Urinary incontinence (UI) is a common and embarrassing complaint for pregnant women. Reported prevalence and incidence figures show a large range, due to varying case definitions, recruited population and study methodology. Precise prevalence and incidence figures on (bothersome) UI are of relevance for health care providers, policy makers and researchers. Therefore, we conducted a systematic review and meta-analysis to investigate the prevalence and incidence of UI in pregnancy in the general population for relevant subgroups and assessed experienced bother.All observational studies published between January 1998 and October 2018 reporting on prevalence and/or incidence of UI during pregnancy were included. All women, regardless of weeks of gestation and type of UI presented in all settings, were of interest. A random-effects model was used. Subgroup analyses were conducted by parity, trimester and subtype of UI.The mean (weighted) prevalence based on 44 included studies, containing a total of 88.305 women, was 41.0% (range of 9–75%). Stress urinary incontinence (63%) is the most prevalent type of UI; 26% of the women reported daily loss, whereas 40% reported loss on a monthly basis. Bother was experienced as mild to moderate.UI is very prevalent and rising with the weeks of gestation in pregnancy. SUI is the most common type and in most cases it was a small amount. Bother for UI is heterogeneously assessed and experienced as mild to moderate by pregnant women. Urinary incontinence (UI) is the complaint of involuntary loss of urine . It is aThe prevalence and incidence of UI in pregnancy is widely researched. However, these prevalence and/or incidence figures vary greatly throughout published reports, depending on the local setting, case definitions applied, recruited population (trimester of pregnancy and parity), and study methodology , 9. FormTherefore, the primary aim of this systematic review and meta-analysis was to examine the pooled overall prevalence and incidence of UI in pregnancy in the general population, specified for relevant subcategories . A secondary aim was to provide an overview of the measurement instruments and their outcomes for bother in relation to UI as used in included studies.The MOOSE statement for reporting systematic reviews and meta-analyses was followed . The resWe performed a systematic review and meta-analysis of observational studies reporting on the prevalence and/or incidence of UI during pregnancy and experienced bother in relation to UI. We searched the electronic databases of PubMed, EMBASE and CINAHL.We used the following search terms to search all databases: pregnancy, pregn*, prepartum, pre-partum, pre partum, peripartum, peri-partum, peri partum, nulliparous, primiparous, primigrav*, primipar*, multiparous, multigrav*, multipar*, urinary incontinence, urine loss, pelvic floor disorders, pelvic floor dysfunctions, leaking urine, incontinence, prevalence, incidence, epidemiology, bothersomeness, bother* and quality of life. In the Appendix the complete search strategy for PubMed is provided. This search string was adapted for use in the other databases.Observational studies published between January 1, 1998, and January 1, 2019, in Dutch, English, Portuguese, German and French were included. All studies examining prevalence and/or incidence of UI among adult primi- and multigravid women, regardless of weeks of gestation, type of UI, setting and country, were of interest. Outcomes of interest were prevalence and/or incidence of (bothersome) UI. Exclusion criteria were: articles not available in full or not reporting an overall UI prevalence of any frequency and studies examining only twin pregnancies. When articles did not report a prevalence or incidence figure or response rate, an attempt was made for estimation from the information provided. Throughout this article we use the term bother (in relation to UI) as umbrella term for related constructs [impact on daily life or quality of life (QOL)].Titles and/or abstracts of studies retrieved using the search strategy and those from additional sources were screened independently by two reviewers (HM and EB) to identify studies that potentially meet the inclusion criteria. The full text of these potentially eligible studies were retrieved and independently assessed for eligibility by two reviewers. Any disagreement on eligibility was resolved through discussion with a third reviewer (BB). All the included articles were reference checked.Information on each study was extracted in a standardized data extraction form, based on the Cochrane Public Health Data Extraction and Assessment template.To assess the risk of bias, the Joanna Briggs critical appraisal tool for studies reporting prevalence data was used , 18. TheCharacteristics regarding measurement instruments for bother were extracted in a separate standardized extraction form. The form contains items such as measurement instrument, related construct and measurement results.2 statistic, with I2 > 75% labelled as considerable heterogeneity [We used a random effects model to pool the inverse variance (IV) weighted prevalence of UI in individuals to avoid undue influence on the summary estimate from smaller and less precise studies or studies with a very small prevalence. Pooled prevalence and incidence values were reported with 95% confidence intervals (CI). The degree of heterogeneity was determined by the Iogeneity .We performed subgroup analyses based on trimester, parity, type and frequency of UI, as these factors may explain why studies show varying prevalence figures. Trimesters 1, 2 and 3 were defined as weeks 1–13, 14–26 and 27 to at term (42 weeks), respectively. STATA Statistical Software, release 15, was used for analysis.To determine the overall experienced bother in relation to UI across included studies, the total scores of the different measurement instruments for bother were converted to a (standardized) 0 to 100 scale, with 0 indicating no bother and 100 indicating extremely bothered. We classified 1 to 20 as no to mild bother, 20 to 40 as mild to moderate bother, 40 to 60 as moderate to severe, 60 to 80 as severe to very severe and 80 to 100 as extremely severe bother.Among the 1338 papers initially identified, 44 met the eligibility criteria  hospital. Other studies included women from a civil registration system , midwifeThirteen studies reported on (measurement instruments for) bother, whereas one study (73) reported on two measurement instruments. The result of only one measurement instrument was reported for this study, as the second one (SF-36) was incomplete. Table Six different measurement instruments for bother were used, of which the ICIQ-UI SF was most frequently used. Two studies reported the results of the ICIQ-UI SF as categories , 26. One2: 99.77%), regardless of trimester, parity or type of UI . Twenty-four studies recruited women from trimester 1–3, with an overall UI prevalence of 40% (95% CI: 34.0–45.0%). Based on 24 studies, SUI accounts for 63% of UI cases, whereas UUI, MUI and unexplained UI were 12%, 22% and 3% respectively.2 = 98.6%), whereas four studies reporting only on primiparous women found an overall UI prevalence of 31% . Twenty-seven studies included women with any parity, resulting in a pooled prevalence of 42% .When parity is taken into account, 42% of nulliparous women experience UI , 19%  and 34%  respectively.Based on 12 out of 44 studies, the overall prevalence for UI in trimesters 1, 2 and 3 is 9% , weekly UI for 33%  and daily UI for 26% .Based on ten studies, monthly UI accounts for 40% of UI cases , reporting on the amount of urine loss (n = 14), used the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) to assess this parameter  [The majority of studies ( amount) . Three s amount) , 32, a f amount)  and drop amount) , 34.n = 7). In two studies question 3 of the ICIQ-UI SF on interference in daily life was reported as a measurement instrument for bother. Other measurement instruments that were used only once were the Incontinence Quality of Life (I-QOL), Incontinence Impact Questionnaire (IIQ-7), Wagner’s quality of life questionnaire and a self-constructed non-validated questionnaire. The overall bother of UI during pregnancy, on a 0 to 100 scale, ranges between 9.5 and 34.1, consistent with mild to moderate bother, whereas the experienced bother is higher in the 3rd trimester (between 13.3 and 57.6)  did not specify a case definition for UI. Four studies used as a case definition ‘any leakage’ or used the frequency (n = 5), amount/volume (n = 1), timeframe (n = 2) or UI type (n = 3) criteria in their case definition, or a combination of those (n = 3).The majority of studies . As studies with a low risk of bias tend to have a slightly lower prevalence, it is likely that the real prevalence of UI in pregnant women is in the range of 38–41%.Only 13 out of 44 studies reported bother in relation to UI; these studies used a variety of measurement instruments. In an attempt to provide an overall assessment of experienced bother in relation to UI, we (arbitrarily) chose to standardize the measurement results of different bother scales to a 0 to 100 scale. Bother of UI during pregnancy ranges between 9.5 and 34.1 on a (standardized) 0 to 100 scale. The 0 to 100 scale can be regarded as a visual analogue scale (VAS). The VAS is a valid and reproducible method to measure the impact of UI on QOL . No studThe ICI provides an overview of (recommended) grade A  measurement instruments for bother in relation to UI  and adviThis systematic review revealed that the reporting of prevalence with a measure of bother is not common practice yet. To improve the reporting of UI prevalence, it is recommended that in research projects both prevalence and bother should be measured with high quality measurement instruments in line with the recommendations of ICI. In clinical practice, measurement results of bother support healthcare professionals in the clinical reasoning process as it may provide information on diagnosis or prognosis or may evaluate one’s own actions. At the same time, it standardizes communication with colleagues. Moreover, measurement results can be used to better inform patients about their situation and to involve them more easily in joint therapy decisions (shared decision making).The construct bother in relation to UI seems difficult to grasp, as included studies used different definitions. The following terms were used: effect on daily activities/everyday life, interference on daily life, health-related quality of life, severity, lifestyle changes, (perceived) impact on quality of life, distress, experienced discomfort and amount of bother. As the degree of bother is related to help-seeking behaviour for UI , 48, it Based on the prevalence figures, it would appear that UI in pregnancy is an enormous healthcare problem. However, not everyone seeks  help for UI immediately. Several factors determine help-seeking behaviour of pregnant women, such as awareness of treatment possibilities and the experienced burden of UI , 49. AlsManagement of UI should be directed to women who seek help for UI, but may also be directed towards women who experience bother or have risk factors for developing UI (prevention). Such uncertainties require further evaluation and data on duration of treatment effects of PFM(G)T . MaterniThe strength of this systematic review is the large number of included studies, which resulted in the availability of prevalence and incidence numbers for different subpopulations  and for different purposes . To our knowledge, this review is the first one that focused on assessment methods for bother in relation to UI and degree of adherence to the recommendations of ICI with regard to this topic.The limitations of this systematic review are, first, the presence of substantial clinical heterogeneity of the studies. Clinical heterogeneity is due to differences in: case definition (any UI or different frequencies of UI in a certain period of time), population (primigravida-multigravida) or periods researched . Second, the considerable statistical heterogeneity of the studies resulted in large CIs. Third, as the Joanna Briggs critical appraisal tool does not recommend cut-off points for high, moderate or low risk of bias, we arbitrarily chose the cut-off points reported in this systematic review to explore possible differences in prevalence numbers if stratified for risk of bias. However, we did not include or exclude studies based on risk of bias.UI is a very common symptom in pregnancy, and the prevalence rises as weeks of gestation progress. SUI is the most common types and in most of the cases a small amount of urine was lost. The level of bother for UI is heterogeneously assessed and is experienced as mild to moderate by pregnant women.


The groups were comparable pre-treatment in terms of ROM, pain, and functional outcome. Group I had statistically and clinically significantly better ROM and function at three and six months post-treatment than Group II. Despite being statistically significant, the between-group differences at twelve-month follow-up in ROM and function were too small to be considered clinically notable. The between-group comparison of pain revealed no significant differences at any post-treatment point of time. The early arthroscopic capsular release preceding corticosteroid injection and physiotherapy seemed more effective at three- and six-month follow-up; however, it brought a comparable result to corticosteroid injection and subsequent physiotherapy at twelve months follow-up.This retrospective study compared the clinical and functional outcomes of patients diagnosed with an idiopathic frozen shoulder with symptom onset of a maximum of six months, treated by arthroscopic capsular release followed by corticosteroid injection and physiotherapy to patients who received only corticosteroid injection followed by physiotherapy. The patients who underwent arthroscopic capsular release, intraoperative corticosteroid injection, and physiotherapy (Group I,  Although a prevalence of 2% to 5% in the general population makes frozen shoulder one of the most common causes of shoulder pain and disability in the upper extremity , the besThe therapy aims to regain a painless and functional shoulder with the full range of motion. Routinely, the first choice of intervention is a nonsurgical one, represented by pharmacotherapy of the synovitis and inflammatory mediators and/or physiotherapy treatment modalities to prevent or modify capsular contracture ,8,9. HydHowever, the optimal time to perform operative treatment in patients with frozen shoulder remains controversial. Surgical intervention in the early stages is still a relatively rarely handled topic ,15,16. POn the other hand, it has been indicated that some patients are seeking a quicker resolution of symptoms and are willing to undergo surgery , as it sRecent studies showed that arthroscopic capsular release performed less than six months after the onset of frozen shoulder symptoms does not provide a poor prognosis than delayed arthroscopy . NonetheThe study aimed to compare short- and middle-term clinical and functional outcomes of patients diagnosed with an idiopathic frozen shoulder with symptom onset of a maximum of six months treated by arthroscopic capsular release, corticosteroid injection, and subsequent postoperative physiotherapy to patients who received corticosteroid injection followed by the physiotherapeutic procedure.The study used a retrospective comparative design. The experiment was conducted according to the Declaration of Helsinki’s ethics guidelines and principles and was approved by the Bioethics Committee of the Wroclaw Medical University, Wroclaw, Poland (KB 772/2017). The data gathered in this study are available as a n = 33), secondary frozen shoulder (n = 50), diagnosed diabetes (n = 4), diagnosed thyroid disorder (n = 2), diagnosed adrenal disorder, diagnosed cardiovascular disease, and diagnosed hyperlipidemia. The remaining patients were divided into two groups: Group I (n = 30) received an early arthroscopic capsular release, corticosteroid injection, and subsequent physiotherapy, and Group II (n = 29) received only the corticosteroid injection and physiotherapeutic procedure.The initial sample comprised 148 patients diagnosed with a frozen shoulder and consecutively treated in 2010–2016 in the Department of Orthopaedics, St Luke’s Hospital, Bielsko-Biała, Poland. The frozen shoulder diagnosis was made based on the patients’ history and physical examination. Due to the retrospective character of the study, to be sure of the decision whether the frozen shoulder was primary or secondary, the initial sample comprised only patients with magnetic resonance imaging to rule out any other causes of a painful, stiff shoulder. The exclusion criteria were bilateral incidence of frozen shoulder  and 69% of Group II (n = 20). The time from onset of symptoms that the patients referred to at baseline was comparable in the studied groups . In all 59 patients, the right upper limb was the dominant one. In Group I, 43% of the involved limbs were right limbs (n = 13). In Group II, 48% of the involved limbs were right limbs (n = 14).The studied groups were similar in age . Women constituted 57% of Group I (Arthroscopic capsular release in patients from Group I was performed by two experienced orthopedic surgeons (R.B. and W.S.). Surgery was conducted in the beach chair position without arm traction. Arthroscopy was started from the posterior portal in a typical way. Arthroscopic optics  were inserted through the posterior portal to visualize the anterior part of the joint. Then, in the triangle between the long head of the biceps tendon (LHB), subscapularis tendon (SSC), and the glenoid, the anterior portal was performed under visual control. Subsequently, the anterolateral portal was created above the LHB. After confirming synovial hyperplasia and extensive congestion in all cases, a subsequent synovectomy was performed using a 4.5 mm shaver. It was crucial to identify proper landmarks of rotator interval (RI)—the edge of the supraspinatus tendon to the upper edge of the SSC tendon, coracohumeral ligament (CHL). The CHL was released and separated from the base of the coracoid process, and the whole RI was removed in the first step. Subsequently, the middle glenohumeral ligament was dissected, and the SSC tenolysis was performed, with its separation from the glenohumeral ligaments by electrocautery. The articular capsule was successively released from the base of the coracoid process along the glenoid margin in the posterior direction. Then, the camera was placed on the anterior portal. Under direct visualization, the posterior and inferior capsule were cut by electrocautery inserted through the posterior portal. The remaining adhesions within the articular capsule were released if they were present. After the capsulotomy, mobility of the joint was assessed to ensure that the full range of motion was restored.Methylprednisoloni acetas + Lidocaini hydrochloridum (40 mg + 10 mg)/mL, namely, 1 mL of Depo-Medrol , was injected.After removing the residual saline solution from the joint at the end of the procedure, The supervised postoperative physiotherapeutic procedure was focused on increasing the range of passive and active joint ROM, preventing muscular atrophy, and restoring proprioception. The process was based on exercise therapy, including assisted exercises of the involved shoulder, isometric exercises, contralateral and ipsilateral exercises, pendulum exercises, and proprioception exercises. The elements of manual therapy and the proprioceptive neuromuscular facilitation (PNF) method were also used. Furthermore, stretching, including mainly self-stretching, was required. The exercises were performed in the pain-free ROM and introduced sequentially in the sagittal, frontal, transverse, and rotation planes. Consecutively, muscle strength was increased by performing exercises in a closed kinematic chain and then in an open kinematic chain. Patients were also encouraged to do short 10–15 min home exercise sessions several times a day. The whole supervised postoperative procedure lasted for about 16 weeks, with a mean frequency of three visits per week.Methylprednisoloni acetas + Lidocaini hydrochloridum (40 mg + 10 mg)/mL, namely 1 mL of Depo-Medrol  was injected once into the joint. The ultrasound-guided injections in Group II were performed by the same experienced orthopedic surgeon (R.B.).Before starting the physiotherapeutic procedure, The supervised physiotherapeutic procedure was primarily focused on anti-inflammatory and analgesic effects, increasing the range of passive and successively active joint ROM, preventing muscular atrophy, and restoring proprioception. Physical modalities were used, including laser therapy and transcutaneous electrical nerve stimulation. The exercise therapy included passive and assisted exercises of the involved shoulder, isometric exercises, contralateral and ipsilateral exercises, pendulum exercises, and proprioception exercises. Elements of manual therapy, such as traction and elements of the PNF method, starting with patterns for the scapula, were carried out. Auto-stretching was also provided. The exercises were performed painlessly and were introduced sequentially in the sagittal, frontal, transverse, and rotation planes. After restoring the ROM without pain, exercises were performed to increase muscle strength, initially in a closed kinematic chain and consecutively in an open kinematic chain. First, bands with progressive resistance were used, followed by weights and dumbbells. Just as in Group I, the patients were encouraged to do short 10–15 min home exercise sessions several times per day. The whole supervised procedure lasted for about 16 weeks, with a mean frequency of three visits per week.Outcomes were taken at baseline  and consecutively in short-term , early mid-term , and late mid-term  follow-ups.The test procedures included clinical examination based on the ROM measurements, pain assessment, and functional evaluation. Based on the methodology of other studies assessing patients with frozen shoulder , the biln. The data collected during the clinical examination and functional evaluation were numerical data. The arithmetic mean (x) and standard deviation (±) were calculated for particular studied features. The Shapiro-Wilk test for normality was used to study the distribution of the features.TIBCO Statistica™  and Microsoft Office Excel 365 Personal  were used for statistical analysis. The number of patients was indicated as t-test for dependent samples was used for this analysis. Second, in the within-group analysis, the values obtained in the involved limb in a particular group were compared between the consecutive follow-up points using a parametric t-test for dependent samples. The same comparison was performed for the uninvolved shoulder. In the between-group statistical analysis, the ROM results in the involved shoulder in one group were compared to the involved limb in the second group at particular time intervals using a parametric t-test for independent samples. The ROM values obtained in the uninvolved limbs between the studied groups were compared in the same way. The values of pain intensity on the VAS (mm) and the number of points obtained on the Quick DASH were analyzed within studied groups by comparing the results obtained at consecutive time intervals using a parametric t-test for dependent samples. To compare the results between the studied groups at individual time intervals, a parametric t-test for independent samples was used. Statistical significance was set at p < 0.05. No statistically significant differences were indicated as ns.The within-group analysis was first based on comparing the ROM values obtained in the involved shoulder to values obtained in the uninvolved shoulder in the particular groups at particular follow-up points. The parametric Apart from statistical significance, the results were also interpreted in terms of their clinical relevance. Following Challaoumas et al. (2020), the minimal clinically relevant difference amounted to 10° for ROM and 10 mm for VAS . Followip ≤ 0.001). At this point, the involved shoulder internal rotation was comparable in terms of clinical meaning to uninvolved shoulder, so no clinically or statistically significant improvements in involved shoulder internal rotation were observed at T2 and T3.The between-limb comparison of shoulder forward flexion, abduction, and external rotation in Group I revealed statistically significant and clinically relevant worse values in the involved limb compared to the uninvolved limb at T0 and T1, as presented in In Group II, the forward flexion, abduction, and external rotation values in the involved shoulder were statistically and clinically worse than in the uninvolved shoulder at T0 and consecutively at T1 and T2 . The betValues expressed as arithmetic mean and standard deviation, ±. As also presented in p ≤ 0.001) and Group II (p ≤ 0.001), which is presented in The VAS values obtained were significantly different between the follow-up points in Group I (p ≤ 0.001) at T1. The improvement in the functional score was also clinically relevant. Although not clinically meaningful, the improvement in functional assessment results between T2 and T1 was statistically significant (p ≤ 0.001). The result at T3 was statistically and clinically at the same level as at T2. Furthermore, in Group II, the number of points obtained in Quick DASH was significantly lower at T1 than at T0 (p ≤ 0.001). However, the difference was too small to be considered clinically notable. The more considerable improvement in the functional assessment was statistically (p ≤ 0.001) and clinically meaningful in Group II between the T1 and T2 months and consecutively between T2 and T3.The obtained values of Quick DASH scores significantly differed between the follow-up points in Groups I and II as presented in In two cases (7%) in Group II, patients underwent arthroscopic capsular release six months from the baseline after an unsuccessful attempt of physiotherapeutic treatment. They did not attend the last examination that took place 12 months after the baseline. Their data were therefore not included in the statistical analysis in the last examination in Group II. No adverse events were noted in Group II.p ≤ 0.001), abduction (p ≤ 0.001), and external rotation (p ≤ 0.001) were stated in the involved shoulder in Group I in comparison to the involved shoulder in Group II. However, note that the raw mean differences between the two studied groups were much higher at T1 than at T2. When it comes to involved shoulder internal rotation, the obtained values were statistically (p ≤ 0.001) and clinically better at T1 in Group I than in Group II. At T2 and T3, the values were comparable in both groups, and the noted differences were not statistically nor clinically meaningful. At T3, the involved shoulder’s abduction range in Group I was statistically (p = ns) and clinically comparable to the range of motion in the involved shoulder in Group II. Even though forward flexion (p ≤ 0.001) and external rotation (p ≤ 0.001) were statistically significantly better in Group I, the difference was too small to be considered clinically notable. The two studied groups were also comparable in terms of the range of flexion (p = ns) and abduction (p = ns) of the uninvolved shoulder. There were noted statistically lower external rotation values in the uninvolved shoulder in Group I than in Group II at T0 (p = 0.011), T1 (p = 0.013), T2 (p = 0.015), T3 (p = 0.002); however, the difference was too small to be clinically meaningful. The same was for uninvolved shoulder internal rotation, which was statistically significantly larger in Group II than Group I, but the differences were too small to be considered clinically significant.At T0, no statistically significant differences were noted between the studied groups regarding involved shoulder flexion, abduction, and external and internal rotation. At T1 and T2, statistically significant and clinically meaningful better values of flexion , as presented in p ≤ 0.001) and clinically notable difference in functional outcome between the studied groups was noted at T1 and T2, favoring Group I. Even though the difference between the two studied groups was statistically significant (p = 0.004) at T3, it should not be considered clinically relevant.Group I and Group II were comparable in functional assessment results at baseline (Patients with an idiopathic frozen shoulder with symptom onset of a maximum of six months receiving an arthroscopic capsular release, corticosteroid injection, and subsequent physiotherapy showed faster improvement in the involved shoulder’s range of motion and functional outcome than patients who received the corticosteroid injection and consecutive physiotherapeutic procedure. Furthermore, at the early mid-term follow-up point, the arthroscopy had a pronounced effect on range of motion and function. However, the arthroscopic capsular release had no beneficial effect on late mid-term clinical and functional outcomes, as both studied multimodality treatments were successful in that matter. Furthermore, both studied multimodality therapies were equally efficacious at all follow-up points in reducing pain in patients with an idiopathic frozen shoulder.Despite being relatively common, one might say a frozen shoulder remains full of controversy. One of the debatable issues concerns the best treatment method. Through various nonsurgical procedures remaining a gold standard of treatment, many studies investigated nonsteroidal anti-inflammatory drugs, corticosteroids including oral steroids and local injectable steroids, and physiotherapy ,32,33,34The justification for waiting to decide on surgical treatment in patients with an idiopathic frozen shoulder is that it has always been considered a disease starting with a decreasing function in the first month in every case, with symptoms resolving spontaneously sooner or later . Some stA second reason for delaying surgical intervention is a common suggestion that early surgery in patients with a frozen shoulder leads to a poor prognosis . NonetheAnother critical reason for delaying surgical intervention is the possibility of complications occurring in case of manipulation under anesthesia in at least 0.4% and 14%. The postoperative complications that primarily affect manipulation under anesthesia rather than arthroscopic capsular release include humerus shaft fracture, rotator cuff tear, shoulder dislocation, labral tear, nerve injury, and complex regional pain syndrome ,49,50,51An undoubtedly most significant limitation of the present study is its retrospective design which made the rigor and strength of the randomized trial impossible to provide. The question of early arthroscopic treatment in patients with a frozen shoulder will certainly not be resolved until large prospective randomized clinical trials compare this method of treatment with nonsurgical procedures and with patients who have not received any treatment. In our opinion, besides the need for a better pathophysiological understanding of the disease and its causal cause and development, it also seems necessary to look for improvement and standardization of nonsurgical ways to bring successful and more rapid reduction of symptoms, being not invasive and do not bring the burden of the possibility of postoperative complications.Patients diagnosed with an idiopathic frozen shoulder with symptom onset of a maximum of six months receiving arthroscopic capsular release and corticosteroid injection followed by postoperative physiotherapy showed faster improvement in the involved shoulder range of motion and in the functional outcome than patients who received only the corticosteroid injection and physiotherapeutic procedure. Furthermore, at the early mid-term follow-up point, the early arthroscopy had a pronounced effect on range of motion and function. Nonetheless, the arthroscopic capsular release had no beneficial effect on late mid-term clinical and functional outcomes, as both studied multimodality treatments were successful in that matter. Moreover, studied multimodality therapies were equally efficacious in reducing pain in patients with idiopathic frozen shoulders. Therefore, it seems that no recommendation for the early arthroscopic release can be given; however, conclusions should be interpreted with caution, given that they are based on a retrospective analysis.


P < 0.001), agriculture and livestock , age ≤ 50 years , and predominantly meat-based diet  were significantly associated with the odds of KSHV seropositivity correlation. Three unique sequences of KSHV were obtained in this study; genotypic analysis showed that the three unique sequences were all subtype A2.Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), which is endangering human health worldwide, especially in Africa, Europe, the United States, and parts of Asia. The aim of this study was to investigate the prevalence of KSHV in Xinjiang. Three KSHV recombinant proteins  were used to detect KSHV infection. The serum samples to be tested were detected by an indirect ELISA method. The overall infection rate of KSHV in Xinjiang was 25.60%, with a higher infection rate in the Uygur population of 29.79%. After adjusting for possible confounders, Uygur (OR = 3.95, 95% CI 2.64–6.12,  Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus type 8 (HHV-8), , 2 belonIn China, the overall positivity rate for KSHV is between 10.00% and 16.80%, and the infection rates of KSHV in the general population in the vast majority of provinces is lower than 10.00%. –15 XinjiKSHV is known to be associated with four types of KS, including classical KS, local KS, transplanted KS, and AIDS-related KS.  The K1 gHowever, not much is known about KSHV infection in Xinjiang. Xinjiang is inhabited by the Uygur and Han populations, and the risk factors for KSHV in the region are also not well understood, and the potential risk factors for KSHV infection have not been fully assessed. The aim of this study was to investigate the seroprevalence of KSHV among different ethnic groups in the region and to assess the relationship between KSHV prevalence and the relationship between demographic factors and everyday behavior.γ were selected as the target genes [E. coli BL21 (DE3). Proteins were expressed with induction of IPTG at a concentration of 1 mM. The resulting target proteins were collected after lysozyme treatment and ultrasonic fragmentation. The target proteins were purified using nickel column affinity chromatography to obtain a purified viral protein monomer.The C-terminal of ORF65, the C-terminal of ORF73, and K8.1et genes , 28. Allet genes ; recombiThe concentration of antigen and the dilution of serum antibodies in the ELISA indirect method were determined using the chessboard method.  Each of This study was conducted in the Shihezi prefecture in Xinjiang, China, from the beginning of June to the end of August in 2019. Participants were recruited using the multistage sampling method. Participates with no age restriction, no clinical symptoms for the last 6 months, and living in Xinjiang province were eligible for enrollment. Participants were asked to complete a detailed questionnaire, which included name, gender, age, education, exercise, dietary preferences, and so on. A total of 1078 sera were tested in this study, and all test samples were provided by Professor Yan Zeng from the School of Medicine, Shihezi University. The sera to be tested were stored at −80°C in a refrigerator, all samples were from the First Affiliated Hospital of Shihezi University, and all samples were assigned to a unique number.Permission to conduct the study and informed written consents were obtained in accordance with a protocol approved by the Biomedical Ethics Committee of the Anhui Medical University.Three target proteins were used as antigens to coat the three 96-well plates to detect OD values in the sera of known KSHV-negative patients, and standard deviation (SD) values were obtained for each target protein based on OD values. Each serum to be tested was subjected to an ELISA for each of the three target proteins, with detection based on positive wells, negative wells, and blank wells. The cut-off value is the mean OD value of the negative control well plus 5 times standard deviation (SD). In all tests, serum S945 from AIDS-KS patients and serum H475 from healthy blood donors were used as positive and negative controls, respectively, all of which were stored in our laboratory, and the blank control was PBS. Each sample was also tested three times. If the OD value of any of the three tests is above the cut-off value, the sample is determined to be a KSHV-positive sample. P values were introduced when assessing hazard ratios, and P < 0.05 is considered a statistically significant difference; 95% CI was used to show the significant differences. CI is calculated on the basis of logistic regression coefficients and standard deviations.SPSS 16.0 software was used to analyze the different independent factors of KSHV seroprevalence. The DNA of peripheral blood mononuclear cells from KSHV serum-positive patients was extracted by QIAamp MinElute Virus Spin Kit, and the experimental procedures were strictly followed by the instructions. The VR1 region of K1 of KSHV was amplified by nested PCR, and the amplified product size was 455 bp.  Clustal 2+ column affinity chromatography. Then, 96-well plates were used to detect antibodies to the virus in serum samples based on an ELISA method with these proteins. [Three viral proteins, ORF65, ORF73, and K8.1, were expressed. The three gene sizes are 270 bp, 651 bp, and 537 bp, respectively. The three genes were inserted into the expression vector pQE-80L. The molecular weights of the three expressed proteins were 9 kDa, 27 kDa, and 25 kDa, respectively. Purified proteins were achieved by using Niroteins. P < 0.001), older (P < 0.001), more likely to drink alcohol (P < 0.001) or smoke (P = 0.023) compared to Uygur patients. In contrast, Uygur serum sample patients were more likely to be engaged in farming and animal husbandry (P < 0.001) and to have a more dietary preference for predominantly meat-based diets (P < 0.001).A total of 1078 serum samples  were investigated; the basic characteristics of the subjects are summarized in The combined sensitivity of serological tests was 100%, and the specificity was 96% in previous studies. , 16 Of tP < 0.001), working in agriculture and livestock , and age ≤ 50 years . KSHV seropositivity was found to have a significant correlation with dietary habits. Subjects with predominantly meat-based diet  were more likely to have KSHV infection compared with vegetarian diet. From the multivariate logistic regression analysis, it was also clear that KSHV seropositivity was associated with ethnicity  and meat-based diet . However, the correlation with greasy eating habit, age, and centripetal obesity was not very significant, which might be influenced by sample size and confounding factors.Univariate and multivariate logistic regression analyses were performed on the sample data, as shown in Tables Fifty positive samples were randomly selected, and DNA of their peripheral blood mononuclear cells was extracted. Three unique sequences were amplified by nested PCR and named SHZ1, SHZ2, and SHZ3, respectively. According to the phylogenetic tree drawn by MEGA, SHZ1, SHZ2, and SHZ3 were all subtype A2 .KSHV belongs to the gamma herpesvirus group and is a double-stranded DNA virus. The structure is the same as that of a common herpesvirus, with the innermost layer being genetic material, the middle layer being an icosahedral protein coat and the outermost layer being lipid. The double-layered outer membrane is also embedded with various glycoproteins. –32 TheseIn this study, we chose an indirect ELISA method for the detection of antibodies to KSHV in the samples. There are three reasons why we use ELISA to detect KSHV in sera. First, the overall cost of the method is low, which is suitable for serological testing of large numbers of samples; second, the method has good accuracy and repeatability, which facilitates the detection of indeterminate samples;  third, tThe Xinjiang Autonomous Region, located in northwest China, is a multiethnic region with a total of about 13 ethnic minorities and Han Chinese. There are different living habits, food styles, and religious beliefs among them.  Among thThe results showed that the KSHV seropositivity rate of Uygur in this region was significantly higher than that of Han Chinese in the same region, and this ethnic difference might be due to different genetic backgrounds. This result is also consistent with the results of previous studies , 44. In In this study, more than a thousand serum samples were detected for KSHV infection using an ELISA method. The prevalence characteristics and susceptibility factors of the region were analyzed. However, more in-depth studies are lacking. For example, the amount of meat or vegetarian food consumed daily by the population of the region was not considered in analysis, and the genetic or underlying diseases were also not considered. All these factors have the potential to influence KSHV infection. Nonetheless, this study contributes to a better understanding of the prevalence of KSHV in the region's population.It is common that the human population comigrate with viruses. KSHV subtypes A and C are most seen in the Mediterranean, Middle Eastern, and Asian regions,  which weIn conclusion, the overall prevalence of KSHV infection in Xinjiang is higher than that of the rest of China, and the KSHV prevalence in Uygur population is higher than that in Han Chinese living in the same area. It is worth noting that the cultural and culinary exchanges between different ethnic groups may facilitate the interethnic transmission of KSHV. The results of this study will provide a scientific basis for the prevention and control of KSHV infection in the region.


Results from standard multiple regression show that motor impairment (Fugl–Meyer assessment) accounted for the largest part of the explained variance in all sensor measures (18–61%), with less motor impairment resulting in higher UL activity values (p < 0.001). Higher activity ratio, magnitude ratio, and variation ratio were further explained by having the dominant hand affected (p < 0.007). Bilateral magnitude had the lowest explained variance (adjusted R2 = 0.376), and higher values were further associated with being young and female. As motor impairment and biological aspects accounted for only one- to two-thirds of the variance in UL activity, rehabilitation including behavioral strategies might be important to increase the different aspects of UL activity.We examined factors associated with different aspects of upper-limb (UL) activity in chronic stroke to better understand and improve UL activity in daily life. Three different aspects of UL activity were represented by four sensor measures: (1) contribution to activity according to activity ratio and magnitude ratio, (2) intensity of activity according to bilateral magnitude, and (3) variability of activity according to variation ratio. We combined data from a Belgian and Danish patient cohort ( A main goal of upper-limb rehabilitation after stroke is being able to perform everyday tasks . Most evA reliable and valid way of measuring the UL activity in daily life is using wrist-worn accelerometry ,4. PreviFirst, there are the so-called sensor measures of symmetry . These aThe contribution of both ULs to an activity is not the only variable of interest when looking at daily task performance. Not only are some tasks performed unilaterally and others more bilaterally, but different tasks are also performed at a different intensity. Therefore, another important aspect of UL activity is the intensity, quantified by the bilateral magnitude .Lastly, next to the contribution to and intensity of UL activity, there is the variability of UL movement, quantified by the variation ratio. Although this variable has been explored to a lower extent , it may Several studies investigated factors influencing daily UL activity post stroke ,19,20,21Most studies focused mainly on activity ratio, in single associative analyses . FurtherThis was an exploratory study of cross-sectorial data obtained from two cohort studies, performed in two different countries. We combined data collected at either 6 months post stroke in Denmark  or laterDemographic and health information was provided from medical records in Denmark or self-report during home visits in Belgium. This information includes age at the time of inclusion, gender, time post stroke, lateralization of symptoms, and pre-stroke hand dominance.Then, the observed UL motor impairment was assessed with the FMA-UE . The FMAWe used wrist-worn accelerometry to measure UL activity as the reliability and validity are well established in adults with stroke ,13,14. PThe accelerometers (ActiGraph GT3x+ and wGT3-BT Activity Monitors) were worn from 8:00 a.m. to 8:00 p.m. on a weekday in Denmark and from 12:00 p.m. until 12:00 p.m. 72 h later in Belgium. Participants were instructed to go about their normal, daily routines without changing behavior or trying to increase their UL activity. After the wearing period, accelerometers were returned to the research lab or picked up by the researcher. Accelerations were recorded along three axes at a predefined frequency (30 and 50 Hz) and converted into activity counts (0.001664 g/count) ,28. ActiActiLife 6 software  was used to visually inspect the data and ensure that accelerometers were worn for the planned time and functioned properly. To have comparable intervals for the two cohorts, we then isolated 8:00 a.m. to 8:00 p.m. intervals for both cohorts in Matlab R2020a  and exported them to IBM SPSS Statistics for Windows, version 27.0  or Stata Statistical Software: Release 16 . Afterward, we calculated different UL sensor measures as described by Lang et al.  and in tIn summary, we calculated (1) hours of affected and unaffected UL activity by summing all seconds when the VM was nonzero and converting them to hours, (2) the activity ratio by dividing total hours of affected UL activity by total hours of unaffected UL activity, (3) the magnitude ratio by taking the natural log of the VM of the affected UL divided by the VM of the unaffected UL, whereby values greater than 7 and less than −7 were replaced by 7 and −7, (4) the bilateral magnitude by summing the VM from both limbs, and (5) the variation ratio by dividing the standard deviation of the VM of the affected UL by the standard deviation of the VM of the unaffected UL.The activity ratio and the magnitude ratio quantify the contribution to the activity of one limb versus the other, whereas the bilateral magnitude quantifies the intensity of activity across both ULs. The activity ratio gives a general overview of the contribution to the activity over the entire wearing period, in which an activity ratio of 0.5 indicates that the affected UL was active 50% of the time the unaffected UL was active. The magnitude ratio and bilateral magnitude on the other hand give insight into the UL activity for every second of data. For the magnitude ratio, values go from −7  to 7 , in which every value between −7 and 7 indicates bilateral UL movement. Negative values indicate the unaffected UL contributed more to the activity, positive values indicate the affected UL contributed more, and a value of 0 indicates that both ULs contributed to the activity to the same extent. For the bilateral magnitude, values can go from small values for low intense unilateral activities  to high values for high-intensity bilateral activities  . Lastly,p < 0.05. This study conformed to the STROBE guidelines and reported the required information accordingly.Normality was checked for all variables with Shapiro–Wilk and histograms. Normally distributed variables were summarized by the mean and standard deviation (SD), while not normally distributed variables were summarized by medians with first quartile (Q1) and third quartile (Q3), and frequencies with percentages for counts. Data were analyzed with SPSS Version 27.0 with the level of statistical significance set two-tailed at We developed models to determine variables associated with different aspects of daily UL use, i.e., contribution of the ULs to activity, intensity, and variation of UL activity. Measures of contribution were the activity ratio and magnitude ratio, the measure of intensity was the bilateral magnitude, and the measure of variation was the variation ratio. Activity ratio, magnitude ratio, bilateral magnitude, and variation ratio were analyzed as the dependent variables. Independent variables assessed for their contribution to the models were FMA-UE, dominant side affected, lesion side, lesion type, age, gender, time post stroke, and country. These potential variables were chosen on the basis of the results of previous studies ,17,20, cn = 114  [p < 0.001 criterion) and Cook’s distance for possible problems with outliers and influential data points, in which points with a Cook’s distance <1 were considered problematic [To maintain adequate power for the statistical analysis, we complied with the events per variable rule, which calls for a sample size of at least + 8 × 8) ,32. Furt+ 8 × 8) . Lastly,blematic .p < 0.05). However, it might be that, in this model, which included all variables, beta weights are not statistically significant due to multicollinearity among determinants in the same model. Therefore, in the case of multicollinearity, different models were made for the dependent variable, whereby each model included one of these correlated independent variables. Lastly, for each dependent variable, the model with the lowest number of significant determining variables and the largest explained variance for the dependent variable was kept.As this was an exploratory study, we performed standard multiple regression in which, for each dependent variable, all potential determining variables were simultaneously entered into the equation. Next, we repeated the regression with only those determining variables that were significant determinants in the model with all variables included , and the squared semi-partial correlations [The strength of the association of the dependent and independent variables was assessed by the size of the adjusted elations . These sp < 0.05 (two-tailed). Statistical analyses were performed using IBM SPSS Statistics for Windows, version 27.0 .For all statistical analyses, the level of significance was set at We combined data from 60 Belgian and 66 Danish community-dwelling persons at a median of 193 days (Q1–Q3 = 182–880) after stroke. Demographic and stroke-related characteristics of included persons are displayed in Data for sensor measures are presented in the lower part of A standard multiple regression analysis was performed for each of the four dependent sensor measures with FMA-UE score, dominant hand affected, lesion side, type of stroke, age, gender, time post stroke, and country as independent variables. Assumptions were checked and resulted in a reflection and logarithmic transformation of FMA-UE and a logarithmic transformation of time post stroke. However, the results from the multiple regression with transformed variables did not differ from regression with non-transformed variables; thus, we decided to report the regression with non-transformed variables. No multicollinearity between independent variables existed. No cases had missing data, and no suppressor variables were found.As seen from R2 value of 0.663  = 124.2, p < 0.001) indicates that more than two-thirds of the variability in activity ratio was accounted for by UL motor impairment and dominant hand affected. The size and direction of the relationship suggest that a higher activity ratio was achieved by those with higher FMA-UE scores and the dominant hand affected.For model 1, FMA-UE accounted for 60.5% of the total variance for activity ratio, with an additional 3.3% explained by dominant hand affected. The adjusted p < 0.001), with an additional 1.4% for type of stroke. The size and direction of relationships indicate that those with a higher FMA-UE score, the dominant hand affected, a right-hemispheric lesion, and ischemic stroke would reach a higher magnitude ratio.For model 2, along with FMA-UE (57.9%) and dominant side affected (3.6%), lesion side accounted for 1.8% of the total explained variance in magnitude ratio  = 63.8, p < 0.001). FMA-UE accounted for 18.1%, completed by age (6.2%), gender (3.5%), and type of stroke (2.9%). According to the size and the direction of the relationships, it is suggested that those who have a higher FMA-UE score, are younger and female, and had an ischemic stroke would achieve a higher bilateral magnitude.The smallest amount of explained variance was found in model 3 with bilateral magnitude as a dependent variable  = 19.81, p < 0.001). As with the activity ratio, a higher variation ratio was achieved by those with higher FMA-UE scores and the dominant hand affected. The addition of time post stroke and country did not increase the total explained variance in any of the models.Lastly, for model 4, the same independent variables as for activity ratio accounted for 58.7% of the variability in variation ratio, with 54% unique contribution by FMA-UE and 2.6% by dominant side affected  = 89.74, In this exploratory study, in a group of adults with chronic stroke, we developed models to determine variables associated with three aspects of daily UL activity represented by four sensor measures. Firstly, the contribution of each of the ULs to activity was represented by the activity ratio and the magnitude ratio. Secondly, the intensity of UL activity was represented by bilateral magnitude. Thirdly, the variation ratio gave insight into the variability of UL activity.For all sensor measures, a large part of the variance 18–61%) was explained by FMA-UE, a measure of motor impairment 1% was ex. This isA second important explanatory variable was dominant side affected. Although to a much smaller extent than FMA-UE, dominant side affected had a unique contribution to the explained variance of three out of four sensor measures. If the dominant UL was affected, persons showed a higher activity ratio and magnitude ratio (contribution to the UL activity) and a higher variation ratio (higher variability of UL activity). Accordingly, activity ratios and magnitude ratios were lower in persons in the chronic phase post stroke with the nondominant UL affected than in persons with the dominant UL affected ,16. PersFMA-UE score and dominant side affected accounted for the entire explained variance of activity ratio and variation ratio. The fact that activity ratio and variation ratio were explained by the same two variables to a similar extent is not surprising. Both sensor measures are ratios, calculated by dividing data on the affected UL activity by the unaffected UL .For the magnitude ratio, along with FMA-UE and dominant side affected, an additional but minor part of the explained variance was accounted for by lesion side and type of stroke. Firstly, persons with a left-hemispheric lesion would have a lower magnitude ratio. This is somewhat contrary to what we would expect on the basis of the influence of lesion side on the paretic body side. As a left-hemispheric lesion results in a right hemiparesis and, thus, a dominant hand affected (87% of the cohort was right-hand dominant), we would expect a higher magnitude ratio. However, there might be other consequences of a left-hemispheric lesion resulting in a lower magnitude ratio such as limb apraxia, a common disorder associated with left-hemispheric stroke and a potent predictor of disability . SecondlFor bilateral magnitude, the explained variance was much smaller despite more independent variables contributing to the model. Compared to the other three outcome measures, we were surprised to discover that FMA-UE explained much less of the total variance. Along with FMA-UE and type of stroke, age and gender were determining factors. A young woman would have a higher and, thus, better bilateral magnitude than an old man. This is in line with UL activity plots from the acute phase post stroke, indicating that the intensity of UL activity is generally higher in female patients with stroke compared to male patients . Higher As the included independent variables accounted for not more than one- to two-thirds of the variance in UL activity, other factors may contribute. Firstly, time spent in sedentary activity was associated with hours of UL activity in nondisabled adults  and mighn = 126). This large sample size allowed us to perform multiple regression, which included several independent variables. Furthermore, the large sample comprised persons over the entire range of UL motor impairment (FMA-UE min 0 max 66), representative for the stroke population, with a similar distribution of gender, dominant side affected, and lateralization.Some limitations should be mentioned. Firstly, we recognize the fact that accelerometers do not exclusively reflect functional movements and that there are some barriers to the use of available wearable sensor technology . HoweverAs the goal of rehabilitation is to improve UL activity in daily life, clinicians need to quantify UL activity. Wrist-worn accelerometry is a reliable and valid way to quantify UL activity in adults with stroke ,13,14 anThe present study contributes to a better understanding of what influences different aspects of UL activity in the chronic phase post stroke, which may further guide strategies to improve UL activity and, thus, enhance the performance of everyday tasks. As hypothesized, all aspects of UL activity were mainly explained by UL impairment. However, the amount of variance explained by UL impairment, as well as the total amount of explained variance, depended on the specific aspect of UL activity and was lowest for the intensity of UL activity. We conclude that, when choosing an appropriate sensor measure, it is important to consider the specific aspect of UL activity one is interested in. Furthermore, a substantial part remains unexplained by UL impairment and biological factors, which warrants further investigation. As precision medicine is getting more attention in today’s research and clinical practice, personalized rehabilitation including behavioral strategies might be important to find the best fit for each individual.


Difficulties in walking, controlling balance, and performing activities of daily living are common problems encountered by individuals affected by Parkinson disease. Scientific evidence suggests that exercise performed with music or auditory or rhythmical cues facilitates movement and improves balance, gait, mobility, and activities of daily living (ADL) performance in patients with PD. The aim of this umbrella review was to summarize available high-quality evidence from systematic reviews and meta-analyses on the effectiveness of rhythmically cued exercise to improve gait, mobility, and ADL performance in individuals with PD. PubMed, Cochrane, and Embase databases were searched from January 2010 to October 2020 for systematic reviews and meta-analyses which had to be (1) written in English, (2) include studies on populations of males and females with PD of any age, (3) analyze outcomes related to gait, mobility, and ADL, and (4) apply exercise interventions with music or auditory or rhythmical cues. Two independent authors screened potentially eligible studies and assessed the methodological quality of the studies using the AMSTAR 2 tool. Four studies, two systematic reviews and meta-analyses, one a systematic review, and one a meta-analysis, were selected. Overall results indicated positive effects for gait and mobility of the use of rhythmic auditory cueing with exercise and suggested that it should be incorporated into a regular rehabilitation program for patients affected by PD. Nonetheless, more primary level research is needed to address the identified gaps regarding the application of this method to physical exercise interventions. Parkinson disease (PD) is the second most-common age-related neurodegenerative disease present in modern societies. According to recent research, the number of individuals affected by the disease has doubled between 1996 and 2016 to reach an estimated 6 million worldwide and will rise to 13 million people in 2040, suggesting a potential “pandemic PD affection” . Gait prCurrently there is no effective cure for Parkinson disease and the treatments in use so far help alleviate mainly the motor symptoms of the disease but are not sufficient to restore motor function completely. These include pharmacological interventions, mainly through levodopa to increase the level of available dopamine, and surgical treatments with deep brain stimulation. Not all motor symptoms respond to pharmacological treatment. Tremor, bradykinesia, and akinesia improve following dopamine supplementation, and benefits are also observed in gait velocity and step and stride length. However, cadence, freezing of gait, balance, and axial rigidity are mainly unaffected and findings for other gait parameters remain controversial ,8. SimilInvestigating alternative treatments to alleviate gait and mobility impairments is, therefore, of major importance in the interest of maintenance of patients’ health and quality of life. In this regard, physical exercise interventions are emerging as useful adjunct therapies to control both motor and non-motor symptoms in PD.Exercise may benefit gait and mobility in patients with PD through the improvements in general health and physical and motor fitness or by triggering neuroprotective mechanisms and increase neuroplasticity. Though much remains to be uncovered, exercise may induce a protecting effect on the residual neurons of the nigrostriatal dopamine system or a restoring action of the dysfunctional cortico-basal ganglia motor control circuit. These benefits seem mediated by exercise-triggered production of endogenous neurotrophic factors ,14,15. IAs a result, besides traditional physiotherapy, a large variety of physical exercises, such as aerobic and strength exercise, treadmill training, aqua-fitness, dance, Taiichi, and Qigong, are being studied and tested for people with PD. Research findings support the practice of a large variety of physical exercise ,18,19,20Among the multitude of interventions, the use of music and rhythmically cued exercise or rhythmic auditory stimulation (RAS) is gaining wide attention for its positive effects not only on mobility and gait, but on general motor coordination in PD patients .Recent research shows the benefits of using external sensory cues demonstrating a significant decrease in the use of levodopa equivalent to 1-year follow-up in a group of patients following movement therapy with external sensory cues . SimilarThe auditory cue can take many forms, such as music, the beat of a metronome, vocalization such as counting, or any other type of rhythmic stimulation. People usually synchronize their actions through an innate rhythmic entrainment . This prThe effectiveness of RAS has been summarized in several systematic reviews and meta-analyses. However, the literature so far appears confusing as reviews mix interventions with different cues , physical therapies (exercise with or without auditory cue), or various neurological conditions ,39,40,41The present umbrella review was conducted according to the PRISMA statement, which involved critically examining the literature, starting from a synthesis of the previously published, second-level research, and performing a critical review of all available evidence.PubMed, Cochrane, and Embase electronic databases were comprehensively searched for systematic reviews and meta-analyses published from January 2010 to October 2020. To be included in the present review, these had to meet the following criteria: (1) deal with individuals with Parkinson disease of any age and level of severity; (2) describe effects of interventions of physical exercise/activity or physical therapy applying music or any other rhythmical or auditory stimulus; (3) assess effects on gait and mobility including freezing of gait and ADL; (4) reviews published in English; and (5) reviews including only randomized controlled trials, controlled clinical trials, and quasi-randomized controlled trials. Music therapy and dance in any form were excluded as considered specific methods of activity not comparable with physical exercise or physical activity. Sensory stimuli that did not concern the objective of the review were also excluded. The inclusion and exclusion criteria are shown in The following string, adapted for use in the different databases, was used by the authors to conduct the search: ((Parkinson disease) AND (music* OR rhythmic movement OR music-based intervention OR acoustic stimulation OR auditory stimulation OR cueing OR cue) AND  NOT (dementia OR cognitive impairment OR frail)).The methodological quality of each eligible study was assessed independently by two investigators using the AMSTAR 2 questionnaire , which eData extraction was performed independently by two researchers according to standard guidelines . Information gathered concerned: (1) the study details, authors names, year of publication, the objective of the study; (2) participants’ characteristics, number, age, gender, disease level; (3) the description of the intervention, type of exercise and auditory stimulus, duration, frequency; (4) the number of included studies and type of included studies; (5) the appraisal instruments used and results; (6) the analysis performed; (7) the outcomes measured; (8) the results of the study; and (9) the conclusions. Any incongruity in the data extracted by the investigators was resolved by discussion between reviewers until consensus was reached.There were 395 papers retrieved . After 181 duplicates were removed, title and abstract screening was performed on 214 studies, which led to 170 studies being judged as irrelevant. Reference lists of selected papers were checked for relevant literature and no further study was retrieved. Therefore, 44 studies underwent full-text screening, which resulted in a further 40 studies excluded. Consequently, four studies were found eligible to proceed to data extraction. Any disagreement was resolved by discussion between reviewers until a consensus was reached , r = number of rows (primary publications), and c = number of columns (number of reviews). Three levels of overlapping may by identified: slight 0–5, moderate 6–10, high 11–15, and very high >15. A slight level of overlapping was observed for the present analysis.The eligible studies were also screened for overlapping references according to Pieper et al. . The autn = 4); explaining the selection of the study designs for inclusion ; consulting content experts in the field ; providing a list of excluded studies and justifying the exclusions ; assessing the risk of bias of individual studies included in the review ; reporting the sources of funding of individual studies ; and investigating and discussing publication bias . All reviews considered heterogeneity as a source of variation between the different studies. Regarding the consideration of the risk of bias when interpreting the results of the review (item 13), though not all authors directly declared it, the issue was limited by including studies of levels II to IV of the National Health and Medical Research Council hierarchy of evidence [With respect to the methodological quality of the included reviews, one study resulted as moderate quality , two as evidence ,47 or foevidence . CompletA narrative synthesis of the data extracted from the eligible studies is presented in All the reviews ,44,45,46Regarding exercise volume, information was often incomplete. Ghai et al.  reportedThe measured outcomes are summarized in p-value. RAS = Rhythmic Auditory Stimulation; ES = Effect size; CI = confidence interval; g = Hedge’s g adjusted effect sizes; I2 test of heterogeneity.Summary Estimates and Related 95% CI p < 0.001, [p < 0.05, [p < 0.01, [p < 0.05, [p < 0.01) on gait cadence with a reduction in the number of steps was reported by Ghai et al. [Overall studies reported significant positive effects of the application of auditory stimuli during training on the measured parameters. Details are reported in < 0.001, ; small e < 0.05, ). One st < 0.05, ; two in  < 0.05, ), and sm < 0.01, ); and on < 0.05, ). Moreovi et al. , and Roci et al.  reportedp = 0.04).Among the reported studies, one study only  evaluatep = 0.011) and at follow-up (p = 0.001) under the random-effect model [MD = −2.27 (95% CI = −4.03 to −0.52); I2 = 0%, p = 0.512; and MD = −3.57 (95% CI = −5.72 to −1.42); I2 = 0%, p = 0.531, respectively).Finally, one study  showed tThis review summarizes the findings of systematic reviews and meta-analyses on the benefits of using RAS during exercise to improve gait and mobility in patients with Parkinson disease. Despite the small number of available reviews and meta-analyses specific to RAS and physical exercise, the results confirmed the general view that RAS presented in different forms with exercise improves gait parameters such as gait speed and stride length and facilitates overall mobility.p < 0.05 [p < 0.01 [p < 0.001 [The changes in gait parameters following the RAS intervention were consistent across the selected studies , stridep < 0.05 ; g: 0.50p < 0.05 ; z = 6.7p < 0.01 ), gait vp < 0.01 ; g: 23 [p < 0.01 ; z = 5.4 < 0.001 ), and ca < 0.001 ; g: −0.0 < 0.001 )), for w < 0.001 . The ana < 0.001 . In fact < 0.001  found foIn this respect, some comments are needed on the relationship between gait speed, stride length, and cadence, which are all critically affected by PD , and thep < 0.05 [Regarding the UPDRS II scale, though it is not a direct evaluation of walking and mobility, but an evaluation of the effects of motor and non-motor symptoms of PD on various motor experiences of daily living including walking and mobility, it gives necessary information on the level of the disease, which may be overlooked by an objective spatiotemporal gait assessment. Indeed, UPDRS II scores demonstrated significant improvement following interventions with RAS .Two main hypotheses have been formulated to explain how RAS may compensate the timing deficit in PD, the compensation and restoration hypotheses . The coRegarding the necessary evidence to build recommendations for the use of RAS for gait and mobility exercise in PD patients, the reviewed studies did not provide a complete range of information. It is well known that for exercise to be effective the patient must adhere to the training principle of overload , specificity (of the exercise in relation to the objectives), and individual differences.The existing guidelines of exercise for PD patients are very generic. For example, the American College of Sports Medicine recommends 20 to 60 min of aerobic exercise, such as walking, cycling, and dancing, 3 to 5 days per week, and strength and stretching exercises for 2–3 days per week. Other forms of recommended exercise include exercise specifically targeting balance and gait . HoweverIndeed, none of the included reviews was able to derive sufficient information from their primary studies to draw up conclusions related to such principles. One study only  gatheredStrictly regarding the use of RAS for gait and mobility, in spite of the apparent large number of reviews and meta-analyses, very little material was available. This resulted in a lack of information on to how to modulate the “overload” of RAS. An additional challenge was posed by the identification and definition of the reviewed outcomes. While kinematic measures of gait are clearly defined and standardized measures, difficulties arise when meta-analyses or systematic reviews have similar but not identical definitions of outcomes such as mobility, which may include a wide variety of functional tasks and related measures.The present review also highlights limitations in the present literature on the use of RAS for gait-related impairment and may help in planning future research on this extremely important issue. The first-level studies summarized in the reviews and meta-analyses reviewed in the present work appeared extremely heterogeneous in all their components, participants, levels of the disease, state of medication, and proposed exercise interventions, with some studies evaluating the acute effects of exercise and RAS and others evaluating the long-term with training, and did not allow establishing the optimal elements of exercise prescription.Intervention studies are increasing in number. However, there are still too many variations in designs. This is an area that needs addressing in future research: the design of specific exercise interventions aiming at determining the guidelines for optimal exercise application for PD patients. None of the interventions seemed to design the exercise following the key training principles or adapting them to the specificity of the disease. Some standardization has been proposed in terms of tempo of stimuli with respect to preferred cadence. Though the method is highly promising, it is extremely difficult to reach a definite conclusion to establish guidelines for the optimal use of RAS in PD patients. Future research should aim to fill these gaps with more methodologically sound intervention studies.It also needs to be mentioned that despite the selected studies being carefully evaluated for methodological quality, these often presented inadequate description of methods or a confusing presentation of results, making difficult a full assessment and a detailed synthesis. Most studies did not explicitly state several of the requested issues of the quality assessment without necessarily being of low quality and, on the other hand, high-quality studies, responding to all the quality assessment issues, presented flaws in the manuscript presentation. Some studies did not describe information of paramount importance regarding the applied exercise.Some negative effects of RAS on gait stability parameters have also been described, suggesting that RAS should be “calibrated” to the subjects’ conditions and used appropriately. In fact, when the auditory stimulus was slower (−20%) or faster than a preferred cadence, if no instruction was given to coordinate gait with the external beat or if combining auditory with tactile stimuli, detrimental effects on gait parameters were described, possibly due to an excessive cognitive load exceeding the individual’s attention capacity . In addiRecent systematic reviews and meta-analyses summarizing results of several intervention studies led to the general conclusion that RAS is a feasible and valid tool to significantly improve balance and gait parameters such as velocity, cadence, and stride length ,45,46,55This method certainly merits further investigation and future research to reinforce the findings with specific design to identify optimal dosage in term of frequency, intensity, duration, and optimal type of exercise. Developing effective non-medical intervention to relieve gait and balance impairments would represent a great advancement in Parkinson disease therapy.Limitations of the present work include the narrative nature of the review and the very limited number of included systematic reviews and meta-analyses, which did not allow us to clarify the evidence necessary to establish guidelines for practice. Though three main databases were searched, and the search string was as comprehensive as possible, there is the possibility that some research may have not been included.


The amygdala is known to be related to cognitive function. In this study, we used an automated approach to segment the amygdala into nine nuclei and evaluated amygdala and nuclei volumetric changes across the adult lifespan in subjects carrying the apolipoprotein E (ApoE) ε3/ε3 allele, and we related those changes to memory function alteration. We found that except the left medial nucleus (Me), whose volume decreased in the old group compared with the middle-early group, all other nuclei volumes presented a significant decline in the old group compared with the young group. Left accessory basal nucleus (AB) and left cortico-amygdaloid transition area (CAT) volumes were also diminished in the middle-late group. In addition, immediate memory recall is impaired by the process of aging, whereas delayed recall and delayed recognition memory functions were not significantly changed. We found significant positive correlations between immediate recall scores and volumes of the bilateral basal nucleus (Ba), AB, anterior amygdaloid area (AAA), CAT, whole amygdala, left lateral nucleus (La), left paralaminar nucleus (PL), and right cortical nucleus (Co). The results suggest that immediate recall memory decline might be associated with volumetric reduction of the amygdala and its nuclei, and the left AB and left CAT might be considered as potential imaging biomarkers of memory decline in aging. The amygdala is a prominent limbic formation and plays a key role in emotional and cognitive processes . DysfuncAge and apolipoprotein E (ApoE) are the mightiest risk factors for Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. In human, ApoE is expressed by the polymorphic alleles: ε2, ε3, and ε4. The ε4 allele is the most risky gene for AD, ε2 allele may provide a protective effect, and ε3 is the most common allele in all human populations, at frequencies ranging from 69 to 85% . EvidencThe objective of this study is to describe age-related volumetric growth and/or decline of the amygdala and its nuclei structures across the human adult lifespan. Furthermore, we examined the relationship between the amygdala and its nuclei volume and memory function. We hypothesized that specific nuclei of the amygdala would be associated with memory recall scores. To this end, we used a cross-sectional sample of 315 individuals, aged from 20 to 89 years, to investigate different stages of the adult lifespan with respect to alterations in amygdala and its nuclei volume and memory function. Simultaneously, in order to eliminate the potential impact of ApoE, only ApoE ε3/ε3 allele carriers were analyzed.1 The inclusion and exclusion criteria were as follows:A total of 315 healthy adults, aged 20-89 years, were selected from the Dallas Lifespan Brain Study (DLBS).Inclusion criteria: (1) right-handed and native English speakers, (2) without a history of neurological disease, (3) well-educated and cognitively normal as measured with the Mini-Mental State Examination (MMSE > 26), and (4) with high-quality sMRI data.Exclusion criteria: (1) No genotype information, (2) ApoE ε2 or ε4 carriers, and (3) incomplete cognitive tests. Therefore, 70 subjects with no genotype information, 56 ApoE ε2 or ε4 carriers , 40 subjects with incomplete cognitive tests were excluded.Finally, a total of 149 subjects  were included in the present study. The subjects were classified into four groups: Young group , Middle-early group , Middle-late group , and Old group .In the present study, participants went through the Hopkins verbal learning test and the Cambridge Neuropsychological Test Automated Battery verbal recognition memory (CANTAB_VRM) test for memory assessment. The Hopkins verbal learning test is composed of three consecutive tasks for immediate recall, delayed recall, and delayed recognition. First, participants listened to a list of 12 words, and then they were asked to recall as many words from the list as they could. Twenty minutes later, participants were asked again to recall as many words as they could remember. After that, participants listened to a new list of 24 words and had to determine if the words were part of the initial list. The three scores were as follows: HOP immediate recall, number of words correctly recalled; HOP delayed recall, number of words correctly recalled after a 20-min delay; HOP recognition, number of items correctly identified as “old” or “new” in delayed recognition.The CANTAB_VRM task also assesses immediate recall. In this task, the participants were shown a list of 12 words and asked to read each word aloud one at a time. Immediately after presentation, participants were asked to recall as many words as they could remember. The task was scored on the total number of words remembered.3. The parameters were as follows: slice thickness = 1 mm, repetition time (TR) = 8.135 ms, echo time (TE) = 3.7 ms, flip angle = 12°, matrix = 256 × 256, field of view (FOV) = 204 × 256.All participants underwent T1-weighted imaging in a Philips Achieva 3T scanner . The MRI data acquired were 160 sagittal slice high-resolution T1-weighted images using magnetization-prepared rapid gradient-echo (MP-RAGE) sequences with a voxel size of 1 mm2 The “recon-all” processing stream with default parameters was used for subcortical volume analysis. Details of the segmentation methods and procedures are described in prior publications .ications . Brieflyications  was applications . UltimatP-values and correlation coefficients (r) were calculated, with gender, education years, and eTIV regarded as covariates. Correlation results were corrected by the false discovery rate (FDR). Meanwhile, we tested the mediating effect of the hippocampus in the relationship between amygdala nuclei volumes and memory function, using single-mediator model with gender, education years and eTIV as covariates. The significance level for all results was set at P < 0.05.Statistical analysis was performed using SPSS software . The chi-square test was used to evaluate the differences in gender among four groups. The Kruskal-Wallis test was used to analyze group differences in education years. Amygdala nuclei volumes and cognitive tests scores were standardized using Z-score method. Analysis of covariance (ANCOVA) was performed for group differences in MMSE and memory tests scores, with gender and education years as covariates. To examine amygdala nuclei volume group differences, we performed ANCOVA with gender, education years, and estimated total intracranial volume (eTIV) as covariates. Pairwise comparisons using the Bonferroni method were performed for indexes with significant group differences. Spearman correlation analysis was applied to examine the correlations between memory scores and amygdala nuclei volumes across the life span, P < 0.001). Pairwise comparison results are detailed in Description and analysis of demographic characteristics for the 149 subjects are shown in Description and analysis of the cerebral compartment volumes for the 149 subjects are shown in The statistical data and ANCOVA analysis results of memory scores are provided given in As shown in Amygdala nuclei volumes changed with age. P < 0.001) compared with the other three groups. The volumetric changes of most amygdala nuclei were similar to those of the whole amygdala, including the bilateral La, Ba, AB, AAA, CAT, as well as the right Ce and right Co (P < 0.05). In addition, a significant decrease in left AB and left CAT volumes was observed in the Middle-late group, earlier than in the whole amygdala. The volumes of the left Ce, right Me, and left Co decreased in the Old group compared with the Young and Middle-early groups. The volume of the left PL declined in the Old group compared with the Young group, and that of the right PL decreased in the Old group compared with the Young and Middle-late groups. Additionally, the left Me volume decreased in the Old group compared with the Middle-early group.Volumes of the bilateral La, Ba, AB, AAA, CAT, whole amygdala, left Co, and left PL declined with age. The bilateral Ce, Me, and right Co presented an inverted U shape, with the largest volume in the Middle-early group. Right PL volume decreased in the Middle-early group and the Old group but increased in the Middle-late group. The Volume of the bilateral whole amygdala declined consistently with age, and the volume in the Old group declined significantly (P < 0.05). CANTAB_VRM scores were also correlated with the left Co and right Ce (P < 0.05). Hopkins immediate recall scores were also correlated with the left PL (P < 0.05). Details of the Spearman correlation were presented in Spearman correlation analysis was applied to examine the association between the two immediate recall memory scores, CANTAB_VRM scores and Hopkins immediate recall scores, and the amygdala nuclei volumes. As shown in In this cross-sectional study of cognitively normal ApoE ε3/ε3 carriers, we explored the volumetric changes of the whole amygdala and the amygdala nuclei across the adult lifespan, as well as the correlations between neuroimaging and memory performance.P < 0.05).Except the left Me, whose volume decreased in the Old group compared with the Middle-early group, all other nuclei volumes presented significant decline in the Old group compared with the Young group, though they differed in trajectory. The left AB and left CAT volumes were already decreased in the middle-late group. Immediate recall memory scores declined significantly in the Old group compared with the Young group, while no significant alteration was observed in delayed recall or delayed recognition. The decline of immediate recall memory scores was associated with the volumes of the bilateral whole amygdala, Ba, AB, AAA, and CAT and the left La and right Co , which may have influenced our results. At the same time, the DLBS indicated that all participants were healthy adults, but it did not specify the excluding criteria in the subject screening procedure. Therefore, we cannot rule out that our results were affected at least to some extent by these factors.To our knowledge, this is the first study to relate immediate recall memory to the amygdala and its nuclei on ApoE ε3/ε3 allele carriers. Our findings suggest that immediate recall is impaired by aging. Furthermore, the volumetric decrease of the bilateral Ba, AB, AAA, and CAT nuclei, whole amygdala, and left La and right Co associated with the reduction of immediate recall memory function. The present study highlights the left AB and left CAT might be considered as potential imaging biomarkers of memory decline in aging.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and the University of Texas at Dallas. The patients/participants provided their written informed consent to participate in this study.WqL and DC designed the study. WqL performed the statistical analysis and prepared the original draft. DC collected the data, performed the neuroimage processing, and reviewed and edited the draft. TY, ZL, JJ, WbL, HW, and XW reviewed the manuscript. All the authors read and approved the submitted manuscript.WbL was employed by Sinovation (Beijing) Medical Technology Co., Ltd. The research was not sponsored by the company, and the data was from a public database. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.