Aims: Neck circumference (NC) was found to be related to the risk factors for coronary heart disease (CHD). However, the effects of NC on CHD are still controversial. To evaluate the relationship between NC and CHD, a meta-analysis of observational studies was performed. Method: Eligible studies on the association between NC and CHD were searched in Medline, Embase, Ovid, and Web of Science databases published in English from January 1980 to December 2016. Moreover, studies published in Chinese in Wanfang and China Hospital Knowledge databases were also searched. Random effects models in the metafor package in statistical analysis software R 3.3.3 were used for the meta-analysis. Heterogeneity was analyzed with Q statistics. Results: Eight studies were selected for the meta-analysis. A larger NC was associated with a higher prevalence of CHD . The eight studies were further divided into three subgroups according to the criteria for diagnosing CHD. In the subgroup of coronary angiography, NC was also found to be associated with the prevalence of CHD with low heterogeneity . However, in the subgroup of computed tomography or past history, no association between NC and CHD was found. In addition, subgroup analyses were also conducted according to the regions of the study. No association between NC and CHD was identified in either Chinese studies or Brazil studies . Conclusion: Larger NC is associated with increased risk of CHD, especially when coronary angiography was taken to diagnose CHD. Coronary heart disease (CHD) is one of the most common chronic non-communicable diseases in the world. CHD is also the leading reason of all-cause deaths in adults in many countries, accounting for 30.8%–40% of all deaths worldwide . IdentifIn recent decades, the prevalence of CHD increased dramatically, and the onset age of CHD significantly decreased with more CHD patients younger than 40 years old. Obesity has been shown to be an important risk factor for CHD, and always accompanied by multiple metabolic abnormalities, such as insulin resistance, diabetes, hypertension, dyslipidemia, and gout. Obesity now is a global health problem, not only in the general population , but alsHowever, the effects of NC on predicting CHD and CHD events are still controversial . Preis eThe controversial results from different studies on association between NC and CHD make it necessary to perform a meta-analysis to evaluate the relationship between NC and CHD by combining the data of all relevant studies. The meta-analysis follows the guideline provided in the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) .Eligible studies on the association between NC and CHD were searched in Medline, Embase, Ovid, and Web of Science databases published in English from January 1980 to December 2016. Moreover, studies published in Chinese from January 1980 to December 2016 in Wanfang and China Hospital Knowledge Database (CHKD) databases were also searched. The key words “neck circumference,” “cardiovascular disease,” “coronary heart disease,” and combinations of these were used. References cited in the retrieved articles were also examined to find relevant studies that had not been identified by database searches. The articles were first selected through title and abstract screening. The secondary abstract review was performed on the first screened articles with review of the full text. The final inclusion of articles was determined by consensus between two co-authors. r) or other forms of effect sizes. We excluded: (i) abstracts, letters, editorials, expert opinions, case reports, and reviews; (ii) studies that included people aged less than 18 years. Disagreement was solved by the discussion within the team authors.Inclusion criteria included: (i) observation or cohort studies; (ii) adult patients aged 18 years or older; (iii) articles that reported the association between NC and CHD in terms of odds ratios (ORs) or correlation coefficients .Q statistics. The heterogeneity was further quantified by inconsistency index (I2) with 25%, 50%, and 75% representing the evidence of low, moderate, and high heterogeneity, respectively  as effect sizes were converted to log odds ratios for the meta-analysis.Random effects models were utilized to obtain the summary ORs and their 95% CIs for the association between NC and CHD in all eligible studies and subgroup analysis. Statistical heterogeneity among studies was evaluated using the Cochran ectively . Accordip-values less than 0.05 were considered statistically significant for testing association between NC and CHD.The funnel plot and radial plot were generated to assess the publication bias. Egger regression asymmetry test for funnel plot asymmetry was also performed to detect publication bias. The metafor package in statistical analysis software R was used for the meta-analysis , and p-vSensitivity analyses were conducted to measure the robustness of the result. The study with the biggest contribution was removed from the meta-analysis. Then, the two studies using correlation coefficients as effect sizes were removed. Subgroup analysis was based on different nations and different diagnosis criteria for CHD were performed.The screening process for articles used for the meta-analysis is shown in A total of eight articles were included for the meta-analysis. Of them, three were conducted in China , three iI2 = 93.06%, p < 0.05). The weighted odds ratio estimated from the random-effects model indicated that a higher NC was associated with a higher prevalence of CHD , as shown in The random-effects model was selected for data analysis, as the test for heterogeneity showed a statistically significant result . The publication bias was assessed using funnel plot and radial plot because the heterogeneity existed. The funnel plot showed relative symmetry .The homogeneity was analyzed with symmetry . Egger rp = 0.0063, I2 for heterogeneity was 87.78% (p < 0.05). The funnel plot showed relative symmetry .To measure the robustness of the result, sensitivity analyses were conducted. According to the contribution plots of each study, the study with the largest contribution was done by symmetry . Egger rp = 0.0345, I2 for heterogeneity was 71.09% (p < 0.05). The funnel plot remained relative symmetry .Next, we removed the two studies using correlation coefficients as effect sizes . After rsymmetry . Egger rp = 0.113, I2 for heterogeneity was 98.7% (p = 0.001). The funnel plot remained relative symmetry .Subgroup analysis was conducted stratified by nations. Among the eight studies in the meta-analysis, three studies were conducted in China . A randosymmetry . Egger rp = 0.2604, I2 for heterogeneity was 77.11% (p = 0.0193). Egger regression test for funnel plot asymmetry model show that there were no significant bias among these studies .There were three studies conducted in Brazil . NC was p = 0.0007, I2 for heterogeneity was 17.02% (p = 0.1668). The funnel plot remained relative symmetry .There were four studies in which coronary angiography was performed to diagnose CHD . NC was symmetry . Egger rp = 0.7606, I2 for heterogeneity was 43.23% (p = 0.1844).There were two studies in which computed tomography was performed to evaluate the conditions of the coronary arteries . NC was p = 0.2721, I2 for heterogeneity was 99.16% (p < 0.001).In the two studies, CHD was diagnosed by the history of past myocardial infarction, acute coronary syndrome, and cardiac death . NC was Overweight/obesity is recognized as one of the most common risk factors for CHD . NC was There are several anthropometric indicators to evaluate overweight/obesity, such as BMI, waist circumference, waist hip ratio, and NC. Several meta-analysis studies on the association between anthropometric indicators with CHD showed that BMI, measured continuously or categorically, had deleterious effects on the risk of incident CHD in people across diverse populations . In a me2 per decade from 1980 to 2008 in the Cook and Nauru Islanders . The Pacific Islander Health Study had shown that the majority of the male Pacific Islander adult was already overweight by aged 18 years   . The assg obese) . A studyg obese) . An obseg obese) . Anotherg obese) . Due to g obese) , NC mighg obese) . Howeverg obese) .A variety of study designs were used for this meta-analysis, with various study population  and uncontrolled confounding factors . These variations may affect the heterogeneity and the results. In some studies related to NC and obesity, it was shown that NC in males was higher than that in females, so the cutoff of NC for evaluating obesity was sex-specific . HoweverIn studies used for the meta-analysis, CHD was diagnosed by using coronary angiography in four studies , by usinDue to the nature of observational studies used in the meta-analysis, the inherent biases cannot be controlled as in the randomized controlled studies, and some confounding effects are inevitable in observational studies. In addition, the study design and subject selection for each analysis are not coherent. For example, a cross-sectional study is more likely performed in a particular area with a high incidence, and is less likely in an area with a rare incidence. Therefore, the results could have bias and are difficul in generalizing the population of interest .Additional potential limitations to this meta-analysis include: (1) The limited number of studies included in the meta-analysis could affect the association between NC and CHD, for example, no statistical significant association exist between NC and CHD when the number of studies decreased to three; (2) Different diagnose criteria for CHD was used in these eight studies in the meta-analysis; (3) Participants in some studies were patients with high risk for CHD, for example, Our results indicate that NC may be associated with CHD, especially when coronary angiography was taken to diagnose CHD. Given the high incidence of CHD, further large-scale and prospective studies may be worthwhile to confirm this relationship between NC and CHD.We would like to thank the anonymous reviewers for their insightful comments and suggestions that helped to improve our manuscript.The authors declared no potential conflicts of interest concerning the research, authorship, or publication of this article.This study is supported by Capital’s Funds for Health Improvement and Research [2016-2-2054], and the Beijing Municipal Training Foundation for Highly-qualified and Technological Talents of Health System [2014-3-013]. Dr. Li’s, Dr. Zand’s, Mr. Fogg’s, and Dr. Dye’s time is supported by the University of Rochester’s Clinical and Translational Science Award (CTSA) number UL1 TR000042 and UL1 TR002001 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Zand is also supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Immunology, grant numbers AI098112 and AI069351. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


Bipolar disorder (BD), a type of psychiatric mood disorder, is manifested by chronic and recurrent mood fluctuations. This study aims to determine whether hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a risk factor for BD.A total of 48,215 patients with newly diagnosed viral hepatitis from 2000 to 2010 were identified and frequency-matched with 192,860 people without hepatitis. Both groups were followed until diagnosis with BD, withdrawal from the national health insurance program, or the end of 2011. Patients with viral hepatitis were grouped into 3 cohorts: HBV infection, HCV infection, and HBV/HCV coinfection. The association between viral hepatitis and BD were examined using Cox proportional hazards regression models.The incidence of BD was higher in HBV/HCV coinfection than in the control group, with an adjusted hazard ratio of 2.16  when adjusted for sex, age, and comorbidity. After further adjustment, we noted that an age more than 65 years and female may be associated with an increased risk of BD in patients with chronic hepatitis B and C.Viral hepatitis may be associated with increased risk of subsequent BD.The online version of this article (10.1186/s12967-018-1542-3) contains supplementary material, which is available to authorized users. Viral hepatitis is the major cause of hepatitis . Among aBipolar disorder (BD), a type of psychiatric mood disorder, is manifested by chronic and recurrent mood fluctuations and involves a spectrum of symptoms including depressive, hypomanic, and manic manifestations . In the In treatment of hepatitis, interferon-α, one of the treatment of HBV and HCV, was reported having neuropsychiatric side-effects . Also, iThe study was conducted using data from the Longitudinal Health Insurance Database (LHID), a data set comprising the claims data of people enrolled in the Taiwan National Health Insurance (NHI) program. The National Health Research Institutes (NHRI) randomly selected 1 million insured people from 1996 to 2000 and followed them. According to the NHRI report, the demographic characteristics showed no difference between the people in the LHID and those enrolled in the NHI program. The claims data in the LHID include a beneficiary registry, inpatient and outpatient files, and other medical services. All patient histories were collected from inpatient and outpatient files and recorded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHRI released the database with anonymous patient identification numbers to protect the privacy of the insured people.This was a retrospective, population-based cohort study, and we included a cohort of hepatitis patients and a comparison cohort to observe the occurrence of BD. The hepatitis cohort comprised patients with new onset HBV  or HCV  from January 1, 2000 to December 31, 2010. The date of first diagnosis of hepatitis was defined as the index date. The comparison cohort contained patients in the LHID without a diagnosis of hepatitis. Each patient in the hepatitis cohort was randomly frequency-matched with 4 controls according to various criteria including age (per 5 years) and sex. For the index date of the comparison cohort, patients were assigned the same date as those of the matched cases. Both cohorts excluded patients without complete characteristic data and aged younger than 20 years or those with a history of BD before the index date. In addition, considering the undiagnosed mood symptoms, we also excluded the patients having depression  before the index date. Moreover, HBV/HCV can be contracted during sex  and unsat test to analyze age and a Chi square test to analyze sex and comorbidities. Furthermore, we calculated the incidence density of subsequent BD in both cohorts. The cumulative incidence curves for the 2 cohorts were evaluated using the Kaplan–Meier method. The log-rank test was used to test the difference between the incidence curves. To measure the risk of BD in the hepatitis cohort compared with the comparison cohort, we transformed all categorical variables into dummy variables and evaluated crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) by using Cox proportional hazard models. We also analyzed the risk of BD stratified by age, sex, and comorbidities. We used SAS Version 9.4 software  to manage the data and conduct the statistical analyses. The incidence curves were plotted using R software . A 2-sided p < .05 reached the level of significance.In this study, the demographic characteristics and medical records in LHID included continuous data (such as age) and binary variables . They were all in reasonable range. The characteristics of the study population, which were represented by their age, sex, and comorbidities, were described using mean and percentage values. To examine the difference between the hepatitis and comparison cohorts, we used a We selected a total of 48,215 patients with hepatitis in this study. As shown in Table We observed 136 and 58 BD occurrences in the comparison and hepatitis cohorts, respectively Table . The incTable In Table In this study, we demonstrated that HBV or HCV infection may be associated with subsequent BD, and, to the best of our knowledge, we demonstrated their correlation for the first time by using a matched population-based cohort and 10-year follow-up period. The major findings of our study suggest a higher incidence of subsequent BD among patients with HBV/HCV coinfection. Also, we demonstrated the comorbidities related to the subsequent occurrence of BD, including hyperlipidemia, anxiety, and major depressive disorder. Anxiety was frequently comorbid with BD . PatientWe noted that female patient with HBV infection was associated with the subsequent occurrence of BD. To the best of our knowledge, we hypothesized that the mechanism was possibly related to the interaction between sex hormone and the disease activity of HBV infection. Evidence shows that HBV infection is characterized by its lifelong persistence and inflammation . In addiIt has been shown elsewhere that the anti-HCV treatment (ribavirin and interferon) are related to the development of depression . In our In addition, our statistically matched study, including age, gender, and comorbidity, demonstrated increased risk of subsequent BD in patients having concurrent HBV and HCV infections. Our results reveal that this condition was associated with patients aged more than 65 years and having any comorbidity. HBV and HCV have been reported to be associated with CNS involvement through neuroinflammation , 45. HBVTo the best of our knowledge, this is the first population-based study designed to investigate the association between viral hepatitis and BD. We employed a matched case–control design and a population-based cohort of patients with viral hepatitis and adequate controls as well as a sufficient number of comorbidities, thus further strengthening the study. However, limitations inherent to the use of claims databases were encountered. First, the diagnosis of hepatitis in the NHIRD was based on ICD-9-CM codes; therefore, the severity of hepatitis as a risk factor for developing BD was not explored. Also, we mark the temporal association by the chronological order, so we could not confirm the effect or the causal relationship between hepatitis infection and BD. Additionally, considering the possibility of reactivation, we included hepatitis carrier, ICD-9-CM codes of V02.61 and V02.62, in our study, and this management could affect the result revealed in our study. Nevertheless, in our study design, we conducted a 10-year follow-up to observe the long-term influence of HBV or HCV infection on the subsequent development of BD. Second, the association was evaluated according to the chronological order in which these two diseases were diagnosed. Whether the patients previously had BD-related symptoms without being diagnosed with BD was unknown. Third, information on numerous demographic variables, including socioeconomic status and family history, was unavailable; such information may provide useful data regarding factors associated with viral hepatitis and BD. Forth, BD was reported having early presentation in lifetime prevalence . ExcludiThe findings suggest that HBV/HCV infection may be associated with increased risk of subsequent BD. Additional prospective clinical and basic studies on the relationship between hepatitis and BD are warranted.Additional file 1: Table S1. Distribution of age, gender, and comorbidity between hepatitis infection and comparison cohort with propensity score matching. Table S2. Estimation of bipolar Incidence and hazard ratio by Cox proportional hazard models with propensity score matching.


The aim of this meta-analysis was to evaluate the effects of STN DBS on sleep quality and restless leg symptoms in individuals with PD.  We searched the PubMed, Web of Science, EMBASE, CNKI, and WANFANG databases published between 1990 and 2019. The articles included were those that contained both pre- and postsurgery data acquired using International RLS Study Group criteria and the Pittsburgh sleep quality index (PSQI) questionnaire with patients' follow-up of at least three months. All studies that met the quality requirements were included in a meta-analysis performed using STATA 12.0 software. P=0.007). Subgroup analysis showed that different sleep scoring criteria had different effects on the condition of sleeping after surgery.  Of 73 articles identified, 7 studies comprising 82 patients were qualified for the current meta-analysis. After adjusting for heterogeneity in study effect sizes, the random effects meta-analysis indicated that STN DBS improved sleep quality and restless leg symptoms significantly (SMD = −1.111, 95% CI: −1.918∼−0.304,  STN DBS is a powerful method in the management of sleep quality and restless leg symptoms in PD patients, but its long-term effects with larger populations must be thoroughly assessed. Parkinson's disease (PD), as a primary reason of morbidity and mortality worldwide, is a debilitating neurodegenerative condition characterized by motor and nonmotor symptoms among middle-aged and elderly individuals. As for treatment methods, currently, antiparkinsonian medication and surgical interventions have become mainstream , 2. GeneDeep brain stimulation, which involves the application of electrical stimuli in specific nuclei, was clinically used in the late 1990s for the treatment of PD, and this technique has been widely and increasingly accepted during last 20 years. Currently, STN DBS significantly improves patients' primary motor symptoms as well as the quality of life, reducing their need for medications , 6. The Sleep disturbances are an integral aspect of the NMS of PD, which are common in PD patients, becoming increasingly more frequent and severe during the advanced stage of the disease , 10. LeeWe selected the studies which investigated sleep quality and restless leg symptoms of patients with PD before and after bilateral DBS. An initial literature search was done by means of PubMed, Web of Science, EMBASE, CNKI, and WANFANG databases for the years 1990 to 2019. The search terms were  OR  AND (“Parkinson disease” OR “Parkinson's disease”) AND (“sleep” OR “restless legs syndrome”). In addition, we searched the references of the recognized studies to find other satisfactory studies. This task was completed by two reviewers independently. When disagreements arose, a third reviewer was consulted.The inclusion criteria were the following: (1) patients with idiopathic PD were treated with bilateral STN DBS, (2) the patients were followed up for at least 3 months, (3) presurgery and postsurgery data were obtained through International Restless Legs Syndrome Study Group (IRLSSG) criteria or PSQI questionnaire, respectively , which involves eight items. Each item was scored from 0 to 2: 0 representing that it was not reported in the article, 1 representing that it was reported but inadequately, and 2 representing that it was reported adequately .Two investigators reviewed the publications independently and extracted the applicable data from each qualified study, whereas objections were resolved by consulting a third reviewer. The below mentioned details were extracted: name of the first author, year of publication, sample size, duration of disease, time of following up, DBS programming, and the relevant pre- and posttreatment IRLS score and PSQI score concerning the STN DBS.I2-statistics were used to evaluate the degree of it. An I2 > 50% or P < 0.05 designated significant heterogeneity, then a random-effects model would be used for meta-analysis [STATA statistics software  was used to analyze accessible data. Since two scales were used in our study, standardized mean difference (SMD), that is, Cohen's d, was used to estimate the size of the combined effect, with a confidence interval of 95%. SMD, as a standard statistic, was used to evaluate the comparisons of presurgery and postsurgery change. This value reflects an intervention-induced change of the outcome on an average and is used as a summary statistic in meta-analysis if the studies were measured in different ways. As for the heterogeneity of all the studies, Q-test and analysis . Sensitianalysis .We recognized 73 published studies, from which we omitted 12 because of the duplication. We further excluded 41 studies after evaluating titles and abstracts as they did not meet the inclusion criteria. After reading the full text of the remaining 20 articles, we omitted 13 studies due to lack of control groups. Finally, we had 7 eligible studies which fulfilled the inclusion criteria. I2 = 80.4%; therefore, the random effects model was used to count the combined SMD. Based on the comparison of preoperative and postoperative change, we found that there was a significant change in the score among the presurgery stage and the postsurgery stage   .P=0.005), whereas no significant difference was observed in the PSQI score between the presurgery stage and the postsurgery stage   .P=0.293)  .Deep brain stimulation (DBS) has become an attractive alternative for the treatment of neurodegenerative diseases. STN DBS has been well established over the past 20 years for the symptomatic treatment of motor symptoms and complications in advanced PD. It provides more constant and predictable benefits than pharmacological therapy. Numerous studies have documented that the majority of patients who undergo STN DBS achieve amelioration of motor symptoms and quality of life. Nonmotor symptoms (NMS) are nowadays recognized as an integral part of the clinical characteristics of PD, both at the early stages and throughout the whole course of the disease, and even at the very beginning of the disease, before any of the classical motor symptoms develop . Many puIn particular, sleep disturbances in addition to neuropsychiatric symptoms  affect numerous PD patients. Sleep disruption is one of the most common nonmotor symptoms of PD and problematic in PD with estimates that as many as 90% of PD patients suffer from sleep problem . There iP=0.007), which means that bilateral STN DBS did seem to improve the PD patients' sleeping condition. However, the subgroup analysis showed that different scoring criteria for sleeping had an impact on the condition of sleeping quality after surgery.The present meta-analysis included 7 studies containing 82 PD patients comparing the differences in sleeping changes between presurgery and postsurgery patients. Through strict methodological and statistical analysis, our data suggested that there was a statistical significant difference in the scores between the presurgery stage and the postsurgery stage , cognitive/emotive functions (mesocorticolimbic system), and prolactin secretion (tuberoinfundibular system) , 39. DopThis study provides evidence that STN DBS significantly improves sleep quality and restless leg symptoms at more than 3 months postoperatively compared to the preoperative baseline. There are several limitations of this article. First, the sample size of STN DBS was small, so additional studies are required to completely clarify the sleeping quality related to STN-DBS. Second, only the short-term effectiveness of DBS in treating PD was evaluated, thus, if our conclusion was suitable for long-term treatment was not clear. Significant heterogeneity was observed in this analysis. A potential explanation may be that relevant variables  in each study were diﬀerent.In conclusion, STN DBS is a powerful method in the management of sleep quality and restless leg symptoms in PD patients. Further improvements, through basic research and methodological innovations, should make it applicable to long-term treatment of the disease. Considering the limitations stated above, further larger samples and multicenter cooperative studies in different populations should be carried out, and the precise intervention protocols for PD patients with different disease stages should be taken in future findings.


The current classification of tremor types in Parkinson disease (PD) is potentially confusing, particularly for mixed tremor, and there is no label for pure resting tremor. With a view to better defining the clinical phenomenological classification of these tremors, our group relabeled the different types as follows: pure resting tremor (type I); mixed resting and action tremor with similar frequencies (type II) divided, according to action tremor presentation, into II-R when there is a time lag and II-C otherwise; pure action tremor (type III); and mixed resting and action tremor with differing frequencies (type IV). We performed a descriptive study to determine prevalence and clinical correlates for this new tremor classification. X2 tests were used to assess tremor type associations with categorical variables, namely, sex, family history of PD, motor fluctuations, and anticholinergic and beta-blocker use. With tremor type as the independent variable, ANOVA was performed to study the relationship between dependent quantitative variables, namely, age, age at PD diagnosis, disease duration, and UPDRS scores for rigidity.  A total of 315 consecutively recruited patients with PD and tremor were clinically evaluated.  The studied patients had tremor types as follows: type I, 30%; type II, 50% ; type III, 19%; and type IV, 1%. No significant association was found between the studied clinical variables and tremor types.  Mixed tremor was the most common tremor type in our series of patients with PD according to our proposed classification, which we hope will enhance understanding of the broad clinical phenomenology of PD. Tremor, one of the most characteristic manifestations of Parkinson disease (PD) and often the presenting sign, occurs in approximately 75% of patients with PD, who rank it as their second most troublesome symptom , 2.PD tremor, whether resting or action tremor, is a highly variable symptom . The claIn 1998, the Consensus Statement on Tremor issued by the Movement Disorder Society (MDS) classified the different tremor types observed in PD in 3 categories: type I, resting and action tremor with similar frequencies; type II, resting and action tremor with differing frequencies; and type III, pure action tremor. Finally, the term monosymptomatic rest tremor refers to patients with rest tremor and no other parkinsonian signs . A more With a view to better defining the clinical phenomenological classification of PD, our group relabeled the different PD tremor types in what appeared to us to be a more intuitive and logical way, as follows: type I, pure resting tremor; type II, mixed action and resting tremor with similar frequencies (subdivided into re-emergent and continuous tremors); type III, pure action tremor; and type IV, mixed action and resting tremor with different frequencies.Below we describe a descriptive study of prevalence and clinical correlates for this new tremor classification, based purely on clinical phenomenology, for a consecutive series of patients with PD.Included consecutively in the study were patients with PD and visibly detected tremor who attended the Movement Disorders Unit at Sant Pau Hospital Neurology Department between December 2015 and April 2017 (16 months). PD was diagnosed using the London Brain Bank criteria . The stuResting tremor was defined as a tremor present when arms were resting in the lap or by the side. Since it was not always easy to ensure that a patient was completely relaxed, when in doubt and in order to rule out gravitational force and muscle co-contraction, the patient was tested lying down on a bed or walking with their arms hanging at the sides. We also asked patients to complete tasks that increased tremor amplitude, either mental tasks  or motor tasks .Action tremor can be either kinetic or postural. Kinetic tremor was defined as tremor present during hand movement . Postural tremor was assessed for stretched-out arms, the bat-wing position, and wrist extension.For mixed tremor, accelerometric recordings were made using a previously described methodology . RestingThe tremor types are summarized in In the neurological examination, for the most affected arm in each patient, the rigidity item from the motor evaluation section of the Unified Parkinson Disease Rating Scale (UPDRS) was used as a measure of parkinsonism severity. The Hoehn and Yahr scale for describing progression of PD symptoms was also scored. Also assessed based on a chart review and on patient reports were several clinical factors correlating with PD tremor types: age, sex, family history of tremor, disease duration, motor fluctuations, and treatment with anticholinergics or beta-blockers.X2 tests were used to assess tremor type associations with the categorical variables of sex, family history of PD, presence of motor fluctuations, anticholinergic use, and beta-blocker use. Analysis of variance (ANOVA) was performed to study the relationship between dependent quantitative variables—age, age at PD diagnosis, disease duration, and UPDRS scores for rigidity—with tremor type as the independent variable. For all analyses, the statistical level of significance was established at 5% . The statistical package used was IBM-SPSS (ver. 22.0).For the descriptive analysis, categorical variables were reported as percentages and number of cases, and quantitative variables were reported as mean ± standard deviation. A total of 315 patients (166 men and 149 women) with a mean age of 76.4 years (range 60–85 years) were included in the study. Around 30% of patients had tremor type I, 50% had type II (25% II-R and 25% II-C), 19% had type III, and 1% had type IV.p=0.232), sex (p=0.092), disease duration (p=0.238), Hoehn and Yahr score (p=0.358), family history of PD (p=0.766), percentage of motor fluctuations (p=0.788), and rigidity score (p=0.990). There were no statistically significant differences in the percentage of patients with each tremor type in terms of anticholinergic use. No patient with type I tremor in our series was taking beta-blockers.No significant association was found between the clinical variables studied and tremor types: age . In our opinion, this new classification improves on the MDS classification as it is more intuitive and logical. Our classification based on a descriptive cross-sectional study does not have a pathological, prognostic, or therapeutic value, but represents a first step for future pathological and prospective studies to determine its usefulness.There are two main differences between our classification and the MDS classification , 7. We iOur study found that action tremor is prevalent in PD. In fact, pure or mixed action tremor was experienced by 70% of the patients in our series, a finding that corroborates previous studies reporting action tremor prevalence of as high as 92% in patients with PD , 13, 14.Interestingly, we found that 19% of our patients had pure action tremor, that is, essential tremor-like tremor. Our group has previously reported that this may be the first symptom of PD in about 6% of cases . While sThe basis for action tremor in PD is not clear . SeveralIt has been hypothesized that re-emergent tremor (type II-R in our classification) is a form of resting tremor in PD . Few stuThe main limitation of our study is the small number of patients included, although we suggest that the sample is quite representative. Furthermore, we did not control for the effects of antiparkinsonian medication that might modify the tremor phenomenology. However, the patients in our study were evaluated in OFF time.Furthermore, as a weighted limb test was not performed, some degree of misdiagnosis cannot be ruled out in cases of physiological action tremor. The classification of pure action tremor is difficult because rest tremor may be very mild and intermittent, especially when patients are treated with dopaminergic drugs.Finally, another limitation of this cross-sectional study is that we did not study shifts between tremor subtypes; i.e., we did not assess how many patients switched from one type of tremor to another, although the absence of any significant correlation between disease duration and tremor type would suggest that shifting is not relevant. This issue, however, would need to be analyzed in future studies.We propose new labels for tremor types observed in PD based purely on clinical phenomenology. Mixed tremor was the most common tremor type in our series of patients with PD according to our proposed classification, which we hope will enhance understanding of the broad clinical phenomenology of PD.


Purpose: We aim to provide a comprehensive overview of the health consequences of female genital mutilation/cutting (FGM/C), with a particular focus on the psychosexual implications of this practice and the overall impact of reconstructive plastic surgery.Methods: A MEDLINE search through PubMed was performed to identify the best quality evidence published studies in English language on long-term health consequences of FGM/C.Results: Women with FGM/C are more likely to develop psychological disorders, such as post-traumatic stress disorder, anxiety, somatization, phobia, and low self-esteem, than those without FGM/C. Most studies showed impaired sexual function in women with FGM/C. In particular, women with FGM/C may be physiologically less capable of becoming sexually stimulated than uncut women. Reconstructive surgery could be beneficial, in terms of both enhanced sexual function and body image. However, prospective studies on the impact of reconstructive surgery are limited, and safety issues should be addressed.Conclusion: Although it is clear that FGM/C can cause devastating immediate and long-term health consequences for girls and women, high-quality data on these issues are limited. Psychosexual complications need to be further analyzed to provide evidence-based guidelines and to improve the health care of women and girls with FGM/C. The best treatment approach involves a multidisciplinary team to deal with the multifaceted FGM/C repercussions. Worldwide, it is estimated that ∼200 million girls and women have undergone FGM/C,6 and >3 million girls are at risk of cutting every year.7Despite the implementation of laws prohibiting this practice, FGM/C is still performed in ∼30 African countries and in a few Asian and Middle East countries.1 In addition, in some communities, cutting is seen as a rite of passage to adulthood, and is part of the history and cultural tradition of the specific ethnic group.1 Contrary to common belief, neither the Koran nor the Bible condones this procedure.8 However, religious interpretations have been used to justify FGM/C in some communities.8FGM/C has been practiced for centuries and has established its roots in ancient sociocultural traditions, which vary from one region and ethnic group to another. Reasons for performing FGM/C include social acceptance, the safeguard of virginity before marriage, and the promotion of marriageability.9 and 18 countries developed a national legislature against genital mutilation.10 In 2012, 194 United Nations member states approved a resolution aimed at raising awareness and allocating adequate resources to protect and support women victims of FGM/C.11 Legal frameworks are essential elements of a comprehensive response aimed at abolishing this practice10; in this regard, positive change is now happening in terms of slow decrease of global FGM/C rates.12 However, there is also need for measures addressing the underlying sociocultural traditions that are the core of this practice.10FGM/C is a deeply entrenched social norm, and its eradication appears extremely difficult. Nevertheless, in 2009 the majority of the African states where this practice is performed have adopted laws against FGM/C1 In this narrative review, we aimed to provide a comprehensive overview of the health consequences of FGM/C, with a particular focus on the psychosexual implications of this practice and the overall impact of reconstructive plastic surgery.Another fundamental aspect is the need for adequate health management of women with FGM/C, which frequently present various long-term health consequences, including gynecological, obstetrical, urological, psychological, and sexual complications.For this review, the best quality evidence was selected with preference given to the most recent and definitive original articles and reviews. Information was identified by searches of PubMed/MEDLINE and references from relevant articles. We selected appropriate research terms by reviewing keywords, titles, and abstracts of a sample of studies. “Female genital mutilation,” “complications,” “obstetric outcome,” “reconstructive surgery,” “plastic surgery,” “health problems,” “mental problems,” “sexual function,” “sexual problems,” “psychological impact,” and “clitoral reconstruction” were used and combined as research terms. The search was limited to full-text articles in the English language. For most issues, papers published between November 1983 and April 2018 were considered. No attempt was made to find unpublished studies. Since only published data were considered, the current research project was exempt from Institutional Review Board approval, and informed consent was not obtained because we did not recruit any human subject.1 Even if the WHO classification is very detailed, sometimes women's genital appearance may not fit precisely into one specific FGM/C type. To overcome this classification bias, UNICEF has proposed another simpler classification system  has classified FGM/C into four categories .1 Even in system .13 The mocedures , whereasocedures , althoug12 This procedure is evidently associated with immediate and chronic health repercussions that are influenced by different cofactors, such as the physical condition of the girl undergoing the mutilation, the skill of the cutter, the cleanliness of the procedure, and especially the type of FGM/C executed.1 In particular, women who had endured a type III procedure present a double risk of complication compared with those who had undergone a type II mutilation.14In the majority of cases, FGM/C is performed by a traditional practitioner, generally a woman, without any form of anesthesia and using nonsterile devices, such as scissors, broken glasses, or razor blades.15–17 Obstetric outcomes greatly vary depending on the study context. In a 2006 African multicenter study on 28,393 women with FGM/C, participants with genital mutilation were at increased risk of prolonged labor, postpartum hemorrhage, caesarean section (CS), and perineal trauma relative to women without FGM/C.17 The risks seemed to be greater in case of more extensive FGM/C. Moreover, infants born from a mother with FGM/C were at increased risk of stillbirth and early neonatal death, with FGM/C estimated to lead to an extra 1–2 perinatal deaths per 100 deliveries. The authors underlined the fact that this prospective study was performed in hospitals; because the majority of women who have undergone FGM/C live in countries with limited infrastructures for health care, which most of them are not able to afford, the study population may have over-represented a small selected group that could afford hospital care. Thus, the proportion of obstetrical complications in women with FGM/C might have been underestimated. On the contrary, a recent Australian descriptive study18 on 196 births from women with FGM/C showed comparable maternal and neonatal outcomes, except for statistically significant higher rates of first- and second-degree perineal tears and CS; however, none of the CS had FGM/C as an indication. Essen et al.19 did not confirm the association between prolonged labor and female circumcision. In 2009, a Swiss retrospective case–control study20 reported no differences in 122 FGM/C patients and 110 controls regarding the fetal outcome, maternal blood loss, or labor duration; nevertheless, women with FGM/C had significantly more often an emergency CS and third-degree vaginal tears. A 2013 systematic review21 of data derived from 28 comparative studies involving ∼3 million participants indicated that prolonged labor, obstetric lacerations, instrumental delivery, obstetric hemorrhage, and difficult delivery are related to FGM/C. The authors highlighted that the overall quality of the included studies was low, and thus encouraged additional research to further examine these associations.Complications secondary to FGM/C are classified into short- and long-term consequences , which a17 In addition, FGM/C is associated with an increased rate of urinary and genital infections, which could negatively affect the obstetric outcome.17The most accredited potential mechanism related to the augmented risk of obstetrical complications in women with FGM/C is the presence of inelastic pelvic and vaginal tissues, subsequent to an excessive and abnormal wound-healing process.22 FGM/C represents a violation of women's physical intactness. Moreover, it may cause psychological trauma to the point of developing a post-traumatic stress disorder (PTSD) according to the DSM-IV criteria,23 as well as to those of the more recent DSM-5.24 One should also consider that the Istanbul Convention adopted by the Council of Europe Committee of Ministers in 2011 recognized FGM/C as a form of gender-based violence.25 Despite the evident clinical and social relevance of the phenomenon, there is currently scanty research exploring the psychological impact of FGM/C.As underlined by Behrendt and Moritz,26 In a pilot study on 47 Senegalese women, Behrendt and Moritz22 showed a significantly higher prevalence of PTSD  and other psychiatric syndromes  in 23 cut women (vs. 24 uncut participants). In addition, PTSD was associated with memory problems.22 The high percentage of PTSD (>30%) in women with FGM/C was comparable with that observed in cases of early childhood abuse .22 These results are in line with those found by Chibber et al.27 in a cross-sectional study on 4800 pregnant women; more than half of women with FGM/C showed affective disorders, with PSTD rate up to 30%. Moreover, 85% of circumcised women reported the presence of emotional effects, such as flashbacks to the cutting event. A recent Dutch cross-sectional research28 on 66 genitally mutilated African women has confirmed a high rate of psychopathology in this category of women; in fact, a fifth of the respondents  met the criteria for PTSD, a third met these for depression , and nearly a third met those related to anxiety disorders . Infibulation, vivid memory of the cutting event, lack of income, and avoidant coping style  were significantly associated with psychopathology. A recent cross-sectional Egyptian study29 evaluated the psychological impact of FGM/C among 204 adolescent girls aged between 14 and 19 years, demonstrating a significantly higher level of somatization, depression, anxiety, phobic anxiety, and hostility compared with girls without FGM/C. On the contrary, an Israel case–control study30 failed to demonstrate an association between genital mutilation and psychological disorders. However, as stated by Berg et al.,26 the studies analyzing the psychological consequences of FGM/C are characterized by low-quality designs, small sample sizes, and inconsistent results, thus precluding the drawing of firm conclusions.There is evidence that women with FGM/C are more likely to experience anxiety, somatization, phobia, and low self-esteem than those without genital mutilation.1 Although there are no studies directly investigating the effectiveness of CBT in women with FGM/C, this type of intervention was successfully used to treat PTSD following a variety of events, including torture, wars, and sexual violence.32 Psychological support is also indicated for women who decide to undergo surgery to correct health complications of FGM/C to avoid retraumatization. In fact, the surgical intervention itself and the pain experienced may remind women of the mutilation, to the point of triggering a relapse of PTSD symptoms.33 From this perspective, psychological support would be important for postoperative pain management, recovery, and psychological well-being.1The WHO health consequences guidelines based on the existing evidence suggest that cognitive behavioral therapy (CBT), focused on the complex interaction between thoughts, affects, and behaviors, as well as on emotional regulation and stress reduction, may work with girls and women who experienced FGM/C with current symptoms of anxiety, depression, and/or PTSD.35 In women with FGM/C, parts of the erogenous genital zones and sexually responsive vascular tissue are excised.26 The removal of women's genital parts may lead to damaged nerve endings, as well as to the development of inelastic scar tissue and adhesions surrounding the excised areas, and for this reason FGM/C may cause impaired sexual functioning.36Human sexuality results from the interaction of multiple anatomical, neurological, emotional, physiological, and biochemical mechanisms, and is influenced by sociocultural factors and relationship dynamics.37 performed a meta-analysis on the sexual consequences of FGM/C, showing that circumcised women were more likely to report dyspareunia , poor sexual satisfaction , and absence of sexual desire . In the past, one of the major drawbacks of the published articles was methodological; in fact, few studies have adopted validated questionnaires to analyze sexual function. To overcome this problem, in the last decade several studies have used a validated instrument, such as the Female Sexual Functioning Index (FSFI),38 to measure women's sexual functioning  questionnaire to investigate sexual function in women with FGM/C, as well as with those of Thabet and Thabet,36 who adopted a nonvalidated questionnaire developed by the authors themselves. On the contrary, Catania et al.39 performed a case–control study on 114 women showing comparable results between the two study groups regarding lubrication and pain subdomains, and infibulated women obtained significantly higher scores in desire, arousal, orgasm, and satisfaction subdomains. However, the fact that the control group was composed of 54 Western women, with only three from Somalia, may have affected the findings by making the two groups less comparable in terms of cultural background.Berg and Denisonctioning . Except 26 due to the essential role of the integrity of the clitoris and labia minora for the achievement of sexual response.36 It is important to specify that in women with FGM/C some essential structures involved in the achievement of orgasm have not been removed. In fact, anatomically, the mutilation consists in the excision of the externally visible portion of the clitoris (the glans), whereas the crura and the body remain intact under the scar.44 Nour et al.54 found an intact clitoris in 48% of 40 women undergoing defibulation.Overall, although not all women with FGM/C show sexual issues, it seems that they may be physiologically less capable of becoming sexually stimulated than uncut women,26 Mutilated women identify their breasts, tongue, or vagina as their most sensitive parts of the body.55–57 Moreover, as suggested by Thabet and Thabet36 sexual function in women with FGM/C is the result of multiple cofactors, including a correct sexual and genital knowledge, and an adequate sexual stimulation to achieve a satisfactory response.In addition, another possible compensatory mechanism to overcome the “anatomical barrier” is the ability of women to enhance stimulus originating from other sensory or erotic areas, or through the ideation of emotions and fantasy.2 This theory was supported by Andersson et al.,53 who stated that, in sexually active women, type III FGM/C was associated with the lowest sexual quality of life scores as compared with controls. Mohammed et al.43 found significantly worse sexual functioning in women with type II FGM/C relative to women with type I FGM/C and those without FGM/C. A recent cross-sectional study48 also demonstrated that women with type III FGM/C presented the worst FSFI scale score. Based on these findings, a firm conclusion on this topic is not yet achievable. Future research should compare women with different types of FGM/C to elucidate the possible dose–response relationship involved in FGM/C and sexual functioning.Another important question is the existence of a dose–response relationship between FGM/C and sexual functioning. One can hypothesize that the more severe the woman's excision is, the greater the consequences are.36 in the early 2000s. The procedure consists in the resection of the skin that covers the stump with the aim of revealing the clitoris; the suspensory ligament is subsequently sectioned to mobilize the stump. The scar tissue is then removed, and the glans is placed into a physiological position.58 Surgery is usually performed under general anesthesia to avoid the patient from reliving the traumatic experience of FGM/C.58 The aim of surgery is to restore both clitoral anatomy and function, to improve patient's self-esteem, body image, sexual function, and reduce pain during sexual intercourse.59Clitoral reconstruction is a surgical technique first described by Thabet and Thabet60 Foldès et al.58 published a large prospective study on 2938 women with FGM/C who underwent clitoral reconstruction. In the vast majority of the patients (>99%), the primary expectation for surgery was the recovery of identity, followed by an improvement of sexual life (81%) and pain reduction (29%). Immediate complications after surgery, including hematoma, suture failure, and moderate fever, were registered in 5.3% of the patients, and 3.7% were readmitted to hospital. The 1-year follow-up was completed in 841 patients (29%). After surgery, one woman out of three  who had never experienced orgasm before surgery began to have restricted or regular orgasm, and half of the women who had restricted orgasm before surgery reported a regular orgasm after the procedure. In addition, 97.7% of the participants reported a decrease in pain, and a visible glans was observable in 70% of the patients. In particular, the latter category of patients was 2.2 times more likely to experience orgasms than those without a visible glans (95% CI: 1.40–3.43). However, 23% (n=12/53) of the women who were able to regularly reach orgasm before surgery reported a reduction in orgasmic frequency after surgery. These results are in line with those of Vital et al.,47 who performed clitoral reconstructive surgery on 12 women. In this prospective study, a validated questionnaire, the FSFI, was used to assess the impact of surgery on sexual function. At 6-month follow-up, women showed a multidimensional positive improvement in their sexual function, with a significantly higher FSFI full score  or relational mechanisms  play a central role in sexual functioning.66 Consequently, a comprehensive approach considering all the various aspects of female sexuality should be encouraged. As suggested by WHO guidelines,1 sexual counseling should be proposed for preventing or treating sexual dysfunctions among women with FGM/C.Sexual health represents a fundamental aspect of individual well-being, and sexual dysfunction is related to significant personal distress.68 From this perspective, if a woman is worried about the aspect of her external genitalia, this can lead to negative consequences, such as shame and reduction of self-esteem, with repercussion on her sexual sphere.70 In these cases, careful counseling and a multidisciplinary approach are essential to identify those women who would most benefit from a surgical and/or psychological approach.Several studies have demonstrated that there is a connection between sexual pleasure and the ideas a woman has concerning her genitalia.58 In the postoperative recovery time, an important period of transition, follow-up is central, as well as psychosexual support. However, some concerns have been raised about the potential negative consequences—either physical or psychological—of this type of surgery.71 To date, there are no guidelines recommending clitoral reconstruction. The Green-top Guideline from the Royal College of Obstetricians and Gynaecologists72 on the management of women with FGM/C concluded that further studies are necessary before recommending this procedure, and future trials should evaluate the safety and efficacy outcomes in the long-term period using validated and standardized tools.71Clitoral reconstruction may also represent a valuable option to reduce chronic clitoral pain by excising scar tissues and improve sexual function among women who have undergone FGM/C.71 In conclusion, FGM/C requires personalized treatment, in which the best options should be identified and indicated according to women's individual problems, preferences, and priorities.It is important to inform women seeking reconstructive surgery of the paucity of evidence on the safety and long-term efficacy of the procedure.


In relation to the other behaviors, SB was negatively associated with BM in robust men while BM was positively associated with SB and negatively with LPA and MVPA in robust women. Moreover, LPA also was positively associated with arm BM (p ≤ 0.01). Finally, in pre-frail women, BM was positively associated with MVPA. In our sample, to decrease SB could be a good strategy to improve BM in robust men. In contrast, in pre-frail women, MVPA may be an important factor to consider regarding bone health.The aim of this study was to determine the relationship between bone mass (BM) and physical activity (PA) and sedentary behavior (SB) according to frailty status and sex using compositional data analysis. We analyzed 871 older people with an adequate nutritional status. Fried criteria were used to classify by frailty status. Time spent in SB, light intensity PA (LPA) and moderate-to-vigorous intensity PA (MVPA) was assessed from accelerometry for 7 days. BM was determined by dual-energy X-ray absorptiometry (DXA). The combined effect of PA and SB was significantly associated with BM in robust men and women ( The aging process brings several physiological changes such as a decrease of bone mass and osteoporosis, a skeletal disorder characterized by reduced bone mineral density (BMD) and mass, resulting in damaged bone structure . AccordiTherefore, our hypothesis is that the PA levels would be positively associated with bone health depending on the lifestyle and the frailty status. The present study was therefore designed (1) to determine the relationship between bone mass and the movement behaviors distribution according to frailty status and, (2) to examine whether differences in this distribution between older men and women with adequate nutritional status exist.This cross-sectional research selected subjects from the Toledo Study for Healthy Aging (TSHA), a Spanish population-based prospective cohort study. The full methodology was described previously . To date−2) were carried out by DXA . Whole body and regional sites (arms and legs), lumbar spine (L1–L4), and the proximal region of the femur  were assessed in a supine position, wearing light clothing with no metal, shoes or jewelry. The arm region included the hand, forearm, and arm and was separated from the trunk by an inclined line crossing the scapulohumeral joint, such that the humeral head was located in the arm region. The leg region included the foot, the lower leg, and the upper leg. It was separated from the trunk by an inclined line passing just below the pelvis, which crossed the femoral neck. The bone T-scores were calculated in each participant for the femoral neck. Whole body fat mass (g), lean mass (bone-free) (g) and percentage body fat mass were also obtained from the total body scan. Sarcopenia was evaluated as stated by the specific criteria for our DXA model proposed by Delmonico et al. (2007) [Anthropometric measurements were obtained on each subject immediately before DXA assessment by a balance-stadiometer Seca 711 . BMC (g) and BMD (g/cm. (2007) . PhysiciPA and SB were measured using ActiTrainer and ActiGraph wGT3X-BT  accelerometers. Participants were instructed to wear the accelerometer on the left hip during waking hours for seven consecutive days and remove it during any bathing or swimming activities. The study included only the results from participants with at least four valid days with at least 480 min (8 h) of wear without excessive counts each day , independent of whether it was weekdays or weekends, as in previous studies ,25. DataThe frailty syndrome was evaluated as stated by the criteria proposed by Fried et al. (2001) . To analp < 0.05; however, results with p-values < 0.06 have been discussed in our study, given that results of medical research should be interpreted in the context of the type of study and other available evidence and, in this case, it could provide important information [p < 0.2 and the “none” correction was also used for the complete models. Regarding socio-demographic variables, we used age, gender, education, marital status, and income. Anthropometric and body composition variables considered were body mass index, fat mass and lean mass. For lifestyle factors, we included alcohol intake and smoking and finally, as health variables, we used thyroid disease, arthritis and calcium. Statistical analyses were completed using R statistical system version 3.1.1., following the guide to compositional data analysis for PA, SB, and sleep research published by Chastin and colleagues . The chaormation . Likewisp < 0.05) and, in BMI between robust and pre-frail groups (p < 0.05). No significant differences were found between pre-frail and frail subgroups.Characteristics of the participants are shown in The geometric means for the minutes/day and the % of time spent in each movement behavior are shown in The composition of the day is presented using compositional mean bar plots for each sex in The compositional data analysis models by frailty status for the whole sample (without differentiation by sex) are reported in p = 0.043) and leg BMC and BMD . Time spent in SB relative to other movement behaviors was negatively associated with whole body BMD (p = 0.041) and leg BMC and BMD . No significant associations were found in the pre-frail subgroup. The composition of movement behaviors as a whole in the robust subgroup was significantly associated with whole body BMD (p = 0.015) and whole body and leg BMD and BMC . Time spent in SB relative to other movement behaviors was positively associated with whole body and leg BMC and BMD . Time spent in LPA was negatively associated with whole body BMD and leg BMC and BMD  and positively associated with arm BMC (p = 0.011). Time spent in MVPA was negatively associated with arm BMC (p = 0.011). Just time spent in MVPA relative to the other movement behaviors was positively associated with leg BMC (p = 0.054) and whole body BMC and BMD  in pre-frail women. The composition of movement behaviors as a whole in the robust subgroup was significantly associated with arm BMC  also found some evidence of this beneficial effect of PA in those classified as pre-frail compared to robust and frail . SimilarIn relation to the frail subgroups (men and women), our sample was insufficiently large and therefore, our data does not allow to draw any meaningful conclusions with adequate power. However, due to the differences between different frailty status and the need to study each frailty status independently ,11, our Finally, in relation to the movement patterns, in our study the frail and pre-frail clearly showed the opposite profile of movement behaviors compared to robust older people, both in the whole sample and also in relation to each sex, spending more time in SB and less in LPA and MVPA than the entire sample, similarly to other previously published studies ,45,46. COur study is not without limitations. Despite using older adult-specific cut-off points for vector magnitude counts per minute in this study ,28, specWhile the whole group, without sex differentiation, does not show a consistent result, the PA effects on bone health are clearer when men and women are studied separately and according to the frailty status. We identified that to combine a decrease of SB and maintenance or increase of LPA and MVPA could produce a beneficial effect on bone mass in robust men. Nonetheless, to increase MVPA and maintain or decrease time spent in LPA and SB, respectively, contributes toward a more favorable bone mass in the case of pre-frail women. In accordance with the movement pattern, pre-frail and frail older people spent more time in SB and less in LPA and MVPA than the entire sample, the opposite movement profile than the robust subgroup. Future research in this area could look at defining guidelines/levels that people should use to increase their bone health depending on their frailty status.


Optimizing surgical instrumentation may contribute to value-based care, particularly in commonly performed procedures. We report our experience in implementing a perioperative efficiency program in 2 types of orthopedic surgery .A comparative before-and-after study with 2 participating surgeons, each performing both THA and TKA, was conducted. Our objective was to evaluate the effect of surgical tray optimization on operating and processing time, cost, and waste associated with preparation, delivery, and staging of sterile surgical instruments. The study was designed as a prospective quality improvement initiative with pre- and postimplementation operational measures and a provider satisfaction survey.P = .01) for TKA procedures but did not differ for THA. The number of survey respondents was small, but satisfaction was high overall among personnel involved in implementation.A total of 96 procedures (38 preimplementation and 58 postimplementation) were assessed using time-stamped performance endpoints. The number and weight of trays and instruments processed were reduced substantially after the optimization intervention, particularly for TKA. Setup time was reduced by 23% (6 minutes, Optimizing instrumentation trays for orthopedic procedures yielded reduction in processing time and cost. Future research should evaluate patient outcomes and incremental/additive impact on institutional quality measures. Streamlining the selection and configuration of surgical instrumentation is one promising component of value-based care. Audits of instrument usage across surgical settings have demonstrated that only 13% to 22% of instruments placed on surgical trays are used during a given operation. Reductions on the order of 25% to 50% are feasible, even allowing for infrequently used but necessary instruments requested by surgeons.–8Increasing efficiency for costly procedures is a strategic aim for health care systems around the world, and in 2015 the US Department of Health and Human Services announced a goal that 90% of Medicare fee-for-service payments be based on quality or value in the next 3 years.Research on surgical tray efficiency in orthopedic surgery to date has mostly been limited to implementation of patient-specific instrumentation in total-knee arthroplasty (TKA). The purpose of the present study was to evaluate our experience implementing a perioperative efficiency program to optimize surgical instrumentation for a joint arthroplasty team already operating at high levels of efficiency. We aimed to address product-, cost-, and process-related variation while supporting patient outcomes and surgeon preferences.2We designed and implemented optimized instrument sets for patients undergoing primary TKA or total-hip arthroplasty (THA) at this institution. The study was conceived as a feasibility pilot, with a pre- and postevaluation of practice change. No randomized comparison was planned or implemented. No patient-identifying information was collected and standard protocols were followed for operating room (OR) accessibility. The study was conducted as part of the hospital's quality improvement initiative and was therefore considered exempt from Institutional Review Board review requirements. We followed current guidelines for quality improvement studies in preparing this report.2.1Patients undergoing primary TKA or THA procedures at the University of California - San Francisco (UCSF) Parnassus OR, with basic and noncomplicated joints , were considered eligible. Two surgeons participated, each of whom perform between 150 and 200 TKA and THA procedures per year. Both participating surgeons had extensive experience with the implant systems used in the study. The implant systems used throughout the pre- and postimplementation study periods came from a single vendor, Johnson & Johnson Medical Devices Companies. This consisted of one total-knee system (ATTUNE Knee System) for TKA, and one total-hip system  for THA.2.2The intervention consisted of optimized, surgical instrumentation tray configurations for TKA and THA. The optimized tray configurations were designed to reduce the number of trays and instruments while maintaining consistent availability of equipment Fig. . Tray coThe new instrument configurations were planned in Q4 2016. Baseline data were collected in February 2017, including a preimplementation survey of surgeons, OR staff, and Sterile Processing Department personnel. The new tray configurations were deployed over the course of several months starting in March 2017, during which time procedure data were not collected to allow adjustment of processes before assessing the impact of the reconfigured trays. After this settle down/phase in period, postimplementation data were collected on all eligible procedures performed by participating surgeons in July and August 2017. A follow-up survey of personnel was conducted in September 2017.2.3The OR setup time was the primary endpoint for this study. Setup time was defined as the period between wheeling in the 1st instruments and placing all items on the back table in place for surgery. An in-room observer used tracking software to collect timestamped data on the duration of predefined steps in each procedure. The observer was trained on use of the software and the definitions of each timing variable, but was not blinded to the use of original vs optimized tray configurations, due to feasibility and the pre-post nature of the study.Secondary endpoints included clean down time, total OR time, number of trays and instruments being processed, tray weight, number of trays in blue wrap vs rigid sterile containers, and cost estimates based on the observed parameters. Clean down time commenced when the 1st instrument was put away following definitive implantation and ended once the OR was clean and ready for the next procedure. In addition to the outcomes measured during procedures, provider and staff satisfaction with the intervention were assessed with the pre- and postsurveys mentioned earlier.2.4t test was used for the power calculation. The test of significance used to assess pre-post differences in outcomes was the Kolmogorov–Smirnov 2-sample test, which is a nonparametric test appropriate for use with data that are not normally distributed. Endpoints were assessed for all procedures (pre vs post) and were also stratified by type of surgery (knee vs hip). For continuous variables, means, medians, ranges, and standard deviations of the mean (standard deviation) were computed. The percentage change in the primary endpoint from pre- to postimplementation was calculated as the difference in means divided by the baseline value. P-values <.05 were regarded as statistically significant (no adjustment was made for multiple comparisons). Analyses were performed using SAS Enterprise Guide 7.1 .The primary comparison of interest was between the pre- and postintervention periods. A sample size of 76 patients (38 prior to implementation and a minimum of 38 postintervention) was determined to be sufficient to detect a 5-minute reduction in the primary endpoint with 80% power. As we were only concerned with the potential for improvement for this effort to enhance efficiency, a 1-sided 3The study population consisted of 38 procedures during the preimplementation period and 58 during the postimplementation period, all of which were completed by the same 2 surgeons. Of the 96 procedures, nearly half (49%) were primary TKA and 51% were primary THA. Procedure characteristics were similar in the pre- and postintervention groups, except for a preponderance of cemented primary hip surgeries preimplementation, vs 97% cementless after the optimized trays were in use  for both surgeons, many of which were seldom used. Many instruments in the trays were simply included as a result of historical tray construction without specific attention to the frequency of use. During the optimization exercise, the surgeons reached agreement on elimination of instruments that were infrequently used. Tray configuration strategies included placement of implant instruments in wire baskets inside of rigid sterile containers, paring down the number of existing original equipment manufacturer trays, and creating specialized made-to-order trays via 3rd-party suppliers (for TKA only at the time of this work).In the postimplementation period, 3 trays were used for TKA and 6 for THA, a decrease of 62.5% and 57.1%, respectively. The number of instruments was reduced by 43.6% (TKA) and 17.5% (THA). There was a 47.4% reduction in total weight due to the optimized tray configurations (34% for hip instrumentation and 63.9% for knee instrumentation). The original tray configuration for TKA was 69.9 lbs. and the optimized set was 25.3 lbs; for THA, the original set was 86.3 lbs while the optimized set was 57.0 lbs.3.2P = .06). Among TKA procedures, a 23% decrease (6-minute reduction) in setup time was observed, slightly higher than the 5 minutes assumed to be clinically significant in study planning (P = .01). Changes in clean down time , and total OR time were not significantly different after the intervention  and the estimated cost of $75 to sterilize 1 tray.When surveyed, surgeons and hospital staff reported positive feedback on the intervention. Prior to the intervention, 100% of 13 survey respondents expected the tray efficiency intervention would add value for the institution, and that a reduction in size, number, and/or weight of instrument trays could have a positive impact on patient care. After the intervention, only 5 individuals responded to a similar survey. Four of 5 agreed that the intervention had a positive impact on patient care, and that the program would add some or a good deal of value for other specialties . Sixty percent of respondents felt that the program offered additional value over other facility-led programs, and the same number (60%) agreed that the workload/time commitment required during program implementation was reasonable. Response rate for the survey was 62% preimplementation and 39% postimplementation.4This study demonstrates the efficiency and cost benefit of streamlining surgical instrumentation trays in an academic medical center even when adopted by 2 surgeons in a 5-surgeon arthroplasty practice. As the optimization pertained to the instrumentation set of 1 implant manufacturer, the impact of the intervention could only be measured on the surgeons who routinely used that manufacturer's products. In the case of this particular institution, only 2 of the 5 staff surgeons could be included. The magnitude of reduction in the number of trays (57% for hip and 63% for knee) was in line with previously published estimates of instrument reduction in joint arthroplasty (43–66%), nearly all of which described patient-specific instrumentation vs conventional instrumentation in TKA , which did not require substantial additional effort on the part of hospital staff. We used a settle down/phase in period while the optimized trays were 1st being used, to minimize potential bias from a learning curve for new processes. An effort was made to survey hospital staff impacted by the process change both before and after implementation.Limitations of the study include the lack of a randomized control group, the small sample size especially with regard to the staff survey, and the absence of recorded clinical outcomes for TKA or THA. Survey responses, especially postimplementation, were limited due to staffing schedule and team size. While finding people to complete a survey preoperatively was relatively straight forward and could include any number of technicians and personnel, the people who initially responded to the survey may not have been associated with the optimized trays during the implementation phase on a consistent enough basis to be willing to offer an opinion. This is because of the size of the team: the orthopedic service runs more than 3 rooms per day and surgical team members scrub and support a number of subservices based on varying needs in the OR on any given day. Thus, on any given day a surgeon may have a completely different team. For future research, targeting the survey only to those staff members more likely to assist the surgeons involved in the project might be indicated though this may not actually be possible. A follow-up study is planned to evaluate patient-reported outcomes and institutional quality metrics. The unblinded nature of the pre- and postintervention observation process, while practical for collecting data, could have affected performance by virtue of staff awareness that they were being observed; however, this effect should have been similar in both the pre- and postintervention periods.,21 Further studies with more surgeons, at a variety of experience levels, should be conducted. Additionally, future research should include an assessment of how frequently surgeons required additional instruments beyond what is included in the original order to complete the case. While, anecdotally, this was a very rare event, prospective data collection would strengthen the conclusions of future research. Even ambitious quality improvement initiatives can fail to achieve statistically significant improvement in patient outcomes. However, given the importance of perioperative care in the US health care system, there is a case to be made for continued attempts to implement evidence-based adjustments to usual surgical practice, while tracking the impact on patients. Even small increments of increased efficiency, for instance on OR transition times, may have impact when applied to a frequently performed procedure such as joint arthroplasty. In future research, patient-centered outcomes including safety, effectiveness, and quality of life impacts should be evaluated across a range of settings and contexts.Our data come from a single academic institution, with self-selected and highly experienced surgeons participating in the intervention. Results may not be generalizable to other settings; in particular, prior institutional efforts to streamline surgical processes indicate that this institution was starting from a high baseline in terms of efficiency.Larger sample sizes may be needed to pinpoint effects of incremental changes to complex processes, including potential impact on institution-wide quality metrics. Lastly, controlled studies with the assessor blinded to the group assignment, if feasible, would improve the reliability of this type of observational evidence.We demonstrated that a surgical tray efficiency program can be successfully implemented for orthopedic procedures. The program reduced OR setup time, the number of trays and instruments, and costs associated with sterilization. Anecdotally, surgeon and staff satisfaction with the intervention was high.Conceptualization: Richard Capra, Stefano A. Bini, Dawn E. Bowden, Katherine Etter, Matt Callahan, Richard T. Smith, Thomas Parker Vail.Data curation: Katherine Etter.Formal analysis: Katherine Etter.Funding acquisition: Richard Capra, Dawn E. Bowden.Investigation: Richard Capra, Stefano A. Bini, Katherine Etter, Matt Callahan, Richard T. Smith, Thomas Parker Vail.Methodology: Richard Capra, Stefano A. Bini, Dawn E. Bowden, Katherine Etter, Matt Callahan, Richard T. Smith, Thomas Parker Vail.Project administration: Richard Capra, Dawn E. Bowden.Resources: Richard Capra, Stefano A. Bini, Matt Callahan, Richard T. Smith, Thomas Parker Vail.Supervision: Richard Capra, Dawn E. Bowden.Validation: Richard Capra, Stefano A. Bini, Dawn E. Bowden, Richard T. Smith.Visualization: Richard Capra, Dawn E. Bowden.Writing – original draft: Dawn E. Bowden, Katherine Etter.Writing – review & editing: Richard Capra, Stefano A. Bini, Dawn E. Bowden, Katherine Etter, Matt Callahan, Richard T. Smith, Thomas Parker Vail.


Human brucellosis is a neglected public health issue in China and reports of HIV-infected individuals complicated with brucellosis are rare. This report describes the case of an HIV-infected patient complicated with brucellosis. We want to raise awareness of clinical diagnosis of brucellosis among clinicians. Furthermore, we should be more concerned about cases with pyrexia of unknown origin, especially in non-epidemic areas of brucellosis in China.We encountered the case of a 31-year-old HIV-infected male with a CD4+ T lymphocyte count of approximately 300. On May 1, 2019, the patient had onset of non-specific caustic irregular fever with body temperature reaching 41.0 °C. He was admitted to two medical institutions in Yunnan with pyrexia of unknown origin. Finally, on day 7 of hospitalization in the Public Health Clinical Medical Center in Chengdu City, he was diagnosed as having brucellosis infection based on blood culture results.This is the first reported case of brucellosis concomitant with HIV infection in China. Laboratories in infectious disease hospitals and category A level III hospitals in the southern provinces of China should be equipped with reagents for clinical diagnosis of brucellosis and to strengthen the awareness of brucellosis diagnosis in China. Secondly, in provinces with a high incidence of AIDS and brucellosis such as Xinjiang and Henan, it is recommended to implement a joint examination strategy to ensure the early detection, diagnosis, and treatment of this infection. Brucella spp., and can be transmitted to humans from cattle, sheep, goats, and pigs via direct contact with the infected animals or through consumption of unpasteurized animal products [Brucella infection with a titer of 1:100 or higher as measured by the serum agglutination test (SAT) is considered a confirmed case of brucellosis [Brucellosis is a zoonotic bacterial infection caused by products , 2. Humaproducts . The precellosis . Personscellosis . AIDS iscellosis –8. HowevWe presented the case of a 31-year-old male who had acquired HIV infection through unprotected sex with another man in 2016. He had a CD4+ T lymphocyte count of approximately 300, and had been prescribed antiretroviral therapy (ART) from 2016. On May 1, 2019, he had non-obvious caustic irregular fever and occasional chills, with his body temperature reaching 41.0 °C. The patient then went to a privately operated clinic for 2 days and received unknown medical infusion in Kaiyuan City, Yunnan Province, China. There was no improvement in his condition after 2 days, on May 3, 2019, and he was consequently referred to Kaiyuan People’s Hospital, where a routine blood examination was conducted. The laboratory results showed low leukopenia, low thrombocytopenia, and low hypokalemia. The patient was prescribed cephalosporin, hypothermia, and treatment to replenish fluids for 3 days, but the fever persisted.On May 7, 2019, the patient returned to Chengdu from a business trip in Yunnan. He was hospitalized in Chengdu Center for Disease Control and Prevention on the same day. He received ART and biapenem anti-infective treatment for fever, chills, and bloodstream infection. The next day, he underwent a color Doppler ultrasound examination and the results of the scan revealed enlarged spleen, enlarged bilateral cervical lymph nodes, and enlarged bilateral inguinal lymph nodes. The routine blood examination revealed that he had neutropenia  for acid-fast bacilli. This was initially suspected as tuberculosis infection, but the tuberculosis infection was ruled out by the X-ray check. Two days later, blood culture confirmed Malta Brucella was not found. No abnormal symptoms were observed during the whole period of medication, proving that he was completely cured, and the medication was terminated.No clinical symptoms were observed after the patient was discharged, and rifampin and doxycycline were regularly taken. The standardized 6-week medication was prescribed. The patient continued to take medication for 3 months to avoid chronic infection. On September 15, 2019, the patient visited the local hospital in Yunnan for blood culture, and Brucellosis is an important zoonotic infection that remains to be a global public health issue. Currently, more than 170 countries have reported cases of brucellosis, with approximately 500 000 new cases reported each year . AlthougAt present, many methods have been adopted to detect brucellosis. Bacterial isolation remains the gold standard for testing ; howeverThe treatment of brucellosis may be of great clinical importance in the management of HIV infection in a brucellosis-endemic country . In thisIn summary, this is the first reported case of brucellosis concomitant with HIV infection in China. Brucellosis can be easily overlooked in infectious disease hospitals and in category A level III hospitals in the southern provinces of China; laboratories in these hospitals should be equipped with the reagents to diagnose brucellosis. Awareness of the clinical diagnosis of brucellosis should be improved among doctors in China. Meanwhile, it is suggested that provinces with a high incidence of AIDS and brucellosis implement a joint examination strategy model.


According to some studies, interventions can prevent or delay frailty, but their effect in preventing adverse outcomes in frail community-dwelling older people is unclear. The aim is to investigate the effect of an intervention on adverse outcomes in frail older adults.A systematic review and meta-analysis of Medline, Embase, the Cochrane Library, and Social Sciences Citation Index. Randomized controlled studies that aimed to treat frail community-dwelling older adults, were included. The outcomes were mortality, hospitalization, formal health costs, accidental falls, and institutionalization. Several sub-analyses were performed .Twenty-five articles  were included. Six types of interventions were found. The pooled odds ratios (OR) for mortality when allocated in the experimental group were 0.99  for case management and 0.78  for provision information intervention. For institutionalization, the pooled OR with case management was 0.92 , and the pooled OR for information provision intervention was 1.53 . The pooled OR for hospitalization when allocated in the experimental group was 1.13  for case management. Further sub-analyses did not yield any significant findings.This systematic review and meta-analysis does not provide sufficient scientific evidence that interventions by frail older adults can be protective against the included adverse outcomes. A sub-analysis for some variables yielded no significant effects, although some findings suggested a decrease in adverse outcomes.CRD42016035429.Prospero registration The online version of this article (10.1186/s12877-018-0936-7) contains supplementary material, which is available to authorized users. The secutcomes” .Many studies suggest that frailty is associated with adverse outcomes including mortality, institutionalization, hospitalization, and accidental falls , 9–12. SThis systematic literature review and meta-analysis examines the following three questions: Which interventions are applied to protect frail community-dwelling older adults against adverse outcomes? What effect do interventions have on frail community-dwelling older adults in terms of mortality, hospitalization, formal health costs, accidental falls, and institutionalization? Finally, how do age, study duration, and the multi- versus unidimensional approaches of frailty and recruitment influence the effect of an intervention?A systematic review and meta-analysis was performed. Four electronic databases were consulted: Medline, Embase, The Cochrane Library (CL), and Social Sciences Citation Index (SSCI). The SSCI was consulted to assure that articles with a multidimensional approach to frailty would be found. The recommendations of the Cochrane Handbook for Systematic Reviews for Interventions 5.1.0 were used , and theThe search strategy used four key terms: aged, frail elderly, independent living, and randomized controlled trial (RCT). The final search strategy was developed with the help of a librarian , all types of intervention were allowed, there was no recruitment after hospital discharge (inpatient and outpatient), and the intervention must have been compared with care as usual. The studies needed to have one or more of the following outcomes: mortality, institutionalization, hospitalization, formal health costs, and accidental falls. Pilot studies and studies not written in English, French, German, or Dutch were excluded.Retrieval and selection of studies were performed in a stepwise way. After duplicate records were removed, titles and abstracts were screened. Two reviewers assessed a sample of 12% (MVDE and DD). If their agreement reached 95%, the first author continued the inclusion process alone. In the next step, two researchers (MVDE and DD) independently read the full text of the selected articles for the inclusion and exclusion criteria. In cases of doubt or disagreement, a third researcher (BV) was asked to judge.Two independent researchers (DL and BF) assessed the quality of each article with the Cochrane risk of bias tool . An evalThe first author preformed the data-extraction by preparing an excel sheet including all the necessary data to answer the research questions like average age of a study, number of participants. Subsequently two researchers (DL and BF) controlled the accuracy of the data-extraction. Information concerning average age, percentage of male participants, type of intervention, operationalization of frailty, and method of recruitment of participants  were subsequently collected and categorized  and Review Manager 5.3 . For theThe details of the search process are presented   yielded no significant effects, although some findings suggested a decrease in adverse outcomes.The results of this systematic review are in line with previous studies: the effect is unclear and inconsistent. In a systematic review, You et al. examined the effect of case management on mortality/survival days, and two out of seven articles reported a significant result . Also, HA pooled meta-analysis should lead to more significant and consistent results, yet this analysis did not. However, the literature provides evidence that a pooled meta-analysis could produce significant findings. For example, Elkan et al. reported that mortality and institutionalization are significantly lower after a home-based support intervention for frail older adults in comparison with a control group . Thomas Remarkably, the data in the current work show that the odds of being hospitalized are higher in the intervention group than in the control group Table . BerglunThe studies in the current analysis showed heterogeneity for average age, duration, etc., which could explain the inconsistency in the results . A sub-aA plausible reason for the lack of evidence is the heterogeneity within studies. Within studies, the contextual factors of the population in the experimental group was heterogeneous, with differences in age, educational level, morbidities, and context, etc. If frailty is operationalized with a multidimensional approach, however, the question that arises is: ‘which dimensions were problematic?’ Also the local setting within studies was heterogeneous, Van Leeuwen et al. used two regions, and Kono et al. and Perttila et al. used three regions , 40, 42.Future research should not solely focus on the effect of an intervention but also address the question: why did interventions work when they did or why not, for who did they work and what contextual factors triggered the mechanisms required to make them work. This is described by Pawson and Tilley in ‘realistic evaluation’ (1997). They suggest that a realistic evaluation approach might provide a better understanding of the effect of an intervention . This apA consensus about the concept of frailty is necessary for future research and would enable comparison, evaluation, and replication of interventional studies. Some authors have made valuable efforts toward reaching a consensus ; for exaSeveral other explanations are possible for the current results. The selected population may have been detected too late and already have been too frail , 15. In Previous systematic reviews have focused on the effect of one intervention in comparison with care as usual –58. A st. A second weakness is the concept of frailty. Several methods are used to operationalize frailty, and some may not be accurate enough to recruit frail older adults, making study comparison and evaluation difficult [The analysis also has some weaknesses, so that the results should be interpreted with caution. A first weakness is the small number of original studies, which led to meta-analyses only for case management and information provision and reduced the reliability of the results. One reason for the small numbers of included publications is the lack of operationalization of ‘frailty’ in studies. An absence of an operationalization of frailty is also a feature in other studies , 17. Othifficult . A thirdifficult , which cThe number of frail older adults with a high need of care and support is increasing. According to some studies, interventions can prevent or delay frailty, but their effect in preventing adverse outcomes in frail community-dwelling older people is unclear. The aim of this article was to investigate if interventions for frail community-dwelling older adults can be protective against adverse outcomes. This systematic review and meta-analysis does not provide sufficient scientific evidence that supports this assumption, even though some results suggest a decrease in adverse outcomes.Future research must consider that the research population of older adults is very heterogeneous, also within studies. A good breakdown of all of these characteristics is necessary, and sub-analyses might avoid ecological fallacies. Each patient’s specific needs and how to deliver these services are probably essential for the effectiveness of an intervention. New methods/approaches, for example the realist approach might provide a better understanding of the effect of an intervention. Future research must also consider new societal trends, implementation problems, and heightened awareness about services that may influence the results.Additional file 1:Data S1. Search strategy (DOCX 15 kb)Additional file 2:Text S1. Extra information operationalization and categorization of Variables. (DOCX 19 kb)Additional file 3:Figure S1. Flow chart (PDF 188 kb)Additional file 4:Figure S2. Funnel plot and Forest plot (PDF 257 kb)Additional file 5:Figure S3. Critical appraisal (PDF 187 kb)