. computed tomography (CT) or magnetic resonance imaging (MRI). The colorimetric technique was used to determine the concentration of Mg at 450 nm according to the commercial kit.The mean of magnesium levels in ischemic patients was significantly higher than that in the hemorrhagic patients (P=0.001). Difference in magnesium status was associated with gender in thrombotic patients (P<0.05), while hyperlipidemia was associated with the status of magnesium in embolic patients (P=0.012). Furthermore, magnesium levels were correlated with ischemic heart disease in embolic (P=0.011) and sub-arachnoid hemorrhagic (SAH) patients (P=0.012), and with diabetes mellitus in thrombotic patients (P=0.012). Magnesium status was associated with the severity of ischemic stroke at the time of discharge in ischemic patients (P<0.001). Mg levels had the best area under curve (AUC) for the discrimination of ischemic patients from hemorrhagic ones.Magnesium levels were higher in ischemic patients compared to hemorrhagic ones, and these levels were associated with many risk factors contributing to a stroke. Magnesium may be used as a new predictor of stroke in ischemic patients as opposed to hemorrhagic ones. Stroke is the leading cause of disability and mortality worldwide. Over 80% of all strokes in the world happen in the developing countries and studies conducted on these regions indicate remarkably higher fatality rates , 2. ThisStudies have demonstrated that stroke is associated with alterations in the balance of some trace elements. Indeed, trace elements are essential for maintaining the metabolism of neurons and glia , 7. Mg iStudy population: This cross-sectional analytic study was performed on 447 stroke patients recruited from Ayatollah-Rouhani Hospital in Babol, Iran. This hospital is the main center for admission of stoke patients in Babol and the surrounding areas, and the patients of the present study were chosen from among those referring to the hospital from May 2015 to May 2017. Written consent was obtained from all subjects. The study was approved by the Ethics Committee of the Babol University of Medical Sciences (3407-9542120). Demographic characteristics of patients, type and severity of stroke, risk factors such as HTN, IHD, DM, HLP, and smoking were recorded in a checklist. The study population was divided into two main groups (ischemic stroke group and hemorrhagic stroke group), and each main group was further divided into two sub-groups, namely: embolic and thrombotic for the ischemic group, and intracerebral hemorrhagic (ICH) and sub-arachnoid hemorrhagic (SAH) for the hemorrhagic group. Stroke was diagnosed based on the neurological examination and neuroimaging findings. Computed tomography (CT) or magnetic resonance imaging (MRI) was performed for all patients. Although CT scans determine subarachnoid blood in patients with CT-negative, lumbar puncture (LP) was performed to determine subarachnoid blood criteria,  where scExclusion criteria: Exclusion criteria for the patients were cases with hemiparesis or any focal neurological findings other than stroke including head trauma, metabolic encephalopathy, brain abscess, brain tumor, migraine attacks, and seizure , FBS, and total cholesterol were measured using a commercially available kit. The serum Mg level was measured by Pars Azmoon kit  according to the protocol. Magnesium was assessed based on xylidyl-blue which at alkaline ph Mg and xylidyl-blue produce a purple colored complex. The colorimetric technique was used to determine the concentration of Mg at 450 nm. The normal level of Mg was considered between 1.5 and 2.3 g/dl, and the values less than 1.5 g/dl were considered as low level while values more than 2.3 g/dl were considered as high level. To determine the association of Mg serum levels with prognosis of stroke, we used chi-square test, and the relationship between other variables influencing the type of stroke and Mg serum status was examined by Fisher's Exact Test with calculation of odds ratio (OR) and 95% confidence interval (95% CI). Furthermore, p<0.05 were considered as significant. The diagnostic accuracies of Mg for the discrimination of ischemic stroke and hemorrhagic stroke patients were analyzed by receiver operating characteristic curves (ROC). The optimal cut-off values were selected based on the maximum value of sensitivity and specificity.Included in this cross-sectional study were 447 stroke patients of whom, 225(50.3%) were males and 222 (49.7%) were females. As with the type of stroke, 374 had the ischemic type, of whom 170 patients were embolic and the rest were thrombotic while of the 73 having the hemorrhagic type, 26 were SAH and 47 were ICH. With regard to the relationship between stroke types and risk factors, we observed that there was a significant difference between HTN and the types of stroke and their subgroups  . In addition, 29 patients having ICH stroke and 9 having SAH stroke had diabetes, while 18 having ICH as well as 17 having SAH did not have this disorder. Thus, according to this main risk factor, there was a significant difference between the subtypes of hemorrhagic stroke and DM (P=0.027). Moreover, considering the severity and status of stroke at discharge, we found a significant difference between the severity of stroke at the time of discharge in two types of stroke (P=0.034) and the subtypes of ischemic stroke (P=0.005). We also observed that 36.9% of the ischemic stroke patients and 76.7% of those having the hemorrhagic type had hypomagnesemia. Besides, the mean±SD serum levels of Mg in ischemic and hemorrhagic groups were 1.63±0.42 mg/dl, and 1.31±0.37 mg/dl respectively, and there was a significant difference between the two types of stroke with serum Mg status (P=0.001) while we did not find significant difference between serum Mg levels and both subtypes of ischemic as well as the hemorrhagic stroke  .The results of our data demonstrated that the only significant difference in serum levels of Mg was between both genders of thrombotic stroke patients (P=0.049). According to our findings, there was a significant association between the subtypes of ischemic stroke  and HTN, so in the thrombotic patients having a history of HTN as opposed to thrombotic patients not having a history of HTN, serum levels of Mg was low, and these findings were also observed for embolic patients (both of them P<0.001). Moreover, there was a significant association of serum Mg levels with severity of ischemic stroke in comparison with hemorrhagic stroke at the time of discharge (P>0.05), and we also found that serum Mg levels were significantly associated with the severity of ischemic stroke at the time of discharge in thrombotic (P<0.001) and embolic patients (P=0.003), but they were not significantly associated with severity at the time of discharge in the hemorrhagic group (P>0.05). Meanwhile, we did not find a significant association between serum status of Mg with severity of stroke at the time of admission in ischemic and hemorrhagic groups plus their sub-groups . Besides, there were significant relationships between serum Mg levels with DM only in thrombotic groups (P=0.012). Finally, of the 447 stroke cases, only in the subgroup of embolic, Mg serum status was associated with HLP (P=0.012) . We usedIn addition, to estimate the diagnostic accuracy of Mg for the distinction of ischemic stroke patients from those having hemorrhagic stroke, ROC analysis was performed and the results were presented in figure 1.  According to the ROC analysis, the cutoff value of 1.35 mg/dl serum levels of Mg showed the best diagnostic accuracy for discriminating ischemic stroke patients from hemorrhagic ones: AUC=0.71, P< 0.001 and 95% CI = (0.634 – 0.758).To the best of our knowledge, this is the first study to investigate the relationship between the serum levels of Mg and demographic features, risk factors, and severity among ischemic and hemorrhagic stroke patients. The results of our  study demonstrated that there was a significant difference between the Mg serum level detected in the ischemic stroke group and that of the hemorrhagic stroke patients. In contrast to our study, Bayir et al. reported that mean Mg serum status did not have a significant difference in ischemic and hemorrhagic stroke patients in comparison with a healthy group (P=0.74), which seems to be due to the small sample size . SimilarBesides, we did not find any significant difference in serum Mg status between the subgroups of ischemic stroke  and those of hemorrhagic stroke . Furthermore, in a meta-analysis study, a modest but statistically significant inverse association between Mg intake and risk of stroke was observed. Daily intake increment of 100 mg Mg/d was associated with an 8% reduction in the risk of total stroke, and Mg intake was inversely associated with risk of ischemic stroke but not with ICH and SAH , which wOur findings also showed that the differences in Mg levels were significantly associated with gender in thrombotic patients and that HLP was significantly associated with Mg serum status in embolic patients. In this line, Akarolo-Anthony et al. observed that among women with ischemic stroke, the median status of Mg was not different in comparison with healthy individuals. They showed that there was no significant association between plasma level of Mg and the risk of total ischemic stroke, and when adjusted for HbA1c, history of DM, history of HTN, coronary heart disease, total/HDL cholesterol did not alter the risk estimates . In addiDifference in Mg levels was significantly associated with HTN in both subgroups of ischemic stroke, but not with both subtypes of hemorrhagic stroke. However, according to the findings in DM patients, we observed that there was a significant association between the status of Mg and the presence or absence of DM only in thrombotic patients, as opposed to other subgroups of stroke. With respect to the results of a previous study that reported the Mg levels to be associated with DM and HTN in ischemic stroke patients, 30, we Several studies have investigated the effect of baseline Mg on stroke outcome. The role of serum Mg levels in ischemic recovery, however, remains controversial and deserves further investigation, 32. SevA more recent study has found that the plasma status of Mg was negatively associated with the risk of cardiovascular outcomes including coronary heart disease and atrial fibrillation , 35. AddConsidering the findings about the relationship between stroke types and its risk factors, we found that there was a significant difference between HTN with the type of stroke and its subgroups, and that DM as the main risk factor of stroke, had a significant difference with regard to the subtypes of hemorrhagic stroke. Moreover, there was a significant difference in the severity of stroke at discharge in terms of the two types of stroke and the subtypes of ischemic stroke. In this line, many studies have demonstrated that stroke and its subgroups are associated with some risk factors such as HTN, DM, IHD, and HLP , 25, 33,According to the ROC analysis, we determined the diagnostic accuracy of the measured Mg and extracted the related cut-points and data. Based on the results of the ROC curve analysis, the cutoff value of 1.35 mg/dl serum levels of Mg showed the best diagnostic accuracy for discriminating ischemic stroke patients from hemorrhagic ones with the AUC value of=0.71 which makes Mg consider as a potential marker. Definitely evaluating the diagnostic accuracy of Mg in large and longitudinal studies can open a new window for possible more applications of these molecules in the clinic. However, further large scale studies are needed to verify our results, and there are still some potential limitations that merit considerations. For instance, our study did not have healthy individuals as a control group to compare patients with different types of stroke with healthy persons. Furthermore, the short follow-up time is another limitation. Despite these limitations, the relatively high number of studied patients in comparison with similar studies on this topic was one of the strengths of this study.The mean of Mg levels in ischemic patients was significantly higher than hemorrhagic type. Difference in Mg levels was associated with gender in thrombotic patients, and HLP was associated with serum status of Mg in embolic patients. Besides, serum Mg levels were correlated with IHD in embolic and SAH patients and DM only in thrombotic patients. Moreover, serum Mg status was associated with the severity of ischemic stroke at discharge in ischemic stroke patients. Mg levels had the best AUC, sensitivity and specificity for discrimination of ischemic patients from hemorrhagic ones.


The current state of knowledge related to diet in Hashimoto thyroiditis (HT) is far from satisfactory, as many HT subjects experience several disorders and report reduced quality of life. There are three aims of the study: (1) to develop a qualitative dietary protocol  as a simple, graphic–text tool dedicated to TH subjects, (2) to evaluate the use of the QDP in dietetic counseling compared to conventional dietetic counseling (CDC) in HT women, and (3) to assess the impact of both the QDP and the CDC on the diet quality, quality of life, adiposity, and metabolic parameters of HT women. The QDP is based on subject self-monitoring supported with a graphic–text tool to help them in food selection and adequate food frequency consumption, while the CDC on oral explanation and printed sample menus were provided by a dietician. The QDP contains two lists: (A) foods recommended for consumption and (B) foods with limited consumption, along with indicated consumption frequency per day/week/month. Both approaches include the same dietary recommendations for HT extracted from the literature but differ in subject–dietician cooperation. To summarize the evidence regarding dietary recommendations in HT, the PubMed, Embase, and Cochrane Library databases (to March 2019) and the bibliographies of key articles were searched. The study is designed as a dietary intervention lasting six months in two parallel groups: experimental and control. In the experimental group, the QDP will be applied, while in the control group, the CDC will be applied. In total, the study will include a baseline of 100 women with diagnosed HT. The subjects will be randomly allocated into the experimental/control groups (50/50). Data related to diet quality and other lifestyle factors, nutrition knowledge, quality of life, thyroid function, body composition, blood pressure, serum fasting glucose, and lipid profile at baseline and after a six-month follow-up will be collected. This study was conducted to develop a dietary protocol (Diet4Hashi) that is easy to follow for HT subjects, and it will contribute to providing valuable data that are useful to dieticians and physicians. It is anticipated that this graphic–text qualitative dietary protocol, by improving food selection and diet quality, may reduce adiposity and improve metabolic parameters and the quality of life of HT women. Chronic lymphocytic thyroiditis  is the most frequent autoimmune disorder and the cause of hypothyroidism in iodine-sufficient countries ,2,3. TheThyroid hormones control growth, metabolism, and body development and take part in the production of structural proteins, enzymes, and other hormones. The majority of subjects with thyroid disease experience problems in maintaining normal body weight and have a higher body mass index and waist circumference than healthy subjects . Herwig Medical management with thyroid hormone replacement is the fundamental treatment in HT ,16. NutrThe current state of knowledge related to diet in HT is far from satisfactory, while many HT subjects experience many disorders and report reduced quality of life ,14,18,23There are three aims of the study: (1) to develop a qualitative dietary protocol  as a simple, graphic–text tool dedicated TH subjects, (2) to evaluate the use of the QDP in dietetic counseling compared to conventional dietetic counseling (CDC) in HT women, (3) to assess the impact of both the QDP and the CDC on diet quality, quality of life, adiposity, and metabolic parameters. It is planned to develop a food-only protocol without considering the use of supplements because an adequate, well-balanced diet should be the first step in a dietary approach to improving health.Dietetic counseling with the use of a qualitative dietary protocol can facilitate patient understanding and long-term adherence to dietary recommendations compared to conventional dietetic counseling.A well-composed diet supported with a simple, qualitative dietary protocol, by improving food selection and diet quality, can improve the quality of life of HT subjects, reduce adiposity, and improve metabolic parameters. Furthermore, a better effect of a qualitative dietary protocol than conventional dietetic counseling is possible.The research hypotheses are:The study is designed as a single-center dietary intervention lasting six months, with a random allocation of HT women into two parallel groups: experimental and control. In the experimental group, the QDP will be applied, while the CDC will be applied in the control group. The QDP is based on subject self-monitoring supported with a graphic–text tool to help them in food selection and adequate food frequency consumption, while the CDC will be supported by an oral explanation and printed sample menus given by dietician. Both approaches include the same dietary recommendations for HT, extracted from the literature, but differ in subject–dietician cooperation. The schedule of the enrolment, intervention, and data collection is presented in The study protocol was registered and approved by the Bioethics Committee of the Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn on 17 June 2010 and 25 April 2019, Resolution No. 20/2010 and Resolution No 43/2019). Written informed consent to participate was obtained.The participants will be recruited for the study through ads in the press, via the Internet and by e-mail invitation between October and December 2019. Approximately 140 women with HT are expected to respond to the invitation letter  and will be screened for eligibility . All visTo take part in the study, the participants have to be prior diagnosed as having HT according to the American Thyroid Association guidelines  and havePatients will be randomly allocated to either the experimental group  or the control group . Stratified randomization will be based on age and will be carried out by a researcher not directly involved in the study. The patients will be unaware of whether they belong to the experimental or the control group. The researchers and laboratory personnel who will be involved in data collection and measurements (excluding the researcher who will be involved in dietetic counseling) will not know if a participant is included in the QDP group or the CDC group. The study is designed as a single-blinded study without a placebo.Both dietetic approaches (QDP and CDC) are based on the same dietary recommendations in HT. To identify studies reporting dietary recommendations in HT or hypothyroidism (reviews) and investigations on diet and health outcomes in HT or hypothyroidism , the PubMed, Embase, and Cochrane Library databases (to March 2019) and the bibliographies of key articles were searched. Based on the data extracted, dietary recommendations for HT were established. Justification for these recommendations is presented in detail in the discussion . General dietary guidelines for HT subjects will be distributed as a printed leaflet, which was the same for all participants in both the QDP and CDC groups . In the In the CDC group, dietetic counseling will be conducted in a conventional manner. Respondents will receive detailed oral explanations and printed sample menus given by a dietician. In this model of subject–dietician cooperation, the dietician is more involved while the subject is less (being more passive).In the QDP group, dietetic counseling will be supported with a simple tool containing two lists: (A) foods recommended for consumption (seven items) and (B) foods with limited consumption (six items), both with an indicated consumption frequency per day/week/month . To deveTo collect dietary data, the semi-quantitative food frequency method will be applied, and a food frequency questionnaire (KomPAN) will be used. The KomPAN questionnaire consists of 46 food items and includes a comprehensive variety of foods usually consumed in Poland . The KomParticipants will be asked to indicate the average frequency of consumption of each food item over the 12 last months. Enrolled participants will receive a questionnaire from trained researchers, who will provide guidance and assistance as required on a one-to-one basis. To indicate food frequency consumption, respondents will choose one of six categories (converted into daily frequency): ‘never’ (0 times/day), ‘1–3 times a month’ (0.06 times/day), ‘once a week’ (0.14 times/day), ‘few times a week’ (0.5 times/day), ‘once a day’ (1.0 time/day), or ‘few times a day’ (2.0 times/day) . Daily fSelf-reported data related to physical activity, time spent in front of a screen, and sleep duration (over the 12 last months), as well as smoking status will also be collected with the KomPAN questionnaire ,31. Physical activity in leisure time will be determined by choosing one of three categories: low , moderate  or high . Physical activity at work will be determined by choosing one of three categories: low (more than 70% of time spent sedentary), moderate (about 50% of time spent sedentary and 50% active), or high . Screen time, defined as time spent watching TV or using computer/tablet (including work), will be determined by choosing one of six categories: <2 h, 2 to <4 h, 4 to <6 h, 6 to <8 h, 8 to <10 h, 10 h or more. Sleep duration during weekdays will be determined by choosing one of three categories: ≤6 h/day, >6 to <9 h/day, or ≥9 h/day. The same categories will be chosen for sleep duration during the weekend. Smoking status will be collected for the past and present , and dichotomous categories will then be created: (i) non-smoker or past smoker, (ii) current smoker.To assess QoL, a thyroid-specific questionnaire (ThyPRO) in a Polish version (ThyPROpl) will be applied . There iNutrition knowledge will be assessed with the KomPAN questionnaire ,31. PartData regarding sociodemographic variables will be obtained with the KomPAN questionnaire. Age (in years) will be recorded. The following variables will be collected using closed structured questions: place of residence , level of education , financial situation , and household situation .2) and waist-to-height ratio (WHtR) will be calculated. Central adiposity  will be identified as WHtR ≥0.5 [2, obesity BMI ≥30 kg/m2) or body fat percentage (obesity gender-specific threshold: BF >33%) [The measurements of body weight , height , waist circumference  will be taken. Body fat  and skeletal muscle index  will be assessed using the bioelectrical impedance analysis (BIA) method . All measurements will be taken in light clothing and without shoes according to the International Standards for Anthropometric Assessment (ISAK) guidelines . Body maHtR ≥0.5  or WC ≥8HtR ≥0.5 . GeneralBF >33%) ,39,40. FBF >33%) . The following tests will be applied to monitor thyroid function: serum concentration of thyrotropin (TSH), free thyroxine FT4), free triiodothyronine (FT3), serum auto-antibodies against thyroid peroxidase (TPOAb), and thyroglobulin (TgAb) , free tr. TFTs reOffice measurements  of the systolic (SBP) and diastolic (DBP) blood pressure  will be taken ,43. Seru2) after the six-month follow-up and the expected difference between the experimental and the control group. A decrease in overall QoL and BMI with a 50% difference between groups  was assumed. For this calculation, a 5% significance level and 80% power were considered. The sample size required at baseline is approximately 100 respondents , including a 20% drop-out rate at the end of the study. When the data collection is completed, the adequacy of the study sample will be checked by applying the post hoc statistics to calculate power.The minimum sample size was calculated based on the expected improvement in overall QoL (decrease in points) and BMI  and continuous variables will be presented as means with a 95% confidence interval (95%CI) or medians with an interquartile range (IQR) for variables with normal or non-normal distribution, respectively. To assess the impact of dietetic counseling and verify the differences between the experimental and the control group, two-tailed tests will be applied; The normality of variable distribution will be verified with a Kolmogorov–Smirnov test before the statistical analysis. For continuous variables, e.g., diet quality scores, AdhS, scores of QoL, nutrition knowledge score, TFTs, markers of adiposity, metabolic parameters, and changes after a six-month follow-up with respect to baseline will be verified with a T-test for dependent samples or a Mann–Whitney test, for variables with normal or non-normal distribution, respectively. For categorical variables, logistic regression modeling will be applied to determine the chance of the occurrence of high diet quality, high AdhS, high QoL, as well as low adiposity and elevated metabolic parameters. The odds ratios (ORs) and 95% confidence intervals (CIs) will be calculated. The significance of ORs will be verified with Wald’s statistics. A crude model and models with an adjustment for confounders will be created. All analyses will be performed with Statistica software .The recommendations in the ‘Diet4Hashi’ protocol are based on scientific evidence related to Hashimoto thyroiditis and hypothyroidism, as described in detail in The consumption of vegetables is recommended several times a day, which is in line with the recommendation for the general population ,28,29. VFor foods rich in calcium , the recommended consumption frequency is several times a day, which is in line with the recommendation for the general population ,28,29. CFruit consumption is recommended at least once a day, similar to the recommendation for the general population ,28,29. FThe recommended consumption of whole grains, e.g., buckwheat grain, wholemeal wheat, and rye bread, at least once a day, is in line with the recommendation for the general population ,28,29. AThe consumption of animal foods rich in zinc  several times a week is recommended. This is in line with the recommendation for the general Polish population, who usually consume too much red and processed meats ,61. The The authors’ recommendation to consume animal and plant foods rich in selenium is in line with previous findings that diets rich in selenium may increase the production of active thyroid hormone and reduce TgAb and TPOAb ,68,69. SThe authors have distinguished animal and plant dietary sources of selenium for three reasons: (i) to simplify recommendations for the patient, (ii) to reduce the chance of any unilateral exchange between both food groups and maintain a large variety of diet, and (iii) plant sources of selenium, i.e., nuts and seeds, are also rich in zinc.n-3 polyunsaturated fatty acids in these foods [Fish and seafood are indicated as animal foods rich in selenium with a recommended consumption of several times a week. This is in line with the recommendation for the general population, although a guideline on eating fish and seafood at least twice a week (including fatty fish at least once a week) is mainly based on the content of se foods ,28,29. Sse foods ,69. Nigella sativa in improving thyroid status and anthropometric variables in patients with HT. Nevertheless, its function on the human thyroid requires more trials, and this finding should be interpreted with caution. The thyroid hormone is made by combining iodine and tyrosine. In a balanced diet, a person should receive enough of this amino acid, but tyrosine intake can be supported by the consumption of pumpkin seeds, sesame seeds, and almonds [Various kinds of nuts and seeds are recommended to be consumed several times a week. These foods are a good source of selenium and zinc (both important in thyroid metabolism) and also rich in dietary fiber. Brazil nuts are the richest food source of selenium, although they cannot be recommended as a main selenium source because they are generally not a commonly eaten food, and selenium content is highly variable, ranging from 0.03 to 512 mg/kg fresh weight ,74,75. I almonds ,28,29.p = 0.048).The consumption of raw cruciferous vegetables, e.g., kale, bok choy, white cabbage, red cabbage, broccoli, brussels sprouts, and cauliflower should be limited (once a week or less). Cruciferous vegetables, as well as soybean-related foods, contain goitrogens, which interfere with thyroid hormone production and utilization. A goiter may be a response to an overactive or underactive thyroid gland. Unless there is a co-existing iodine deficiency, these foods are generally of no clinical significance according to the statement of the Institute of Medicine . GoitrogLimiting the consumption of sweets, sugar, and honey including high-sweetened jam and fruits candied (once a week or less) is recommended, as these foods are a source of monosaccharides and many of these foods contain a large amount of saturated fatty acids and trans-isomers of unsaturated fatty acids. This recommendation is in line with the recommendations for the general population (no precise cut-off for Poles was given) to prevent obesity, diabetes, and other diseases, including cancers ,28,29. ILimiting the consumption of sweetened beverages energy drinks (once a week or less) regardless of the sweeteners type  is recommended. Sweetened beverages can affect hormonal levels in the blood by increasing T4 and parathyroid hormones, and lowering T3 and aldosterone levels . Abbott Limiting the consumption of fast food (once a week or less) is recommended. The recommendation for the general population is to avoid fast food ,28,29. TSoybean and millet—e.g., soya: seeds, sprouts, tofu, milk; millet groats—are controversial foods. Limiting the consumption of these foods (twice a month or less) is recommended, despite the potential human health benefits of soy in the prevention of cancer, cardiovascular diseases, the reduction of menopause symptoms, increased bone-mineral density, and decreased insulin resistance . ConversLimiting the consumption of alcohol (once a month or less) is recommended. However, the recommendation for the general population is not to consume alcohol ,28,29. MThe strength of the study was the development of a simple dietary protocol with a user-friendly approach that is easy to use for both individuals with HT and health professionals. This dietary protocol was developed based on scientific evidence and presents the best adherence to current knowledge. Simple markers of adiposity  and metabolic parameters  useful in dietetic counseling and clinical practice (and easy to replicate in other studies) will be applied. In addition, advanced methods of adiposity measurement  will be applied to accurately measure body composition, including fat mass and skeletal muscle mass. Since the data are experimental observations, the causal effect of dietary intervention can be demonstrated. The main limitation is that the study will not have a controlled placebo as there is no ‘dietetic placebo’ for dietetic counseling. Therefore, the graphic–text tool will be controlled with conventional dietetic management. Secondly, the study is not double-blinded because (i) the researcher who will be involved in dietetic counseling will be aware of which participants are included in the QDP group and which participants are in the CDC group, and (ii) it is possible that respondents may be aware of what dietetic counseling they are following. The next limitation is the use of non-thyroid-specific food frequency questionnaires (FFQs) to describe diet quality. Both FFQs have been previously used to study the association between diet and health outcomes in the context of non-alcoholic fatty liver disease , celiac Due to the development of an easy-to-follow qualitative dietary protocol for HT subjects (Diet4Hashi), this study will contribute to providing valuable data for dieticians and physicians. It is anticipated that this graphic-text qualitative dietary protocol, by improving food selection and diet quality, can reduce adiposity and improve metabolic parameters and the quality of life of HT women. Further investigations are needed to verify the use of this dietary protocol in HT males.


Being part of the intervention group as well as finishing training during spring/summer showed an independent association to increased brisk walking after the intervention period. In conclusion, the HiBalance program increases the physical activity on moderate intensity after intervention and at 6 months but not at 12 months, independently of improved balance. Season seems to influence the effect on the physical activity.The HiBalance program is a progressive and highly challenging balance training intervention incorporating Parkinson's disease (PD) specific balance components. The program improves balance and gait and increases the amount of ambulation in short-term, in older adults with PD. Yet, potential short- and long-term effects on habitual physical activity and sedentary behavior are currently unidentified. The aim of this study was to conduct preplanned secondary analyses of short- and long-term effects of the HiBalance program on objectively measured amount and bouts of brisk walking, sedentary behavior, and total physical activity in older adults with PD. Further, our aim was to investigate demographic, intervention-related, disease-related, and function-related factors potentially related to a difference in activity after intervention. A total of 100 older adults with mild-moderate PD were recruited. The intervention group participated in the HiBalance program, and the control received care as usual and was offered the HiBalance program after study termination. Physical activity data were collected using accelerometers at baseline, after intervention and after 6 and 12 months. A multilevel model was utilized to investigate the postintervention and long-term (6 and 12 months) effects on total physical activity, amount and bouts of brisk walking , and sedentary behavior. Between-group difference for the main outcome brisk walking was at postintervention: Δ −10, CI −23.78 to 3.69 min/day ( Parkinson's disease (PD) is a neurodegenerative disease with symptoms such as tremor, rigidity, bradykinesia, and impaired postural stability . Due to the progressive nature of PD, balance impairments gradually increase in severity, which leads to falling , fear ofFalling is common in PD, and it has been estimated that about 18 to 65 percent of afflicted are frequent fallers . FrequenThe HiBalance program is a progressive and highly challenging balance training intervention incorporating PD-specific balance components . ResultsTherefore, the aim of the present study was to conduct the secondary analyses investigating postintervention and long-term (6 and 12 months) effects of the HiBalance program on objectively measured amount and bouts of brisk walking, amount and bouts of sedentary time, and total PA. We hypothesized that the improved balance and walking speed previously found  also incIt is also of interest to investigate whether the increase in PA after the intervention is linked to improved balance, since it has been suggested that improved balance performance is associated with a greater ability of being more active , 20, 21.NCT01417598).This study reports preplanned secondary analyses on habitual PA and sedentary behavior of a randomized controlled trial (RCT) of the BETA PD-project aimed at investigating the effects of the HiBalance program , were included . All incRecruitment comprised three waves (three sets of both intervention and control groups), where two waves started the intervention during spring and one during fall. Both groups were assessed using all the included measures at baseline and after intervention, as well as 6 and 12 months thereafter.The participants were randomly assigned in blocks of four to either the intervention group participating in the HiBalance program, or the control group , 15. ResThe HiBalance program contained a 10-week, three times/week, balance training intervention , 15. EacAccording to the clinical procedure, all participants allocated to the intervention group were given PA on prescription (PAP) at time of the postintervention measurements. The recommended activity was based on current PA recommendations for health (WHO) and their interests, needs, and abilities. In addition, participants were supported to set specific, measurable, attainable, realistic, and time-given goals for physical activity and given a brochure with information on the benefits of physical activity. The PAP was followed up telephonically after three months, by a physiotherapist asking the participant questions regarding compliance to the PAP, performed activity type, frequency, and duration.All assessments were conducted by experienced physiotherapists after a predesigned protocol. Participants were informed about the study, and informed written consent was obtained. The subsequent test procedure included clinical tests of gait and balance, followed by an interview of questionnaires and distribution of accelerometers. Half of the participants did the physical tests first and the other half the interview first. Finally, instructions were given on how to wear the accelerometers during the following week for measuring habitual PA.Habitual physical activity and sedentary behavior data were collected using the accelerometer Actigraph GT3X+ . GT3X+ is an accelerometer that records changes in movement over time (acceleration) in three axes expressed as an arbitrary unit named counts. Participants were assigned the accelerometer attached to a belt and instructed to wear it around the hip and positioned lateral to the spine, for the duration of seven days, only removing it for showering, swimming, and bathing and at night. Participants received oral and written information on how to use the accelerometer and were also asked to fill in a wear-time diary during the period and told that the monitor measures daily movement. After the measurement period, the accelerometer was returned in a prepaid padded envelope.The data were filtered, cleansed, and computed using ActiLife v.6.13.3 . A 15-second epoch was used, where ≥90 minutes of consecutive zeroes was defined as nonwear time and discarded. Spike tolerance and small window length were set to 2 minutes and 30 minutes, respectively . Normal Factors that can influence the effect of the program based on the previous studies and clinical reasoning such as demographic factors, disease-related factors, and motor function, collected at baseline, were included. Demographic data such as age, sex, and BMI of the participants were collected using structured questions.Proxys for disease-related factors were fall history, the motor performance, and activity of daily living (ADL) part of the Unified Parkinson's Disease Rating Scale (UPDRS) , 33, andProxys for motor function was balance control, gait velocity, and step length. Balance control was assessed using the Mini-BESTest, . ImproveDue to the fact that the season during training varied between waves of participants in the HiBalance program (participants finished training during May-June or in December) and since the Swedish climate entails quite cold winters and there is evidence of a seasonal effect of poor or extreme weather on amount of PA , it was α level of 5%, the number of subjects required per group and the hypothesized effect size, respectively, were 24 (effect size = 0.83) for Mini-BESTest, 27 (effect size = 0.83) for gait velocity, 32 (effect size = 0.71) for FES-I, and 19 (effect size = 0.79) for steps per day. Taking an anticipated dropout rate of 15% into account, a sample rate of 40 in each group was needed. Because of long-term follow-up and risk of further dropout, the group size was increased to 50 subjects per group.The main focus of the RCT was postintervention with a secondary aim to study the long-term effect. Hence, the power calculations were primarily conducted for postintervention. Sample size, detailed in the study protocol, was based on the previous calculations based upon a feasibility study on the outcome measures of balance control, gait velocity measured in a movement laboratory, and concerns about falling and steps per day . In ordeDemographic data together with disease-related factors and function-related factors were summarized for descriptive purposes. Missing data analysis of outcome variables was performed using Little's test, a single global test for investigating whether missing values of multivariate data are missing completely at random or depends on the variables in the data set .∗ group, and season (control factor) were set as fixed factors, and the intercept of each individual as well as time were set as random factors, thereby allowing variation in levels of PA at baseline and the effect of time. Repeated covariance type was set to a heterogeneous first-order autoregressive structure, taking into account the higher correlation between measures closer in time compared to those further apart [d), based on between-group differences.Between-group differences were calculated and presented as mean and confidence interval (CI). To investigate the postintervention and long-term effects of the intervention on PA  and sedentary behavior, a multilevel model (mixed effect model) was utilized. This model does not rely on listwise deletion; therefore, all available information even if values are missing is used. Time, group affiliation, time er apart . Effect ∗ season) was also added. The statistical analyses were performed in SPSS v.23 for Windows  and R (R Core Team (2015). https://www.R-project.org/).Further, a multiple linear regression was performed to investigate the factors associated with the (absolute positive or negative) difference in participants' amount of brisk walking . Group affiliation, season, and improved balance were entered , and age was controlled for. In the second step, the potential interaction between group affiliation and season .After exclusion of participants not reaching the set cutoffs for valid data, a total of 83 participants with data from baseline and 74 from postintervention remained . Participant characteristics are presented in p < 0.05) for minutes of brisk walking, in favour of the intervention group. Furthermore, there were significant interaction effects of group and time when comparing baseline to postintervention as well as baseline to the 6-month follow-up (p < 0.05). The effect dissipated when comparing baseline to the 12 months follow-up (p=0.43). This pattern was also visible when inspecting the trajectory of both groups visually  for the between-group comparisons of brisk walking at postintervention, 6 months, and 12 months were 0.34, 0.36, and 0.15, respectively. No other PA variables showed a significant interaction effect of group and time, although total PA and sedentary time showed a significant overall effect of time (p < 0.01), i.e., reduced PA and increased sedentary time.The postintervention and long-term (6 and 12 months) effect analysis using a multilevel model resulted in an overall significant effect of time and an interaction effect between group and time . EffectR2 of 0.24). The model proposed that performing the training during spring/summer and being part of the intervention group were both independently associated with an increase in minutes of brisk walking  related to an increase in brisk walking that is not measured herein. In addition, disease-related factors included might not be sensitive enough and behavioral and mental factors such as exercise self-efficacy, motivation, and previous experiences with exercise were not collected in this study.As mentioned above, the added effect of PAP is unknown and needs to be further investigated in the future trials. However, the feedback from participants on the PAP emphasizes that tools that support management of physical activity in relation to the disease are needed. Participants might not be ready to change or have the tools for self-management and might therefore need further and deeper support in this matter.The results herein indicate that being part of a balance intervention increases physical activity on moderate intensity , but has no effects on sedentary behavior and total PA. Furthermore, the long-term analysis showed a dissipation of the effect on time in moderate intensity before 12 months, with a return to levels similar with those at baseline. This, together with results showing that season had an independent effect of the intervention, may help clinicians plan for extra support such as a booster session if the balance training period ends in the winter and repeated or continued.


To identify the association between night shift work and the risk of various cancers with a comprehensive perspective and to explore sex differences in this association. I2 statistic. Subgroup, metaregression, and sensitivity analyses were performed to explore potential sources of heterogeneity. Contour-enhanced funnel plots and the trim and fill method were used together to analyze bias. Linear dose–response analysis was used to quantitatively estimate the accumulative effect of night shift work on the risk of cancer.  We searched PubMed, Embase, and Web of Science for studies on the effect of night shift work on cancer, including case-control, cohort, and nested case-control studies. We computed risk estimates with 95% confidence intervals (CIs) in a random or fixed effects model and quantified heterogeneity using the P < 0.001; I2 = 76.2%). Night shift work increased the cancer risk in both men  and women . Subgroup analyses showed that night shift work positively increased the risk of breast , prostate , and digestive system  cancers. For every 5 years of night shift work, the cancer risk increased by 3.2% .  Fifty-eight studies were eligible for our meta-analysis, including 5,143,838 participants. In the random effects model, the pooled odds ratio (OR) of cancers was 1.15 (95% CI = 1.08–1.22,  This is the first meta-analysis identifying the positive association between night shift work and the risk of cancer and verifying that there is no sex difference in the effect of night shift work on cancer risk. Cancer risk increases with cumulative years of night shift work. Recent years have witnessed a rise in the number of people working late or night shifts in different employment sectors, such as healthcare, construction, transportation, and food preparation , 2. The There were several postulated causal mechanisms that explain how night shift work multiplies cancer risk. First, melatonin, a marker of circadian rhythms, has a fundamental impact on inhibiting carcinogenesis through antioxidation, regulation of immunity, free radical scavenging, and antiangiogenesis . GeneralPrevious studies have revealed that the circadian timing system differs in the sexes, which is mediated by different neuroendocrine contexts, such as sex hormones and their receptors in SCN , 83, 84.Consequently, we conducted a meta-analysis to investigate this sex difference. We also expanded upon previous meta-analyses by not only evaluating the association between night shift work and a specific cancer but also estimating whether there was a dose–response relationship between night shift work and the risk of multiple cancers.We conducted a comprehensive updated search through May 2018 using PubMed, Embase, and Web of Science databases. Two investigators searched for eligible English articles independently. The search terms were “night shift work” or “rotating shift work” or “night work” or “shift work” and “carcinoma” or “neoplasm” or “tumor” or “cancer”. In addition, we manually reviewed the reference lists of articles for additional relevant studies.Studies were included if they satisfied the following criteria: (i) the research was a case-control study, cohort study, or nested case-control study; (ii) the exposure of interest was night shift work, and the outcome of interest was the risk of any type of cancer; (iii) the study reported adjusted risk estimates  with 95% confidence intervals (CIs) or provided sufficient data to allow calculation. Studies were excluded if they satisfied the following criteria: (i) the study did not provide sufficient data; (ii) the study mentioned recurrent cancer; (iii) when more than one article was based on the same study population, we only included the study with the largest number of cases.Data extraction was conducted independently by two authors for the following items: first author, publication year, study location, study design, number of cases, occupation, quality score, definition of exposure, participant sex, type of cancer, adjusted OR with 95% CI, adjusted covariates, and exposure assessment. As the prevalence of tumor is very low, we considered that ORs equaled RRs or HRs, providing similar risk estimates . AccordiTwo authors performed quality assessment using the Newcastle-Ottawa Quality Assessment Scale (NOS) . The scaI2 for the heterogeneity test was ≤50%, a fixed effects model was adopted to pool ORs; otherwise, a random effects model was selected. To explore potential heterogeneity, we performed subgroup analyses, metaregression analyses, and sensitivity analyses. One subgroup analysis was the classification of work schedules; we used a random effects model to evaluate the effect size for cancer on different work schedules [All statistical analyses were performed using Stata version 12.0 . We preferentially extracted adjusted ORs from original articles to evaluate the association between night shift work and cancer risk. If there were no adjusted ORs for specific subgroup analyses, a number of cases and participants would be extracted to calculate OR. The inverse variance method was used to combine ORs. If chedules . To confchedules .A generalized least-squares trend (GLST) model was used to estimate the overall dose–response relationship of night shift work and the risk of cancer by computing risk estimates for different ordinal levels of night shift work. There were at least three ordinal levels of the exposure category in each study. The midpoint of the upper and lower boundaries of each level was considered the average exposure. The upper boundary of the highest level was considered the same as the adjacent category if it was not provided . We usedP values were two-sided, and statistical significance was set at P ≤ 0.05.Potential publication bias was estimated with the Begg funnel plot. Furthermore, the contour-enhanced funnel plot and the trim and fill method were used together to analyze the cause of bias. All reported The characteristics of the abovementioned studies are summarized in P < 0.001), with high heterogeneity  (shown in online P = 0.003) and women , with high heterogeneity in men  and women  (P = 0.031) but not in women .The random effects model was used to pool the ORs, indicating the relationship between night shift work and risk of multiple cancers. The pooled OR was 1.15  . In cancI2 = 61.6%, P ≤ 0.001) whereas those with low-quality scores did not show this positive relationship and had high heterogeneity . Additionally, increased risk was present in studies with more than four adjusted variables. Studies with fewer than four adjusted variables showed no elevated risk of cancer, with high heterogeneity . We performed metaregression analyses to assess the potential heterogeneity sources . It was found that none of the individual studies could powerfully change the positive result.Sensitivity analysis showed that the pooled ORs were stable and did not identify the origins of heterogeneity. After omitting 19 studies by the leave-one-out analyses, we found a stable positive relationship  between night shift work and the risk of cancer, with low heterogeneity (P < 0.001). For every 5 years of night shift work, the risk of cancer increased by 3.2%   .P = 0.001). After combining the trim and fill method and contour-enhanced funnel plot, the result showed that most of the filled studies were outside the 10% line, which indicated that the previously verified bias was mostly caused by the high heterogeneity, not the publication bias , hematological system cancer , and lung cancer  presented a more reliable conclusion. Previous studies have suggested that a common mechanism might be shared among hormone-dependent cancers including prostate cancer in men and breast and ovarian cancers in women [Tissue-specific functions and output circadian rhythms are related to the different cell-based clock genes in periphery . To exclin women , 92. Melin women , 93, whiOne meta-analysis  analyzinOur subgroup analyses also uncovered other meaningful results. One finding demonstrated that prostate, breast, and digestive system cancers were connected with night shift work whereas night shift work did not raise the risk of cancers of the hematological system, reproductive system, lung, and skin. In addition, Yuan et al.  found thQ and I2 values, we found a significant heterogeneity among the studies included in this article ; therefore, we used a random effects model to decrease the heterogeneity. After subgroup analyses, we found that fixed shift work, digestive system cancer, reproductive system cancer, unclassified occupation, interview data collection, and high-quality studies were related to less heterogeneity, representing more reliable results. However, all P values in the metaregression analyses did not reflect a statistical difference, such that heterogeneity could not be explained by metaregression analysis. One-by-one-omitted sensitivity and leave-one-out analyses showed that the pooled risk estimates were stable and positive, even when 19 studies were omitted, until heterogeneity was reduced to 29.8%. Although we did not find an obvious source of heterogeneity, the specific subgroup analyses, such as a more uniform definition of work schedules, unclassified occupation based on population, more detailed interviews, and high-quality studies, could decrease the potential heterogeneity.Through analyzing Theoretical biological mechanisms for the positive relationship between night shift work and cancer risk are complex. First, night shift work and LAN could disturb the normal synchrony with the day–night rhythm and sleeping and diet patterns and bring about circadian disruption, which could suppress the secretion of melatonin . MelatonTo the best of our knowledge, this meta-analysis is the first and most comprehensive of its kind to identify the association between night shift work and risk of cancer from the perspective of diverse cancers and by sex. There were several strengths in our meta-analysis. First, we enrolled a large number of articles, even using strict inclusion criteria. The massive study population could enhance statistical power and ensure more accurate risk estimation. Second, a linear dose–response analysis was used to quantify the association between accumulative years of night shift work and cancer risk. Third, we classified work schedules and found that rotating shift work could increase cancer risk whereas fixed shift work could not. The classification of work schedules could decrease clinical heterogeneity to make the results more reliable. Fourth, 34 of 57 studies were carried out among the general population, such that the pooled OR could be better extended to the entire population. Our meta-analysis also had several limitations. First, a significantly high heterogeneity was discovered. We observed significant variability in the study design, risk estimates, study population, definition of night shift work, and exposure assessment. Each of these aspects may generate heterogeneity. Even though many statistical methods were used, we still had trouble finding an obvious source of potential heterogeneity; therefore, the conclusions reached in our meta-analysis should be interpreted with caution. Second, the lack of a consistent definition of night shift work may lead to a certain degree of misclassification and result in a dilution of the pooled OR . Third, In conclusion, our meta-analysis identified a positive relationship between night shift work and cancer risk, using a comprehensive perspective of common cancers. We revealed that the risk of cancer increases cumulatively by 3.2% for every 5 years of night shift work. Moreover, we found no difference between men and women in the association between night shift work and the risk of cancer. Overall, on the grounds that public health is adversely affected by night shift work and its prevalence is on the rise, it is indispensable to develop shift work schedules with the aim of reducing cancer risk. Our meta-analysis does not merely increase public awareness, it also supports the recommendation for regular cancer screening among night shift workers.


N = 139,991). These countries show meaningful variation in terms of the Human Development Index (HDI), ranging from very poor, developing countries to prosperous, developed countries. We found evidence of cross-level interactions, consistently showing that individuals’ level of education was associated with an increase in their liberalization values in higher HDI societies, whereas this relationship was curbed in lower HDI countries. This enhanced liberalization mindset of individuals in high HDI countries, in turn, was related to better scores on national indices of innovation. We conclude that this ‘education amplification effect’ widens the gap between lower and higher HDI countries in terms of liberalized mentality and economic growth potential. Policy implications for how low HDI countries can counter this gap are discussed.The present study investigated the relationship between level of education and liberalization values in large, representative samples administered in 96 countries around the world (total  Education increases human capital and, in turn, innovation and economic growth , 2. HoweA classic study on the liberalizing effect of education was conducted in the 1930s by the famous social psychologist Theodor Newcomb , 8. At BCountries show very different levels of development. These differences do not only pertain to economic development, but also to the strength of public services. Indicators of income, health and education constitute the so-called Human Development Index (HDI), a measure of development that combines economic prosperity and well-being . The higInhabitants of poorly developed countries (countries with a low HDI) generally tend to endorse a more closed, conservative worldview with an emphasis on traditional values and economic and physical security, whereas citizens of higher HDI societies typically endorse a more open-minded, liberal worldview, emphasizing freedom, individualization and self-expression , 13, 14.Sociological studies already have shown that the development of a liberalized climate is a basis for the transition from industrialized to post-industrialized, innovative and knowledge-based societies , 13, 14.The present study included data from representative samples administered in Wave 5 (2005–2009) and 6 2010–2014) of the World Values Survey (WVS), and the 2008 Wave of the European Values Study (EVS), which use almost identical questionnaires and methodologies , 22. Our of the WCountry-level measures were Human Development Index  for det and Innor = .28, P< .001, as well as the correlation between liberalization values and innovation, r = .81, P< .001.Because participants  were nested within countries , we first investigated an empty (intercept-only) model. The intraclass coefficients (ICC) was large (.46), indicating that there is substantial between-level variance in the dependent measure, warranting the use of a multi-level analyses. All independent variables were grand-mean centered , and we random coefficient model . The association was somewhat stronger in countries with HDI levels 1 SD below the mean . In countries with a high (1 SD above the mean) and an extremely high (2 SD above the mean) HDI, the magnitude of the relationship between education level and liberalization values further increased . Detailed analyses also revealed a significant interaction effect between country level HDI and individual-level education on country-level innovation (b = 4.11 (SE = 0.57), β = 0.60, P< .001). Again, the association between education and innovation was stronger in high HDI countries.A multilevel model (MLM) based on a nt model  was condb = 0.35 (SE = 0.08), β = 0.05, P < .001]. In other words, the liberalizing effect of education (which is particularly strong in higher HDI countries) further relates to higher country-level innovation.Next, a mediational multilevel path model was examined to test whether individual-level education and country-level HDI relate to country-level innovation via individual-level liberalization values  for the. Consistb = 0.24 (SE = 0.12), β = 0.04, P = .04].Although these analyses confirm our Hypotheses, it should be acknowledged that previous studies have revealed that education increases human capital which leads to innovation , 2, espeThe results of this study show that an individual’s level of education is more strongly related to having a liberalized mindset in higher HDI compared to lower HDI countries. Moreover, through this increased liberalization, education resulted in higher innovation ratings in higher HDI countries. We draw two conclusions. First, education amplifies the differences between the mindset of citizens in highly developed countries who increasingly liberalize, and the mindset of citizens in poorly developed countries who remain as closed-minded and conservative as before, or only show a small increase in liberalization values. This trend is likely to become even more pronounced in the future. Indeed, because education is widely available in Western countries, it will further lead to a shift in the mentality of a large part of the population in the direction of liberalization values. In less developed countries, on the contrary, the small group of highly educated people who only shift a small degree in the liberalized direction  will have too little influence to shift a given country’s mentality.A second conclusion pertains to the effects of education on innovation, and as a result, on the potential for economic prosperity in the long run. The widening gap among countries in terms of mentality has important indirect effects on prosperity as well. Whereas a liberalized mindset has been typically studied in sociology, political psychology and political science, it has not yet been fully considered in previous studies that investigated the relationship between education and innovation and, therefore, economic growth. This is a notable omission. As already shown in literature, educational systems are more successful in creating human capital in developed countries compared to developing countries , 4. As sA limitation of the present study is the correlational design that does not allow for a firm conclusion about the direction of the effects. The availability of more waves of worldwide surveys and tests in the future will undoubtedly create opportunities for scholars to study the present relationships in a longitudinal design. Such a study would allow investigating the presence of reversed paths. It is indeed plausible that a high level of innovation in a given country spurs the development of liberalization values, and that a high level of liberalization values prompts governments to increase the supply of education. Along similar lines, innovative activity brings prosperity that enables governments to invest additional resources in educational systems. Hence, a model with recursive paths in which education leads to liberalization values and innovation, and liberalization values and innovation in turn promote education, is possible. These recursive paths may strengthen each other and constitute an upward spiral, which sustains the development of low HDI countries.The present study has policy implications especially for low HDI countries. Such countries would undoubtedly benefit of educational reforms that support ‘human capital’ in the form of the acquisition of skills and knowledge , 4. HoweIn conclusion, our findings indicate that education has quite different effects on the pace of liberalization, which in turn amplifies the cultural and economic gap between developed and developing countries. So, if “education can change the world”, then this seems to be particularly true for developed countries as opposed to developing countries, as long as the educational system in the latter countries does not foster liberalization values.S1 File(DOCX)Click here for additional data file.