Potential association between oral levofloxacin use and hypoglycemic emergency (HE) have been established. However, a large epidemiological study is required to verify this observation. This study aimed to determine if use of oral levofloxacin increased the risk of HE. The nationwide database between 1999 and 2013, including 1.6 million patients with type 2 diabetes (T2D), was used to conduct a nested case-control study. Cases and controls comprised of patients with and without HE, respectively. To avoid indication bias the control subjects were chosen through propensity score matching with cases in a 10-fold ratio. T2D severity was classified based on the adjusted diabetic complication severity index score. 26,695 and 266,950 matched patients with T2D, were finally used as cases and controls, respectively, for the analysis. Multivariate logistic regression analysis showed that antibiotic use was associated with an increased risk for HE (adjusted odds ratio (aOR) = 6.08, 95% confidence interval (95% CI): 5.79–6.38). When compared with antibiotic non-users, those who used fluoroquinolones and sulfonamides displayed the highest  and second highest  risks of HE, respectively. The associated risk for HE was significantly higher with levofloxacin than that with cephalosporins  and penicillin . In the joint effect analyses, the risk for HE increased with the combination of levofloxacin with insulin  or sulfonylurea . Use of oral levofloxacin, compared to that of other antibiotics, was found to be significantly associated with HE in T2D patients. Clinicians should exercise caution while prescribing levofloxacin, especially when combined with insulin or sulfonylurea. Patients with type 2 diabetic mellitus (T2D) are susceptible to secondary infections that can further disrupt their blood sugar balance and therefore, induce hypoglycemia or hyperglycemia. For hypoglycemia, the risk factors include inappropriate dosing of antidiabetic drugs, dietary indiscretion, and adverse drug side effects –4. HypogFluoroquinolones belongs to a class of antibiotics that inhibits bacterial DNA synthesis, and are one of the most commonly prescribed antibiotics, worldwide, primarily for the treatment of respiratory and urinary tract infections . The dev1.6 million patients of Taiwanese origin, from a specially applied diabetes database from the Taiwan National Health Insurance Research Database (NHIRD) were included in this study. NHIRD was launched by the National Health Insurance Administration (NHIA) of Taiwan in 1995 and currently provides nearly an overall coverage of more than 23.03 million residents (>99% of the entire population). The NHIA releases de-identified patient information and claims data to the National Health Research Institute, which compiles it into NHIRD. The data is of high quality which has been confirmed by several prior studies –15 and tth Revision, Clinical Modification (ICD-9-CM), is used throughout this study. The diagnostic accuracy of T2D in the NHIRD have been validated in a prior study [The diagnosis codes, in accordance with the International Classification of Diseases, 9or study . Baselinor study .The date of initial diagnosis of hypoglycemia in the emergency department (ED) were recorded as the index date between the study period 1999 and 2013. Any other diagnoses, made within one year prior to the index date, were considered as the underlying comorbidities of a patient. The patients were classified based on their usage of certain drugs or usual medications for chronic diseases, for at least one week within a three-month period. The usual medications included biguanides, DDP-4 inhibitors, sulfonylureas, thiazolidinediones, insulin, nonsteroidal anti-inflammatory drugs, aspirin, and statins. Even though patients with type 1 diabetes were not included in the study, certain type 2 diabetic patients with poor blood sugar control were prescribed a combined use of insulin  and oral medications concurrently.The severity of T2D plays an important role in the occurrence of HE. The adjusted Diabetes Complications Severity Index score (aDCSI score) was used as a reference measure for the severity of T2D ,19. The A nested case-control study was conducted. Both the case and the control subjects comprised of only patients with T2D. Patients aged <20 or >90 years and patients with type-I diabetes were excluded from the study. First, the case subjects were chosen based on the following criteria; (i) having a HE necessitating ED visit during the study period with a record of receiving high concentration (10% or 50%) of dextrose infusion, and (ii) intake of certain oral antibiotics within one week prior to the HE . Only thThe control subjects were defined as those who did not have HE but took oral antibiotics during a <7 days duration within the follow up period. The control subjects were retrieved by the PS method of "nearest neighbor matching". The first day of receiving prescriptions of oral antibiotics by the control subjects was defined as the index date. This was also matched to the calendar year for the case subjects. it was ensured that there was no HE in the control group one week prior to the index date. The algorithm of participant selection is displayed in As the NHIRD contains de-identified secondary data for research, this study was exempted from the requirement for informed consent from participants. This study was approved by the institutional review board of China Medical University (IRB# CMUH104-REC2-115).Developing and applying the propensity score (PS) matching in an observational study to balance the probability of exposure to a specific treatment, based on the observed variables, remained popular and practical ,23. The The most challenging aspect of this study was the elimination of drug selection bias to the infected patients whose antibiotic treatments were arbitrary, if within the guideline. Some patients may have had different infections but received the same antibiotics, whereas others may have had the same infections but received different kinds of antibiotics. And these were at the physician’s discretion at that time; therefore, many confounding factors were not controllable.In this study, PS matching was accordingly chosen and conducted to address the primary and inevitable indication bias. After the PS matching, the chance of receiving antibiotics would become nearly balanced between the case and control subjects .In the PS matching, the scores indicated the probability that certain kind of antibiotic would be prescribed to the patients with infection. The PS was calculated by using multivariate logistic regression to adjust for the observed and available covariates. The PS matching was employed in a 1:10 ratio to match the case and control subjects. The scores were calculated by the logistic regression, including age, sex, household income, and baseline comorbidities (not including the DM severity (aDCSI score) and individual medications). One case was matched with 10 controls, according to the "nearest neighbor matching"  ,27. ThusDifferences in demographic and clinical characteristics and baseline comorbidities were examined using the chi-square test and two-sample t-test. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated for each variable in the logistic regression model. Adjusted ORs for HE were obtained by multivariate logistic regression analysis. The covariates included were different from the ones used for PS matching; DM severity (aDCSI score) and individual medications were added into the regression model for adjustment.Comparison of HE events between antibiotic users and non-users were conducted. The antibiotics included fluoroquinolones, cephalosporins, penicillin, macrolides, sulfonamide, tetracycline, and metronidazole. Fluoroquinolones were further compared with cephalosporins and penicillin for the risk of HE. Finally, a joint effect analysis was performed on the combined use of levofloxacin and antidiabetic drugs.All statistical analyses were performed using SAS 9.4 statistical package . A P-value of 0.05 was set as the threshold of significance.Table 1. Using the multivariate logistic regression model, antibiotic use, compared with no antibiotic use, was found to be associated with an increased risk for HE (adjusted odds ratio (aOR) = 6.08, 95% confidence interval (95% CI): 5.79–6.38) .26,695 and 266,950 PS-matched patients, all with T2D, were enrolled as cases and controls, respectively. Comparisons of the demographic characteristics, and clinical characteristics, individual medications, and aDCSI scores between the two groups are presented in Table 2). The associated risk of HE was significantly increased with levofloxacin than with cephalosporins  and penicillin  (Tables 4). The joint effect analysis displayed that the risk of developing HE associated with levofloxacin was increased when used in combination with insulin  or sulfonylurea  (Table 5).As opposed to antibiotic non-users, those who used fluoroquinolones and sulfonamides had the highest  and second highest  risks for developing HE, respectively  and second (7.20-fold) highest risks for HE, respectively. Compared with cephalosporins, levofloxacin had a 5.13-fold increased risk for HE whereas when compared with penicillin antibiotics, levofloxacin had a 9.40-fold increased risk for HE. Moreover, the results identified that the risk for HE was the highest with levofloxacin, followed by moxifloxacin and ciprofloxacin. Furthermore, patients for whom levofloxacin was concomitantly prescribed with insulin or sulfonylurea were prone to develop HE.On July 10, 2018, the FDA published a drug safety communication on the risks of developing hyperglycemia, hypoglycemia, and impairment of mental health with fluoroquinolone use . Most ofA nested case-control study on 78,433 patients from January, 2006 to November, 2007, reported an increased risk for HE with levofloxacin ; ciprofloxacin ; and moxifloxacin , compared to that with macrolides . On the The mechanism of fluoroquinolone-induced hypoglycemia should be further investigated because of its widespread worldwide use. Animal studies demonstrated increased insulin secretion from rat pancreatic islet cells through blockage of the adenosine triphosphate-dependent potassium channels after exposure to fluoroquinolone antibiotics. Another reported mechanism of fluoroquinolone antibiotics, which was similar to that of sulfonylurea drugs, was enhancement of calcium influx, which can help release insulin-filled vesicles that induce HE –34. FlurTill date, this is the largest cohort study that evaluates the risk associated with the use of fluoroquinolone antibiotics, especially oral levofloxacin, when treating infections in patients with T2D. PS matching was conducted to eliminate indication bias for all antibiotics rather than using macrolides as the reference, based on its some similar indications with fluoroquinolone antibiotics. The selection of case and matched control subjects was done to ensure that the matched pairs (1:10) had taken certain oral antibiotics in the matched calendar year. Even with the development of antidiabetic drugs, sulfonylureas and insulin remain popular medications to control blood sugar. In this study, joint effect analysis was conducted to compare the risk level between the combinations of levofloxacin and antidiabetic drugs. Therefore, the study results would be of much help in clinical practice. At the same time, we provided data that would strongly support the FDA warning on the side effects of hypoglycemia with fluoroquinolone use. Finally, this study included T2D severity, as represented by the aDCSI score.One of the limitations of this study was the lack of serial laboratory data such as HbA1c and daily blood sugar records. Nevertheless, as medical resources in Taiwan are readily available, patients with diabetes are believed to receive adequate adjustment of antidiabetic drugs to achieve acceptable HbA1c levels. Next, the infection sites were not reported in This is the largest case-control study, till date, that utilized a nationwide database with PS matching, to demonstrate that the use of oral levofloxacin, compared with other antibiotics, was significantly associated with the risk for HE in patients with T2D. Future studies on independent datasets from Taiwan and other ethnicities will be conducted to validate the findings from this study. Based on the findings from this study, clinicians should take caution in prescribing levofloxacin, especially when combined with insulin or sulfonylurea.


Background: Recent findings indicate that leisure activity (LA) delays cognitive decline and reduces the risk of dementia. However, the association between LA and brain volume remains unclear. This study aimed to examine the association between LA variety and brain volume with a focus on the hippocampus and gray matter.Methods: Data were obtained from the baseline survey of the Neuron to Environmental Impact across Generations study, which had targeted community-dwelling older adults living in Niigata, Japan. We divided LAs into 10 categories, and counted the number of categories of activities in which the participants engaged. We classified them as follows: 0 , 1, 2, or ≥ 3 types. Brain volume was assessed through magnetic resonance imaging, and hippocampal and gray matter volumes were ascertained.Results: The sample size was 482. Multiple linear regression analysis showed that hippocampal and gray matter volumes were significantly greater among participants with ≥ 3 types of LAs than among their no-activity counterparts. Hippocampal volume was significantly greater among those who engaged in one type of LA than among those who engaged in no such activity. Sex-stratified analysis revealed that hippocampal volumes were significantly greater among males who engaged in ≥ 3 types of LAs and one type of LA. However, no such association was found among females.Conclusion: The present findings suggest that engaging in a wide range of LAs is related to hippocampal and gray matter volumes. Furthermore, there was a sex difference in the association between LA variety and brain volume. Non-pharmacological approaches are expected to delay cognitive decline and reduce the risk of dementia. Leisure activity (LA), which refers to activities that “individuals engage in for enjoyment or well-being that are independent of activities of daily living”  is one oThere is another concept called brain reserve, which explains why individuals differ in their susceptibility to cognitive aging and the conditions associated with Alzheimer’s disease . Brain vEngaging in a broad (rather than a narrow) range of LAs may strongly affect brain volume as it may lead to strong stimulation of the brain and enhance neuroplasticity. Several studies have found that engaging in a broader range of LAs lowers the risk of dementia , and broAccordingly, we examined the association between LA variety and brain volume with a focus on the hippocampus and gray matter among community-dwelling older adults in Japan.Data were obtained from the baseline survey of the Neuron to Environmental Impact across Generations (NEIGE) study conducted in Tokamachi City, Niigata, Japan, in 2017. Tokamachi City is a rural area located approximately 180 km northwest of Tokyo. The population of the city was 51,964, and the proportion of older adults was 36.9% as of January 31, 2020. Of all those aged 65–84 years who were living in Tokamachi City, 1346 individuals who were not recipients of long-term care insurance and were not admitted to a hospital or nursing home were randomly selected from a resident registry. A total of 527 individuals, who agreed to participate in the NEIGE study, were enrolled in the survey. A detailed profile of this study  is elsewhere .The study protocol was approved by The University Ethics Committee . We explained the purpose, methods, and ethical considerations of this study and obtained written informed consent from all participants based on the Declaration of Helsinki before enrolment.We developed original questions about LA. First, the participants responded with either “yes” or “no” to indicate whether they were currently engaged in LA. If the participant’s response was “yes,” they were further asked to indicate whether they engaged in any of the following 20 activities: grand golf, golf, pachinko , gymnastics or tai chi, walking or jogging, computer use, reading books, playing board games, painting, fishing, karaoke, dancing, craftwork, calligraphy, tea ceremony or flower arrangement, crop work, gardening, photography, traveling, and others. These activities are regarded as popular LAs in Japan based on previous studies and literatures . ParticiAfter data were collected, we classified the items (including “Others” responses) into the following 10 categories of LAs: (1) physical activities ; (2) gaming ; (3) traveling (traveling and driving); (4) creative activities ; (5) cultural activities ; (6) developmental activities ; (7) agricultural activities (crop work and gardening); (8) singing (chorus and karaoke); (9) gambling (pachinko and stock investment); and (10) technology use (computer use and photography). We developed these categories based on a review of previous studies conducted in Japan . Finally1.Each participant underwent magnetic resonance imaging (MRI) at the Niigata Prefectural Tokamachi Hospital. We used a 1.5 Tesla scanner  in three-dimensional mode with the following parameters: repetition time = 1,700 ms; echo time = 4.31 ms; inversion time = 800 ms; flip angle = 15°; slice thickness = 1.25 mm; field of view = 230 × 230; matrix size = 256 × 256; and number of slices = 144. Segmentation and volume calculations were undertaken using FreeSurfer Version 6.0For this procedure, we removed non-brain tissue , normalized the voxel intensities, and labeled the volumes of each segmentation using FreeSurfer. Hippocampal volume, total gray matter volume, and intracranial volume were automatically derived and labeled. Hippocampal volume was separately determined for the left and right hemispheres, and the total volume of the left and right hippocampus  was used in the analysis.Sociodemographic factors, health conditions, physical activity, and social interaction served as covariates. The information regarding the covariates was collected with a self-reported questionnaire and interviews conducted by trained staff. The assessed sociodemographic factors included age, sex, years of education (≤ 9 years or ≥ 10 years), annual household income , current occupational status (employed or unemployed).The assessed health conditions included comorbidities and depressive mood. Information on comorbidities was obtained through interviews conducted by medical doctors or nurses. Hypertension, diabetes, cardiovascular disease, cerebrovascular disease, and neuropsychiatric disorders served as covariates. Depressive mood was assessed using the Japanese version of the Geriatric Depression Scale (GDS): Short Form . The GDSPhysical activity was assessed using an accelerometer, namely, the Active style Pro HJA-750C . The participants were asked to wear the accelerometer over their waist on an elasticated belt for seven consecutive days while awake, and average daily amount of moderate-to-vigorous  physical activity served as covariates. Participants who did not have valid data for more than 4 days were excluded. A more detailed description of the accelerometer is available elsewhere .Social interaction was assessed based on the frequency of meeting friends and acquaintances. The frequency of meeting friends and acquaintances was enquired with a question comprising six categories . We divided the participants based on this frequency into two groups: < 1 day/week and ≥ 1 day/week.In addition to these covariates, we assessed the participants’ cognitive status using the Mini-Mental State Examination-Japanese version (MMSE-J) . The MMSParticipant’s characteristics by categories of LAs were compared using one-way analysis of variance for continuous variables and chi-square test for categorical variables.We conducted multiple linear regression analysis to examine the association between LA variety and brain volume. We separately entered hippocampal and gray matter volumes as dependent variables; the different categories of LAs (divided into quartiles) served as the independent variable. The LA categories were entered into the regression models as dummy variables, and the no-activity group  served as the reference. Model 1 was adjusted for age, sex, and years of education, which are generally included as covariates in studies on LA, and intracranial volume. Model 2 was additionally adjusted for annual household income, occupational status, comorbidities, GDS score, physical activity, and social interaction which are potential confounding factors. Further, to examine sex differences, the data were stratified by sex, and the analysis was separately conducted for males and females.For reference, we conducted the following two analyses: (1) stratification by left and right hippocampus as some studies indicated differential effect of health behaviors on brain volume by the brain side  and (2) The associations were examined by computing regression coefficients (b) and 95% confidence intervals (CIs). All analyses were conducted using IBM Statistical Package for the Social Sciences version 23 .Of the 527 participants, we excluded 27 individuals whose MRI data were not of sufficient quality and 18 others with missing data for any of the covariates. Thus, the data of 482 participants were analyzed.Participant characteristics are presented in p < 0.05).Further, participants who engaged in one type of LA had greater total hippocampal volumes than their no-activity counterparts in both Models 1 (213.5 [34.3–392.8]) and 2 (205.9 [23.8–388.1]).We separately conducted multiple regression analysis using data collected from males and females . There wFor reference, the results of a separate analysis conducted for the left and right hippocampal volumes are present in These results did not change significantly when we excluded the three participants who had been diagnosed with dementia  from the analysis due to concerns about recall bias .This study examined the association between LA variety and brain volume, with a focus on the hippocampus and gray matter, among community-dwelling Japanese older adults. The results showed that hippocampal and gray matter volumes were significantly greater among those who engaged in ≥ 3 types of LAs than those who engaged in no such activity. Moreover, total hippocampal volumes were greater among those who engaged in one type of LA than among those who engaged in no such activity. Furthermore, there was a sex difference in the association between LA variety and brain volume, which was more pronounced among males than among females.3/7213 mm3) and approximately 1.3% greater total gray matter volume (7954 mm3/569911 mm3) than their no-activity counterparts. This indicates that there is a difference in the brain volume equivalent to 3–4 years of atrophy in those who engage in ≥ 3 types of LAs than those who engage in no such activity. According to the evidence for the basic biological consequences of environmental enrichment, more complex and stimulating environments induce neural and synaptic structural changes, such as dendritic arborization and synaptogenesis  rather than a combination of 2 types of interventions (photography and craftwork) was more effective in improving episodic memory . Those wThis study yielded novel findings about the association between LA variety and brain volume; however, this study also has some limitations. First, we did not assess LAs in great detail. Indeed, the effect of LA on brain volume may differ depending on LA frequency, intensity, location, and group members. Such information should be collected in future studies. In addition, although we focused on LA variety and classified LAs into 10 categories on the basis of the types of LA, there is diversity even within the same type of LA when examined in detail. Therefore, not only the LA variety but also the number of LAs is important. We intend to investigate the relationship between the number of each LA and brain volume in a future study. Second, this study was conducted in a rural area; therefore, care should be taken while generalizing the findings. Third, the fact that the association between LA and hippocampal volume was different in the left and right sides, and the association was stronger in people with diabetes needs to be investigated in future studies. Finally, because this study adopted a cross-sectional design, we could not determine if LA variety results in greater brain volume or if people with greater brain volumes engage in a broader range of LAs. Therefore, future studies should examine the association between LA and brain volume longitudinally.The present findings suggest that engaging in a wide range of LAs is related to greater total hippocampal and gray matter volumes among community-dwelling older adults. Moreover, there was a sex difference in the association between LA variety and brain volume. Further research is needed to longitudinally examine the causal relationship between LA variety and brain volume.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Niigata University and Tokyo Medical University. The patients/participants provided their written informed consent to participate in this study.AI and HM: conceptualization, formal analysis, and methodology. MM, SA, SI, TF, and YS: data curation and project administration. HM, MM, SA, SI, TF, and YS: investigation. YS: supervision. AI and YS: writing–original draft. All authors have read and approved the published version of the manuscript.This study received funding from the Pfizer Health Research Foundation. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Orthogeriatrics is increasingly recommended in the care of hip fracture patients, although evidence for this model is conflicting or at least limited. Furthermore, there is no conclusive evidence on which model  is superior. The review summarizes the effect of orthogeriatric care for hip fracture patients on length of stay (LOS), time to surgery (TTS), in-hospital mortality, 1-year mortality, 30-day readmission rate, functional outcome, complication rate, and cost. Two independent reviewers retrieved randomized controlled trials, controlled observational studies, and pre/post analyses. Random-effects meta-analysis was performed. Thirty-seven studies were included, totaling 37.294 patients. Orthogeriatric care significantly reduced LOS , but heterogeneity warrants caution in interpreting this finding. Orthogeriatrics also resulted in a 28% lower risk of in-hospital mortality [95%CI ], a 14% lower risk of 1-year mortality [95%CI ], and a 19% lower risk of delirium [95%CI ]. No significant effect was observed on TTS and 30-day readmission rate. No consistent effect was found on functional outcome. Numerically lower numbers of complications were observed in orthogeriatric care, yet some complications occurred more frequently in GW and ICM. Limited data suggest orthogeriatrics is cost-effective. There is moderate quality evidence that orthogeriatrics reduces LOS, in-hospital mortality, 1-year mortality, and delirium of hip fracture patients and may reduce complications and cost, while the effect on functional outcome is inconsistent. There is currently insufficient evidence to recommend one or the other type of orthogeriatric care model.The online version contains supplementary material available at 10.1007/s00223-021-00913-5. Hip fractures are the most devastating type of fragility fractures in older patients, as they contribute most to the morbidity, mortality, and economic cost associated with fragility fractures . By the Hip fracture patients are also at high risk of postoperative complications. Comorbidities, polypharmacy, and geriatric syndromes such as sarcopenia, dementia, delirium, and malnutrition challenge orthopedic surgeons taking care of hip fracture patients . A multiSome recent meta-analyses have shown that orthogeriatric care significantly reduces long-term mortality , 12. HowTaken together, previous studies have investigated the effect of orthogeriatric care models on outcomes of hip fracture patients. Although orthogeriatric care is increasingly recommended over usual care to improve outcomes of hip fracture patients, the evidence for some of the outcomes is conflicting, or at least limited. Furthermore, there is no conclusive evidence which orthogeriatric care model is superior. Therefore, the primary objective of this systematic review is to summarize the effect of orthogeriatric care on outcomes of hip fracture patients . The secondary objective is to investigate whether these outcomes are differentially affected by the one or the other type of orthogeriatric care model.For the reporting of this systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed . The resFirst, three databases  were systematically searched and results were extracted from the earliest date available until August 5th, 2020. Secondly, duplicate records were removed using Mendeley. Third, the articles were hand-screened by two independent researchers, based on title and/or abstract. Subsequently, full-text articles were screened by the same researchers. A third researcher was consulted in case of disagreement. Disagreements were resolved by discussion until consensus was reached. Finally, a manual search in the reference section of the selected articles was performed to identify additional relevant articles.Randomized controlled trials (RCTs), controlled observational studies, pre/post analyses, as well as other systematic reviews and meta-analyses (as source documents to find primary studies) in English were considered eligible for inclusion in this review. Studies without a control group, letters to the editor, case reports, comments, and editorials were excluded. We included studies in persons older than 55 years, hospitalized with a recent hip fracture, while studies in persons with other fracture types, pathological hip fractures, and high traumatic injuries were excluded. Since this systematic review compares different orthogeriatric care models, only articles containing a clear description of the orthogeriatric care model and the usual care model were included. More specifically, collaboration between an orthopedic or trauma surgeon and a geriatrician was needed. Authors of several publications were contacted via e-mail to provide additional information on hip fracture outcomes when needed. In case studies described data from the same cohorts, the most recent data were included for analysis. Studies were excluded when they only reported data of which more recent results were available in another included publication of the same cohort.For the quality assessment of the articles, the Cochrane Collaboration’s tool for assessing risk of bias was used, evaluating six criteria . These cStudies were categorized according to the type of care model: (1) geriatric medicine consult service ; (2) geriatric medical ward ; (3) integrated care model ; and (4) standard of care (SOC). The extracted data included type of study, publication year, number of participants, demographic characteristics of the participants, inclusion and exclusion criteria, and country of origin. The following pre-defined outcome parameters were extracted: LOS, TTS, in-hospital mortality, 1-year mortality, 30-day readmission rate, functional outcomes, complication rate, and cost associated with the different orthogeriatric care models.R, using primarily the metacont function from the package meta. Heterogeneity was assessed initially on a fixed-effect model. In light of the high heterogeneity and given the fact that the studies characteristics greatly differ in time and space, we recoursed to random-effects modeling. The variance of the random component was estimated using a Sidik–Jonkman estimator with Knapp–Hartung adjustments. Studies were considered outlying if their confidence interval (CI) did not overlap with the 95% CI of the pooled effect. The CI of the studies were constructed using Dunn’s procedure, i.e., each interval having a confidence level 1—5%/k, where k is the number of intervals constructed. The influence of each of the separate trials was tested using a leave-one-out procedure, which relies on Viechtbauer and Cheung’s cut-off for extreme values in the graph. The aim was to identify studies with important influence on the overall result. To control for publication bias, the results of the included studies are visualized in a funnel plot. Studies were excluded from the analysis if the reported data lack the necessary information that could not be obtained by addressing the authors directly. Decisions to exclude other studies were made based on the aforementioned procedure based on the CI, influence analysis, and funnel plots. Extracted data for functional outcomes, complication rate, and cost associated with the orthogeriatric care models are described with tables in a narrative analysis, since the results were very heterogeneous.A meta-analysis was carried out for LOS, TTS, in-hospital mortality, 1-year mortality, 30-day readmission rate, and delirium. The analyses were performed in The PRISMA flowchart with the study selection process is shown in Fig. vs. 1512 (SOC) in ten studies, 5383 (GW) vs. 8756 (SOC) in eight studies, and 6544 (ICM) vs. 13,963 (SOC) in 20 studies. The majority of the studies (25 out of 37) originated from European countries. The remaining 12 included articles originated from very different areas: Asia (three), USA (four), Australia (two), and the Middle-East (three).Table As indicated in Table Of the 37 included studies, only ten studies were RCTs –25. Six The effect of orthogeriatric care on LOS was evaluated with a meta-analysis. Data on LOS were available in 36 studies. Ten of these could not be included in the meta-analysis as the reported data did not correspond to the data required for the meta-analysis , 42, 48.I2 = 80%), indicating that the results should be interpreted with caution. The above procedure pertaining to the CI was applied and suggested to remove the studies of Duaso et al. and Naglie et al. from the result of the meta-analysis [The random-effects model showed a statistically significant decrease of 1.55 days of LOS [95% confidence interval (CI) ] for all orthogeriatric care models combined compared to SOC. The heterogeneity of the results was very high , which results in large CI . The result of the ICM subgroup was statistically significant, whereas the result of the GW subgroup was not. However, in the GCS subgroup, there was less heterogeneity [I2 = 61%] with smaller 95% CI  and the effect on LOS was significantly different from the control group.Considering the individual effect of the different orthogeriatric care models, the data of ICM and GW were very heterogeneous , which could complicate the interpretation of the results.The random-effects model showed a significant total mean difference of 0.23 days , indicating that orthogeriatric care reduced TTS with 0.23 days (5.52 h) as compared to SOC. However, this result was not significant. In this analysis, three studies were identified as outliers: Biber et al., Duaso et al., and Gregersen et al. , 43, 46., 0.01], I2 = 0%), indicating that all three studies showed similar results. The ICM subgroup showed a non-significant reduction in TTS with 0.29 days (6.96 h), with 95% CI . For the GW, only two studies were included, and the effect of this model was not significantly different from the control group.In the subgroups ICM, GCS, and GW, there was a significant reduction in TTS with 0.40 days (9.6 h) in the GCS subgroup, with 95% CI . Heterogeneity was very low . The study of Deschodt et al. . This indicates a 28% lower risk of in-hospital mortality for hip fracture patients included in an orthogeriatric care model as compared to SOC. No studies were outlying and heterogeneity was moderate  resulted in a 14% lower risk of 1-year mortality as compared to SOC. Subgroup analyses showed no significant differences in 1-year mortality between each orthogeriatric care model separately compared to SOC.The impact of orthogeriatric care on 30-day readmission rate was evaluated in a meta-analysis of six studies , 41, 45 The overall effect was not significant . However, only a small amount of data was included in the meta-analysis. No conclusion could be drawn on the effect of the three subgroups separately because of the low number of trials included in each subgroup .Six articles reported data on functional outcome, evaluated by the performance of activities of daily living (ADL) Table  18, 21–, 27, 34.Bano et al. assessed functional outcome by using the Katz Index of Independence in Activities of Daily Living (ADL), which measures (in)dependence in six self-care activities  . Higher vs. SOC)  . HoweverA short(er) LOS is used as an indicator of the efficacy of the provided care. In addition, it may be associated with a lower total cost per patient. However, since aforementioned factors such as healthcare organization contribute to LOS, the percentage of patients discharged within a specified time frame may be a more useful quality indicator than LOS, as suggested by Baroni et al. . In addiI2 0.0%], but large heterogeneity in the ICM subgroup and too few studies to perform a GW meta-analysis  in an RCT with 2970 hip fracture patients aged ≥ 45 years did not reduce the risk of mortality nor the composite endpoint of major complications  at 90 days after randomization . HoweverHip fracture patients admitted to orthogeriatric care had a 28% lower risk of in-hospital mortality and a 14% lower risk of 1-year mortality as compared to those admitted to SOC. For the subgroup analyses, only in the ICM subgroup, the risk of in-hospital mortality was significantly decreased. A trend to lower in-hospital mortality and a trend to lower 1-year mortality were observed for the GCS and GW subgroups, and for the ICM, GCS, and GW subgroups, respectively.Our data partly confirm the results of previous meta-analyses , 12. GriMortality after hip fracture repair is determined by a number of factors. A recent prospective cohort study in 1083 hip fracture patients aged ≥ 65 years identified advancing age, higher baseline Charlson comorbidity index (CCI), higher pre-fracture dependence in ADL, hospital-acquired pressure ulcers, and lack of recovery from ambulation as independent predictors of 1-year mortality . TTS, hoThe effect of orthogeriatric care as a whole on 30-day readmission rate was not significant. No conclusion could be made about the subgroups because of the limited number of included studies.In a prospective study of 236 hip fracture patients, 30.1% was readmitted within 12 months of discharge and 41% of all readmissions occurred in the first 3 months after discharge. Surgical complicates accounted for less than 10% of the readmissions, and heart failure, stroke, and pneumonia together for 45% . A systeLOS, mortality, and 30-day readmission rate are closely related, with both LOS and readmission rate being strong predictors of mortality. While it is reassuring that reduced LOS does not necessarily increase readmission rate , prolongMore research is needed to determine the effect of orthogeriatric as a whole and of the different orthogeriatric care models on 30-day readmission rate.We found that the effect of orthogeriatrics on functional outcome (measured as ADL performance) was inconsistent, with patients admitted to ICM as well as to GW and GCS showing better ADL performance , 21, 34 I2 = 0%] that persisted at twelve months   .In contrast to LOS, TTS, and  mortality, a limited number of studies has evaluated the effect of orthogeriatric care on functional outcome. Yet, the main purpose of hip fracture repair is to restore the pre-fracture level of functional performance of hip fracture patients. Therefore, more RCTs with standardized orthogeriatric care protocols and outcome measures should be done to determine the effect of orthogeriatric care and its different modalities on functional outcome. In this context, it should be noted that the assessment of functional outcome by tools such as the Barthel index, although commonly used in clinical practice and sensitive to detect declines in health status, may be less sensitive to evaluate small changes in the functional performance of hip fracture patients . TherefoIn general, numerically less medical and surgical complications were observed in the intervention groups (orthogeriatric care) compared to SOC. This is explained by the introduction of the CGA  and the use of standardized protocols  in orthogeriatric care. Remarkably, we observed that some complications occurred more frequently in orthogeriatric care models; more specifically in the GW and the ICM, such as more medical complications in Frenkel et al. (GW)  and a hivs. orthopedic ward) might have influenced the reported incidence, although none of the subgroup analyses showed a significant result. Similar to our findings, the meta-analysis of Wang et al. on the effect of orthogeriatric care found a significant reduction in the incidence of perioperative delirium   .I2 = 0%], but not of medical complications . The large heterogeneity in this meta-analysis of Mukherjee et al. and the fact that only two trials were included strongly limit the possibility to draw conclusions based on those data.Mukherjee et al. recently performed a meta-analysis on the effect of orthogeriatric care on hospital-acquired pressure ulcers and on medical complications. Compared to SOC, the orthogeriatric care group showed a lower risk of pressure ulcers [OR 0.30; 95% CI , vs. SOC, and not in GCS vs. SOC, but there was no significant difference in the complication rate between ICM and GCS [Further research is needed to determine which of the three orthogeriatric care models is the best to reduce complications. The study of Baroni et al. is the only one that directly compares two models: the number of in-hospital complications was significantly lower in ICM  and GCS .A comparison between studies of the healthcare expenditure of orthogeriatric care is difficult because of the variations in follow-up  and costs included in the analyses . In addition, also differences in guidelines, reimbursement criteria, healthcare budget, etc., between regional and national healthcare centers make a comparison of cost-effectiveness a complex exercise . In geneIn Table This systematic review and meta-analysis have several strengths. One of the strengths is the large number of hip fracture outcomes that is evaluated. In addition, a large number of studies is included, some of which have not been included in a systematic review before. 30-day readmission rate is included in a meta-analysis for the first time, although the number of included studies turned out to be too low to make an overall conclusion on the effect of orthogeriatric care on this outcome.Several limitations need to be taken into account as well. First, some studies showed high heterogeneity, were considered outlying or had too important influence on the overall result, making it difficult to interpret the data and to draw final conclusions. Second, not all studies could be included in the meta-analyses because of missing data although the authors were contacted to provide additional information. This could possibly bias some of the results. Other studies were lacking a control group or did not clearly describe the orthogeriatric intervention. Third, to assess the effect on some outcomes, especially of the separate orthogeriatric models, the number of studies that could be included was too low. Fourth, we did not perform an individual participant data meta-analysis. Another limitation is that the subdivision of the different care models is quite arbitrary. We made this distinction based on the involvement of an orthopedic surgeon and geriatrician as well as on the place where the care was given. However, in clinical practice, true orthogeriatric care additionally includes the expertise of a whole multidisciplinary team, including a nurse, physiotherapist, occupational therapist, dietician, speech therapist, and social worker. Fifth, through the title and abstract screening, 14 articles were identified that might have been suitable for the analyses in this study, but were excluded due to the lack of available full-text. The inclusion of these articles could have altered some of the results. Finally, although we included a large set of outcome parameters, we did not assess al the outcomes that were recommended by Liem et al. for the evaluation of orthogeriatric care of hip fracture patients . In addiIn this systematic review and meta-analysis, orthogeriatric care had a positive effect  on LOS, in-hospital mortality, 1-year mortality, and delirium of hip fracture patients. For LOS and TTS, the orthopedic surgeon-led model with the patient on an orthopedic ward and systematic geriatric medicine consult service (GCS) had the most consistent effect, while for in-hospital mortality, only the model with shared responsibility of the orthopedic surgeon and the geriatrician (ICM) showed a significant risk reduction. The evidence for an effect on 30-day readmission rate and functional outcome was inconsistent, while some evidence exists for less medical and surgical complications and less healthcare costs associated with orthogeriatric care. Increased awareness and routine screening, however, may explain the higher incidence of geriatric syndromes that can be observed in orthogeriatric care units. We found substantial heterogeneity and limited number of trials for some outcomes in addition to an almost complete lack of direct comparison between ICM, GCS, and GW. Therefore, adequately powered RCTs with a direct comparison between different models of care are needed to evaluate the effect of orthogeriatrics on hip fracture patients, especially with respect to 30-day readmission rate and functional outcomes.Supplementary file1 (DOCX 30 kb) Search stringsBelow is the link to the electronic supplementary material.


Objectives: To investigate the association between socio-economic factors and the risk of preeclampsia in Sweden, specifically investigating if this relationship is confounded by maternal region of birth. Study design: All singleton births between 1999 and 2009 in an ethnically diverse area in southern Sweden, totaling 46,618 pregnancies, were included in this study. The data on maternal pregnancy outcomes were retrieved from a regional birth register and socio-economic variables from Statistics Sweden. The risk ratios for preeclampsia were calculated for educational level and household disposable income, adjusting for maternal region of birth, maternal age, body mass index, parity, and smoking. Results: Low income levels were associated with a higher risk for preeclampsia, adjusted risk ratio (aRR) = 1.25  and aRR = 1.36  for the two lowest quintiles, respectively, compared to the highest. There was an educational gradient in preeclampsia risk, although not all categories reached statistical significance: aRR = 1.16, (95% CI: 0.89–1.50) for low educational attainment and aRR = 1.23  for intermediate educational attainment compared to women with highest education. The socio-economic gradient remained after adjusting for region of birth. There was a lower risk for preeclampsia for women born in Asia, aRR = 0.60 , regardless of socio-economic position. Conclusion: An increased risk for preeclampsia was seen for women with measures of lower socio-economic position, even in a universal, government-funded healthcare setting. The relationship was not explained by region of birth, indicating that the excess risk is not due to ethnically differential genetic pre-disposition but rather due to modifiable factors. Preeclampsia is one of the most common maternal morbidities during pregnancy, estimated to affect 2–8% of all pregnancies worldwide . In spitIn Sweden, where implementations have been made to make maternal health care universal and accessible to all pregnant women, studies report socio-economic disparities in the risk for adverse pregnancy outcomes, where immigrant women or women with lower socio-economic position have been shown to be at increased risk ,3,4. SimFurthermore, considering that previous studies have shown an ethnic variation in the incidence of preeclampsia ,18, and Hence, the study had two aims. First, to examine whether socio-economic factors, measured as maternal educational level and household disposable income, are associated with the risk of preeclampsia. The second aim was to investigate if the maternal region of birth influences preeclampsia risk, and whether it confounds the relationship with socio-economic factors.The study population comes from previously established pregnancy cohort, The Maternal Air Pollution in Southern Sweden (MAPSS). The cohort includes virtually all singleton births between 1999 and 2009 in the Malmö–Lund–Trelleborg area in southern Sweden. It comprises more than 48,000 births and was constructed by linking a regional birth register, Perinatal Revision South, with socio-demographic variables from Statistics Sweden. All individuals in Sweden are assigned a 10-digit personal identification number at birth, enabling the linkage between different data sources.The Perinatal Revision South is a population-based regional birth register established in 1994, covering the whole of southern Sweden, with the aim of healthcare quality surveillance within obstetrics and perinatal care. All hospitals in the region with delivery units report to the register, and reporting is based on copies of standardized medical journals used during maternal healthcare at birth and the immediate neonatal period. In Sweden, home births are rare, maternal healthcare is free, and almost all pregnant women attend, allowing for very high register coverage.Women with preeclampsia were noted in the register by ICD-10 codes O14.0, O14.9, and O11.9, corresponding to the definitions of preeclampsia for that time: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg (measured twice with at least 6 h in between) and proteinuria >0.3 g/day, after 20 weeks of gestation. The diagnostic criterion for severe preeclampsia was blood pressure ≥160/110 mmHg or proteinuria ≥5 g/day. There were 1383 (2.8%) women with preeclampsia, and 236 (0.5%) of them were classified as severe (ICD-10 codes: O14.1 and O15). No distinction between early- and late-onset preeclampsia is made within the register.n = 2401, 4.9%) were included in the analyses as a separate category.Information on socio-economic determinants and region of birth was retrieved from the LISA database  and the Total Population Register, administered by Statistics Sweden. We retrieved household disposable income  for the year of the birth of the baby. Individuals ≥18 years with common children sharing place of residence are considered constituting a household in the registers, regardless of marital status. However, unmarried couples expecting their first child are not registered as a household, and thus the income levels for unmarried primiparous women are based solely on her income. We divided household disposable income into quintiles based on income levels for the total study population, provided the registered income was ≥SEK 80,000  . The womThe highest maternal educational level was retrieved for the year of the birth of the child and divided into (i) primary education , (ii) secondary education , and (iii) post-secondary education/university level (42%). Statistics Sweden collects data on maternal education mainly from the Register of Education. For the women who did not complete their education in Sweden (mainly foreign-born), the information is collected from additional sources . For 2058 (4.2%) women, there were no data on registered education.n = 8 women with unknown or no region of birth registered.Statistics Sweden does not provide country-specific data on maternal region of birth, but it is proxied by the following groups: 1. Sweden, 2. other Nordic country, 3. other country in the European Union, 4. other European country (non-EU), 5. North America, 6. South America, 7. Africa, 8. Asia, 9. Oceania, and 10. the former Soviet Union. Due to small numbers in several of the categories, we aggregated the data into Sweden, Nordic countries, Europe including former Soviet Union, the Americas, Asia and Oceania, and, lastly, Africa. We excluded 2), and maternal smoking during pregnancy .n = 2058 (4.2%) women with missing data on educational level were excluded from the study, as missingness for education was not at random . Thus, imputing values for education might introduce bias [n = 5645 (12.1%) women with missing data on BMI and n = 3327 (7.1%) on smoking during pregnancy. Having missing data on BMI and smoking was associated with being younger, being born outside of Sweden, and having lower educational attainment but not with the outcome. Missing data for BMI and smoking were imputed using multivariate imputation by chained equations with a generalized logit distribution (50 imputations).A total of 8 women with missing data on region of birth and uce bias . CharactTo describe differences between the populations according to preeclampsia status, chi-square tests and Mann–Whitney U (Wilcoxon) test were used. Risk ratios for preeclampsia by socio-economic variables and region of birth were calculated using a log-binomial regression model, generating risk ratios (RR) and 95% confidence intervals (CI). Dependence between data due to multiple pregnancies within the same woman was accounted for by adding a cluster term to estimate robust standard errors.Initial models investigated maternal education and income separately, after which we included the following set of potential mediators: maternal age, BMI, parity, and smoking during pregnancy. To evaluate the possibility that region of birth confounds the association, we further included region of birth in the model. We also performed analyses with region of birth as the determinant of interest, subsequently adjusting for socio-economic measures and the confounders above.For income, we performed a subset of analyses including only multiparous women to account for potential misclassification regarding unmarried cohabiting women not registered as a household.The statistical analysis was performed using SAS version 9.4 .n = 1345 were diagnosed with preeclampsia. Women who developed preeclampsia were more likely to be primiparous, obese, and non-smokers .The basic characteristics of the cohort are shown in The crude and adjusted risk ratios for preeclampsia by different levels of maternal education and income are shown in There was a statistically significant decreased risk for women from Asian countries, adjusted RR = 0.60 , but all other regions of birth showed similar risks as for Swedish-born women .In these population-based data covering all singleton births in a diverse area of southern Sweden, a socio-economic gradient in the risk of preeclampsia was revealed, where women with lower income levels and lower educational attainment were at higher risk to develop the disease. The gradient was stable after adjustment for the maternal region of origin, indicating that the excess risk does not seem, at large, to be driven by a differential genetic pre-disposition, although we did find that women from Asian countries were at lower risk to develop preeclampsia regardless of socio-economic position.Our study has several strengths. The use of population-based register data, collected routinely within maternal healthcare and including virtually all singleton births within a diverse uptake area, makes the risk of selective participation unlikely. Efforts have been implemented to make maternal healthcare in Sweden accessible and equal, e.g., it is completely free of charge. Attendance rates are very high (with only 1‰ abstaining completely from participating) , which iSocial deprivation , low incThe current study is an addition to previous studies, many of which lacked information on maternal region of birth ,9,10,15 With one exception, we did not find a differential risk in preeclampsia for the other regions of births compared to Swedish-born women. However, it should be noted that the power to detect such differences might have been low for some regions due to few women in these groups. The lower risk for preeclampsia for women born in Asian countries is in line with a previous report . A recenThere are limitations in this study that warrant further discussion. We did not have access to country-specific data on maternal region of origin, and due to small numbers in some of the groups, we had to group women in relatively large geographical regions of origin, rather than stratification by, e.g., low- vs. high-income countries. Consequently, the power to detect associations between preeclampsia and region of birth was low. In addition, different immigrant groups that have been shown to fare differently well in Sweden might have been analyzed together . FurtherUnmarried couples expecting their first child are not registered as a household by Statistics Sweden; the income levels for these women are based on maternal income only, which might have underestimated the income level for some women. After the birth of the first child, the parents are considered a household regardless of marital status if they share place of residency. We believe this would be less of a problem for women born outside Sweden, as studies have shown that they tend to marry to a higher extent and at an earlier age . In addiSome clinical information known to be relevant for preeclampsia risk was lacking, such as certain maternal pre-existing conditions, twin pregnancies, and the use of assisted reproduction. However, these factors are, at large, not associated with socio-economic position in Sweden  and would likely not have altered the results. Lastly, the gestational week of preeclampsia onset is not recorded in the register, which precluded any analyses stratified by early and late onset preeclampsia, respectively.In summary, the findings in this study indicate that socio-economic factors contribute to the development of preeclampsia and that the differential risk likely is not solely a reflection of maternal region of birth, although data granularity was too low to permit detailed analyses on maternal origin. This implies an excess risk that is potentially modifiable and further studies should investigate if maternal health in vulnerable sub-groups can be improved by directed efforts within maternal healthcare.


Objective: To investigate the causal association of domain-specific sedentary behaviors with cerebrovascular diseases and neurodegenerative diseases, and the potential mediators among these associations.Methods: Genetic instruments were identified for television watching, computer use and driving behavior from a genome-wide association study including 408,815 subjects. Mendelian randomization (MR) analysis was used to estimate the causal effect of sedentary behaviors on the cerebrovascular diseases and neurodegenerative diseases. Multivariable MR analysis was applied to adjust potential confounding factors, and mediation analysis was conducted to explore potential mediators.Results: Genetically predisposition to 1.5 h/day increase in leisure time watching television was associated with increased risk of all-cause stroke , and ischemic stroke . Interestingly, television watching may decrease the risk of Parkinson’s disease . Television watching was a detrimental factor of cognitive performance . Sensitivity analyses using leave out method and MR-PRESSO method suggested weak evidence of pleiotropy.Conclusion: We provided genetic evidence for the causal association of television watching with increased risk of all-cause stroke and ischemic stroke, decreased risk of Parkinson’s disease, and worse cognitive performance. The results should be interpreted with caution considering the pleiotropy. Recently, prolonged time spent on sedentary behaviors has been suggested to increase the risk of cardiovascular disease . HoweverMendelian randomization (MR) is an instrumental variable (IV) analysis approach that can be used to strengthen the causal inference in observational epidemiological studies . In brieLeveraging the most updated genome-wide association study (GWAS) data for domain-specific sedentary behaviors, stroke and its subtypes including ischemic stroke (IS) and intracerebral hemorrhage (ICH), neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS) and cognitive performance (CP), and additional confounding traits, we aim to: (i) investigate the association of domain-specific sedentary behaviors with stroke and its subtypes and neurodegenerative diseases; (ii) determine the potential mediators of these associations and clarify the proportions mediated.p < 5 × 10–8. Three phenotypes of domain-specific sedentary behaviors were studied in that GWAS, including leisure television watching, computer use and driving behavior . If SNPs were in linkage disequilibrium, the SNP with greater p value would be removed. If a SNP was not available in the outcome dataset, we would search this SNP in an online tool named SNiPa1 based on European population genotype data and another SNP which was in linkage disequilibrium (r2 > 0.8) with such SNP would be identified as a proxy SNP. For palindromic SNPs, if the minor allele frequency is smaller than 0.42, then this SNP was regarded as inferable. The allele frequency of the effect allele gave us information whether the exposure effect allele and the outcome effect allele were on the same direction of strand. Any palindromic SNPs that had minor allele frequency larger than 0.42  were regarded as not inferable and we would discard these SNPs. The unit for the genetic estimates of exposures was 1 SD increase in leisure sedentary time. Specifically, it was about 1.5 h per day (h/day) for television watching, 1.2 h/day for computer use, and 1.0 h/day for driving. The overall F statistics was 5,747, 1,685, and 193 for the instrumental variables of television watching, computer use and driving, respectively  and non-lobar ICH (n = 881) , as previously described, which was a biomarker of cerebral small vessel disease  were obtained from the MEGASTROKE consortium, with up to 40,585 cases and 406,111 controls of European ancestry. Among all stroke cases, 34,217 were subclassified as IS, which were further divided into three subtypes: 4,373 for large-artery atherosclerotic stroke (LAS), 7,193 for cardioembolic stroke (CES) and 5,386 for small-vessel stroke (SVS) . Geneticn = 881) . In addi disease . Summary disease . Genetic disease . The gen disease . Data soAll studies included in the GWASs had been approved by relevant ethical review committees, and participants provided written informed consent. The current study only used summary-level data which was publicly available. Thus, additional ethical review for this study was not needed.p value of <1.3 × 10–3, corresponding to a Bonferroni correction of 39 independent tests (3 exposures and 13 outcomes). A p value between 1.3 × 10––3 and 0.05 was deemed suggestive evidence of possible associations. Statistical power was calculated using the online tool named mRnd2 (r2).Our primary aim was to assess the associations of three phenotypes of domain-specific sedentary behaviors with stroke and its subtypes and four kinds of neurodegenerative disease traits. In secondary analyses, we investigated the mediation effect of the potential mediators. The statistical significance was defined as a ed mRnd2 . The maiI2-index and Cochran’s Q statistics were calculated to test for heterogeneity produced by different genetic variants in the IVW analyses. An I2-index > 25% and Cochran’s Q p value of < 0.05 were considered as an indication of heterogeneity. The MR-Egger regression intercept test was used to assess the potential pleiotropy between the associations of exposure and outcome. A p value of < 0.05 indicated the present of pleiotropy. The MR-PRESSO method could detect outliers and provide causal estimates after the removal of identified outliers. Multivariable MR (MVMR) analysis  method  was usedanalysis  was applvia the corresponding mediator (or mediators) included in the MVMR. Finally, indirect effect was divided by total effect to estimate the proportion mediated, as previously done , suggestively associated with the risk of LAS, SVS, and ICH, but not associated with the risk of CES, lobar ICH, non-lobar ICH, and WMHV. Computer use was suggestively associated with decreased risk of ICH and non-lobar ICH, but not associated with other stroke subtypes. Driving behavior was not associated with any stroke subtype.The primary IVW analyses results for association of domain-specific sedentary behaviors with stroke and its subtypes were shown in p = 1.3 × 10–3) and worse CP , but not associated with the risk of AD or MS. Computer use was significantly associated with better CP , suggestively associated with decreased risk of AD, but not associated with the risk of PD or MS. Driving behavior was suggestively associated with worse CP, but not associated with the risk of AD, PD, or MS.The associations between domain-specific sedentary behaviors and neurodegenerative diseases estimated using the IVW method were demonstrated in p value > 0.05). Several outliers were detected in the main analyses and the MR-PRESSO method provided causal estimates after the removal of identified outliers. We further re-analyzed these genetic associations using IVW method after the removal of the outlier SNPs as sensitivity analyses. The association patterns did not change and the degrees of heterogeneity were attenuated  to reanalyze the significant associations observed in primary IVW analyses . In linetenuated .Multivariable MR analysis was used to adjust for other traits and reevaluate the significant associations observed in our primary analysis, and to determine the potential mediators together with mediation analysis. The associations between domain-specific sedentary behaviors and confounding risk factors were demonstrated in via the BMI and smoking, and with worse CP through the HDL and WHR in part. Our findings also supported the association between increased computer use and better CP. However, no significant evidence was observed for association between sedentary behaviors and other neurodegenerative diseases.In current study, we investigated the association of domain-specific sedentary behaviors with cerebrovascular diseases and neurodegenerative diseases leveraging the GWAS summary data. Our study provided evidence for association of prolonged leisure television watching time with increased risk of AS and IS, and clarified a possible role for mediation through blood pressure, obesity, smoking and drinking. However, only suggestive or no evidence was observed for association of three phenotypes of sedentary behaviors with other stroke subtypes. In addition, our study suggested that increased television watching was associated with decreased risk of PD partially In line with these findings, previous studies also suggested that prolonged television watching time was a risk for AS and IS. A large prospective cohort study with 22,257 participants and median follow-up of 7.1 years identified a significant association of time spent watching television with all stroke (hazard ratio (HR) = 1.37, 95%CI: 1.10-1.71) and IS  after adjusting for demographic factors . SeveralDespite the evidence observed in conventional epidemiology studies for the association between sedentary behaviors and neurodegenerative diseases, this association might suffer from reverse causality or other confounding. For example, individuals with neurodegenerative diseases adopt a sedentary lifestyle. One cohort study suggested that compared with normal participants, individuals with AD spent larger proportion of time on leisure sedentary behavior and had more long-time sedentary bouts . AnotherThe major strength of current study was the MR design, which reduced the confounding and reverse causation bias. Multiple approaches were applied to estimate the effect of sedentary behavior on the cerebrovascular diseases and neurodegenerative diseases, though the estimates calculated by the MR-Egger method were imprecise . MVMR and mediation analysis were used to determine potential mediators. Another strength was the large sample sizes for both the exposures and the outcomes. This, together with the valid IVs for domain-specific sedentary behaviors, resulted in high precision of the results in our study.There were potential limitations to this study. First, although robust results were observed using multiple MR methods, the pleiotropy could not be fully excluded, which was an established limitation of the MR analysis. Different degrees of heterogeneity were observed in the main analyses, indicating the presence of pleiotropic effects. Thus, the results of current study should be interpreted with caution. Though, MR-Egger regression intercept tests found little evidence for the pleiotropy. In this study, MVMR was also applied to limit the misleading inferences introduced by other traits. Second, the sample sizes for ICH and its subtypes were limited, which might lead to statistically insufficient for MR analysis. Third, only five SNPs were selected as IVs for driving behaviors, which also might lead to statistically insufficient. Thus, the results for association between driving behavior and outcomes might be imprecise and must be interpreted with caution. Fourth, since the research on mechanism for association between sedentary behavior and neurodegenerative diseases was rare, it was difficult to interpret the results of mediation analysis. Fifth, our study was restricted to individuals of European ancestry, as such it was unclear whether our findings could be extrapolated to other ancestral populations. Finally, the sample overlapping might lead to an inflated estimate in the two-sample MR analysis. We provided the information of cohorts used in the GWASs of main outcomes –9. The sOur study provided genetic evidence for the causal association of prolonged television watching time and increased risk of AS and IS, decreased risk of PD, and worse CP, as well as the causal association of prolonged computer use time with better CP. These findings have major clinical and public health implications as sedentary behaviors can easily be modified. However, the results should be interpreted with caution considering the difficulty in completely rule out pleiotropy.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.FY, SC, and HC contributed to the study conception and design. FY and ZQ performed material preparation, data collection, and analysis. FY, SC, and KW wrote the first draft of the manuscript. KW, XX, and HC critically revised the manuscript. All authors interpreted the results in the study and gave final approval of the version to be published.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Lower limb spasticity after stroke is common that can affect the balance, increase the risk of falling, and reduces the quality of life.Objective: First, evaluate the effects of spasticity severity of ankle plantar flexors on balance of patients after stroke. Second, to determine the relationship between the spasticity severity with ankle proprioception, passive ankle dorsiflexion range of motion (ROM), and balance confidence.Methods: Twenty-eight patients with stroke based on the Modified Modified Ashworth Scale (MMAS) were divided into two groups: High Spasticity Group (HSG) (MMAS > 2) (n = 14) or a Low Spasticity Group (LSG) (MMAS ≤ 2) (n = 14). The MMAS scores, Activities-Specific Balance Confidence Questionnaire, postural sway of both affected and non-affected limbs under the eyes open and eyes closed conditions, timed up and go (TUG) test, passive ankle dorsiflexion ROM, and ankle joint proprioception were measured.Results: The ankle joint proprioception was significantly better in the LSG compared to the HSG (p = 0.01). No significant differences were found between the LSG and HSG on all other outcome measures. There were no significant relationships between the spasticity severity and passive ankle dorsiflexion ROM, and balance confidence.Conclusion: The severity of ankle plantar flexor spasticity had no effects on balance of patients with stroke. However, the ankle joint proprioception was better in patients with low spasticity. Our findings suggest that the balance is affected regardless of the severity of the ankle plantar flexor spasticity in this group of participants with stroke. Stroke is a common cause of disability and residual physical impairments following a stroke and can pose a significant threat to quality of life . Every ySpasticity is one of common complications of stroke that negatively affects balance. Spasticity is a common sensorimotor disorder defined neurophysiologically as a velocity-dependent increase in muscle tone and stretch reflex hypersensitivity . It has While lower limb spasticity affects balance, gait, and falling in post-stroke patients , the effThe protocol of this cross-sectional study has been previously reported  with theThe measurements were taken at the Javad Movafaghian Research Center, Tehran, Iran.The study protocol was approved by the Review Board and the Ethical Committee of the Tehran University of Medical Sciences (IR.TUMS.FNM.REC.1397.012) in compliance with the Helsinki declaration. All participants provided their written informed consent prior to the assessments.All eligible participants provided a written formal consent after receiving information about the research procedure. Study details, risks, and outcome measures were explained to participants prior to giving the written informed consent and taking the measurements.Patients with stroke were included from those who were referred to neurology and physiotherapy clinics in Tehran, Iran. The patients were included if they had the following criteria: (1) unilateral, first-ever Hemorrhagic/Ischemic stroke, (2) ankle plantar flexor spasticity ≥ 1 based on the MMAS, (3) walking ability, (4) no fixed contracture in the ankle, (5) independent standing with eyes open/closed, (6) ability to understand and follow the commands, and (7) no pain in the lower limbs. The exclusion criteria were: (1) vision problems, (2) depression, and (3) taking antispastic medications.β = 0.842, α = 0.05, α = Zα = 1.96 (n = 14 in each group).Considering a previous study and β = Zα = 1.96 , the samn = 14) and Low (MMAS < 2) (LSG n = 14) spasticity. The Activities-Specific Balance Confidence (ABC) questionnaire was used to assess the balance confidence  was used for transforming the force plate data numerical mode. Medio-lateral (ML) and antrio-posterior (AP) displacement, average and instant velocity of the center of pressure (COP) and area were calculated using Excel  and MATLAB  softwares.T-tests were used to compare the clinical data between two groups. A mixed model Repeated Measures ANOVA of 2 × 2 × 2 was performed to analyze the “Group effect” (High spasticity vs. Low spasticity), “Limb effect” (affected and unaffected limbs), “Eye effect” (eyes open and closed conditions), and interactions between variables. The relationships between the severity of spasticity and outcome variables were analyzed using the Spearman’s correlation test. SPSS software  was used for the data analysis. Statistical significance was defined at α = 0.05.Normal distribution of the data was assessed by the Kolmogrov-Smirnov test. P > 0.05). Demographic characteristics of the two study groups are illustrated in Twenty-eight post-stroke patients were included in the current study. High and Low spasticity groups were similar in terms of height, weight, age, the time since the stroke onset, etiology  and affected side (p > 0.05). However, ankle joint proprioception was found to be significantly different between the groups (p = 0.01)  .The distribution of spasticity severity based on MMAS in low and high spasticity groups is presented in p > 0.05).Posturography data for the groups are presented in r = −0.55, p = 0.04)  . There wTo these authors’ knowledge, this is the first study that evaluated the effects of ankle plantar flexor spasticity severity on balance and determined the relationship between the spasticity severity with ankle proprioception, passive ROM, and balance confidence in post-stroke patients. We found no differences between the LSG and HSG groups in terms of balance confidence, dynamic balance, and ankle dorsiflexion ROM. In addition, postural sway in the open and closed eye conditions was not different in both the LSG and HSG groups for both the less affected and affected limbs. However, ankle joint proprioception in terms of repositioning error angle was better in the LSG compared to the HSG. A relationship was found between TUG scores and balance confidence in the HSG.In the standing position, the central nervous system keeps an individual’s center of pressure within the base of support . TherefoVarious investigations have examined the balance control of patients post-stroke in the frontal plane . A revieIn this study, in line with previous studies , there wInterestingly, no difference was found in the postural sway between the low and high spasticity groups and between the affected and less affected limbs after the removal of the vision. This was unexpected in that patients post-stroke typically rely on the vision for maintaining their balance . A possiThis study demonstrated that the high spasticity group displayed worse ankle proprioception when compared to the low spasticity group. This finding is in agreement with a previous study that showed proprioception impairment in patients in post-stroke . This fiIn the present study, in line with a previous study , no diffIn this study, dynamic balance, as measured by the TUG, was not different between the low and high spasticity groups. This indicated that regardless of spasticity level, the dynamic balance was impaired in this sample of patients with stroke. However, the scores on the TUG test were worse in the High spasticity group than those in the Low spasticity group (23.4 vs. 17.8). A difference of ∼6 s between the two groups was clinically relevant that indicated that with increasing spasticity level severity the dynamic balance would worsen as demonstrated in previous studies with stroke . ReplicaPassive ankle ROM was not different between low and high spasticity groups. A previous study has reported that a higher spasticity was associated with higher limitations in the passive ROM . In thisThere was a significant negative correlation between the balance confidence and TUG test in the High spasticity group. This finding indicates that the time for the TUG test will be lower with more confidence on balance. However, there was no significant correlation between spasticity and proprioception and passive ROM of the ankle, balance confidence, TUG test, and postural sway in each group. The sample size is very important to examine the correlation in cross-sectional studies. As the number of variables increases, more samples are needed . The nonAlthough the sample size was determined, the number of samples may have been too small to investigate the relationship between clinical data and static and dynamic balance . In the These results show that although stroke patients with spasticity have impaired static and dynamic balance, the severity of spasticity has no effect on the exacerbation of balance control. Therefore, the spasticity post stroke must be considered for management regardless of its severity.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.FNM.REC.1397.012). The patients/participants provided their written informed consent to participate in this study.NN, SN, and AM presented the study conception and idea. NN, SN, AM, OM, EG, BS, and IS designed the study protocol. AM drafted the first version of this manuscript that was reviewed and revised critically for intellectual content by NN. AM, EG, and OM collected the data. NN, SN, BS, and IS revised the manuscript. All authors read, commented, and approved the final manuscript for submission.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.