Previous studies have revealed both sleep alterations and prospective memory (PM) impairments in breast cancer (BC) patients. PM refers to memory of intended actions and is crucial for daily living tasks and treatment compliance. As sleep is known to favor memory consolidation, one may expect that changes in sleep quality related to BC would have an impact on PM performance. This study aimed at assessing sleep-dependent consolidation of intentions using an ecological, virtual reality-based PM task in BC patients not treated with chemotherapy.Thirty-seven early stages BC patients and 21 healthy controls (HC) participated in this study. PM was assessed using a virtual reality task, during which participants learnt a list of intentions and recalled them after a retention interval filled with a day awake or a night of sleep monitored by polysomnography. Sleep spindles and slow waves, brain oscillations involved in sleep-dependent memory consolidation, were quantified automatically using the Aseega software (Physip). Subjective sleep disturbances and markers of quality of life  were assessed by questionnaires.Greater PM performance was observed after sleep than after an equivalent period of daytime wakefulness for both groups (HC and BC). PM performance after sleep did not differ significantly between groups. Yet, BC patients reported greater sleep disturbances than HC which were related with poorer intentions retrieval, greater psychological distress, fatigue and poorer well-being. The frequency of spindles was higher and the amplitude of slow waves lower in BC patients compared to HC. However, no significant association was observed between polysomnography parameters and PM scores in the whole sample of participants.Although subtle changes in brain oscillations involved in sleep-dependent memory consolidation were observed, these changes did not significantly impair overnight PM consolidation in BC patients. Nevertheless, poorer PM performance was associated with greater sleep complaints which in turn were related to poorer quality of life. Overall, these data suggest that sleep-dependent PM consolidation mechanisms are not altered in early stages BC patients not treated with chemotherapy. Further investigations are needed to understand the association between markers of quality of life and sleep-dependent memory consolidation. Sleep disturbances and memory impairments are one of the most frequent complaints from breast cancer (BC) patients . Sleep cAccording to the “Hippocampo-Neocortical Dialog” hypothesis, both slow waves and spindles are involved in the reorganization of newly acquired information into long-term memory stores . The modevent-based (EB) intentions. Two kinds of intentions are classically distinguished in laboratory tasks: EB intentions when the action has to be performed in response to an external event, and time-based (TB) ones when the action has to be executed at a specific time  is of particular interest in BC because it is essential for daily living tasks, medical adherence, and autonomy. Moreover, PM difficulties have been highlighted in this population . The fewfic time . In addific time . The proPrevious studies revealed that sleep facilitates the spontaneous remembering of intentions at the appropriate time . EspeciaIn this context, this study aimed at assessing sleep-dependent consolidation of intentions in PM in BC patients. To do so, we recruited BC patients not treated with chemotherapy and HC who completed sleep questionnaires and underwent ambulatory PSG. PM was assessed using an original virtual reality based task adapted from All participants were recruited between January 2018 and March 2020 and provided written informed consent after detailed information about the study. The study was approved by the ethics committee .Patients’ inclusion criteria were: (i) be less than 70 years old, (ii) no metastatic BC, (iii) already undergone surgical or radiotherapy treatment, (iv) radiotherapy finished since at least 6 months and no chemotherapy treatment, (v) menopausal status since at least 1 year at the time of inclusion, (vi) no personality disorder and progressive psychiatric disorder (vii) no neurological sequelae, (viii) no drug use or alcohol abuse, (ix) be a native French speaker, (x) have at least 7 years of education.Inclusion criteria for HC were the same as for patients, including no history of cancer and a score superior to 25 at the Montreal Cognitive Assessment ; see DuiFifty patients, i.e., 25 patients treated with endocrine therapy (ET) and 25 patients not treated with ET approached in the French regional cancer center François Baclesse  agreed to participate. The rationale for the target sample size was calculated according to the literature on cognitive decline in BC patients under ET . The PSG consisted in recording the electroencephalogram (EEG), electrooculogram (EOG), electrocardiogram (ECG), chin electromyogram (EMG), respiratory movements using thoracic and abdominal belts, respiratory airflow using nasal and oral thermistors, and oxygen saturation using a finger pulse oximeter. For the EEG recording, twenty electrodes were placed over the scalp according to the international 10–20 system , with impedances kept below 5 kΩ. The EEG signal was digitalized at a sampling rate of 256 Hz, high-pass (0.3 Hz) and low-pass (35 Hz) filters were applied for the visual scoring. Sleep stages  were visually scored by an electrophysiology technician (S.R.) in epochs of 30 s according to the AASM rules . StandarSubjective sleep disturbances were assessed using the Pittsburgh Sleep Quality Index PSQI;  a 19-iteThe level of alertness/sleepiness was measured with the Karolinska Sleepiness Score KSS,  before eDepressive symptoms were assessed with the Beck Depression Inventory (BDI), a validated 13-item questionnaire with a total score ranging from 0 to 39 . AnxietyFatigue and well-being were assessed in BC patients only, using the Functional Assessment of Chronic Illness Therapy–Fatigue FACIT-F; , a 13-itThe PM task was adapted from During the encoding phase, participants were asked to learn nine intentions that they had to remember after a certain amount of time . The nine intentions included three TB intentions , and six EB intentions . A new set of nine intentions was learnt in every session. Each intention was presented on a computer screen, then a cued-recall test was performed and repeated until each intention was correctly learnt. Finally, to ensure that all intentions were correctly encoded, they were retrieved in a last global cued-recall test.During the retrieval phase, participants were immersed in the virtual environment for a maximum of 20 min. The environment featured a reproduction of the Memorial museum dedicated to World War II and located in Caen . Participants were placed in an immersive room composed of four wide screens for 3D stereoscopic projections, wore stereoscopic glasses with position sensors and freely navigated in the museum using a joystick. Participants were asked to visit the museum while memorizing pictures displayed in the environment (ongoing task) and recalling intentions at the appropriate place or time. EB intentions had to be recalled in response to a specific cue in the environment, and TB intentions at the appropriate time. For this purpose, a button on the joystick was available to check time.Each intention was rated according to three components, i.e., the prospective component, the retrospective component, and the associative one . A maximum of two points was awarded to every component for a correct recall i.e., if every detail of the retrospective component was recalled at the appropriate time. If the intention was recalled during the second passage or within 1 min of the target time, only one point was attributed to the prospective score. If the intention was recalled at a later passage or within 2 min of the target time, only 0.5 points were awarded to the prospective component  was observed only for the number of awakenings longer than 1 min, with patients having significantly more awakenings than HC.Standard PSG parameters of the two groups are reported in p = 0.025) with patients having a faster frequency than HC (p = 0.040), with lower amplitude in BC patients compared with HC.Sleep spindles frequency differed between groups  = 4.91, p = 0.031].For the sake of completeness, we conducted all the analyses on PSG parameters detailed above adding the ET status as covariate. These analyses revealed that the effect of group on the number of awakenings longer than 1 min, the spindle frequency and slow waves amplitude was no longer significant see . On the F = 0.11, p = 0.74] and group , and no significant interaction between these factors  on encoding performance. No significant effect of time-of-day  and group , and no significant interaction between these factors  on global PM performance  was observed. Moreover, no significant effect of group, time-of-day and interaction were observed whatever the type of intention and component .In each group, half of the participants performed the session 1 in the morning and the other half in the evening in order to control for an effect of time-of-day on PM performance. The ANOVA revealed no significant effect of time-of-day . Neither a significant effect of group , nor a significant interaction between group and session  was observed. Similar results were observed for each intention and component  or the component . When ET status was added as covariate, a significant difference between BC and HC was observed for the prospective  and the associative components , with patients having lower scores than HC.r = 0.38, p = 0,030). Thus, higher fatigue is related with lower retrieval of the retrospective component in BC patients. No other significant correlation was observed.Prospective memory performance was not significantly related with psychological distress, i.e., STAI-B and BDI scores in the whole sample of participants see . A signip values > 0.1, results not shown) and fatigue .No significant correlation was observed during both sessions between encoding performance , scores on sleep questionnaires  and retrospective components of the whole intentions . The ISI score was significantly associated with the retrieval of EB intentions  and retrospective components of the whole intentions . Thus, higher sleep disturbances and insomnia complaints were associated with poorer recall of EB intentions and retrospective components after a night of sleep in the whole sample of participants. Furthermore, FACIT-F score was significantly related with the retrospective component score , indicating that greater fatigue was related with poorer recall of the retrospective component of intentions in BC patients.The PSQI total score was significantly associated with the retrieval of EB intentions  and PM performance , not treated with chemotherapy and assessed at least 6 months after radiation therapy. These criteria were chosen to minimize as much as possible the negative effect of the treatments, particularly the well-known effects of chemotherapy on sleep and memory. However, half of BC patients were under ET at the time of assessment and ET has been associated with higher sleep complaints  and loweThis study reveals greater sleep complaints and subtle sleep changes in BC patients compared to HC. Despite the role of slow waves and spindles in sleep-dependent memory consolidation, the modifications observed in BC patients had no significant impact on sleep-dependent PM consolidation. Our results suggest that PM impairment reported in previous studies would be due more to an altered quality of life reflected by several factors such as poorer sleep quality and fatigue, rather than to a slight alteration of sleep-dependent memory consolidation mechanisms. Thus, in this study focusing on patients at early stages of BC, not treated with chemotherapy and without psychological distress and severe sleep disturbances, sleep-dependent consolidation of intentions was not impaired.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by CPP Ile de France III (n°ID-RCB: 2017-A02778-45). The patients/participants provided their written informed consent to participate in this study.MD collected and analyzed the data and wrote the first draft of the manuscript. SR, CB, and JP realized sleep analyses. CS-D, JG, GE, CL, and FV participated in the investigation. J-MG, BC, BG, and JP participated in the project administration. BG, JP, BD, FE, and FJ participated in the funding acquisition and design of the study. BG, BD, GR, and JP participated to the rewriting and editing of the study. All authors have read and agreed to the published version of the manuscript.


Total hysterectomy (TH) is becoming more and more common in clinical practice, and many patients suffer from postoperative complications such as pelvic floor dysfunction (PFD). How to prevent and treat PFD is an important part of the current clinical work, and it is important to improve patients' postoperative quality of life. This study was to investigate the effect of pelvic floor muscle training (PFMT) combined with estriol on PFD after TH in perimenopause. n = 49) and CT group . After treatment, the two groups were compared in terms of pelvic floor muscle tension (systolic pressure and resting pressure of the vagina), female sexual function index , and the degree of PFD .  Totally, 95 patients who developed PFD receiving TH in our hospital between January 2020 and June 2021 were selected. They were randomly divided into a PFMT+ET (estriol therapy) group ( After 4 months of treatment, vaginal systolic pressure and resting pressure were significantly increased in both groups, with higher levels in the PFMT+ET group. Also, the improvement in female sexual function index score and persistent time of vaginal muscle contraction was observed to be greater in the PFMT+ET group than in the CT group. Additionally, PFMT combined with estriol resulted in lower levels of urinary leakage in the 1-hour pad test, residual urine volume, and frequency of urinary incontinence.  The postoperative intervention of PFMT combined with estriol in perimenopausal patients with TH can significantly improve vaginal muscle contraction, improve the quality of sexual life, and reduce the degree of PFD, which has a good application prospect. Currently, the probability of receiving total hysterectomy (TH) has climbed up . As a coα-adrenergic agonist, and topical vagina hormone therapy. Such nonsurgical treatments improve the symptoms of 30%-60% of patients [Intervention targeting the pelvic floor following TH is an important measure to prevent PFD. At present, the common treatments for the recovery of pelvic floor function after TH mainly encompass PFMT, pelvic floor muscle electrical stimulation, bladder training, patients . Radzimipatients . In addipatients . Estriolpatients . Howeverpatients . The compatients . Howevern = 49) and CT group  using the random number table. Inclusion criteria were as follows: (1) perimenopausal women aged 40-55 had sexual experience; (2) patients underwent laparoscopic TH due to benign uterine diseases and were diagnosed with PFD according to the criteria specified in Advance of Diagnosis and Management of Female Pelvic Floor Dysfunctional Disease [A total of 95 patients who developed PFD after receiving TH in our hospital between January 2020 and June 2021 were selected. They were then randomly separated into a PLMT+ET group  and nursing interventions were given after surgery according to the patient's condition. The ureteral catheter was indwelled for 4 days. In the first 2 days, the catheter was in an open state. On the 3In the PFMT+ET group, estriol vaginal cream  Ltd.) and targeted PFMT were applied in addition to routine nursing. To be specific, there were four steps of PFMT. Firstly, patients were placed in a supine position with legs slightly bending and spreading, and the anal sphincter was forcefully contracted to imitate holding urine for 5 s and then slowly relaxed. Secondly, the patient remains in the supine position with the legs alternately elevated to 90° and then slowly lowers the legs. Thirdly, patients changed to a kneeling position and elevated their legs backwards alternately and then slowly put down the legs. Fourthly, patients returned to a supine position with feet flat on the bed and knees bent and slowly raise the back and buttocks and then slowly put them down. Each step was repeated for 15 min, twice daily (morning and evening), and a course of treatment lasted for 4 months.The two groups were compared at 1 week and 4 months after surgery in terms of pelvic floor muscle tension, female sexual function index (FSFI), and degree of PFD.Pelvic floor muscle tension was quantified as follows. A pressure balloon was placed in the vagina. Later, vaginal systolic pressure (VSP) and vaginal resting pressure (VRP) were measured after inflating 15 ml of gas.FSFI included 6 items  and had a total score of 36 points. The higher the index, the better the sexual life. A score > 26.55 indicated the absence of female sexual dysfunction.The degree of PFD was evaluated by persistent time of vaginal muscle contraction, 1-hour pad test, residual urine volume, and frequency of urinary incontinence.t-test was used for comparison between groups and the paired t-test was used for comparison within groups before and after the intervention. Enumeration data were expressed as frequency (n) or rate (%), and the chi-square test (χ2) was used for statistical analysis. When P < 0.05, the difference was considered significant.SPSS 24.0 was used for data analysis. The measurement data were expressed as mean ± standard deviation (SD), and the independent sample P > 0.05, A total of 95 patients, aged 43-55 years, were randomly divided into the PFMT+ET group and the CT group. There were no significant differences between the two groups in age, number of deliveries, and primary disease before treatment, indicating that the two groups were comparable (P > 0.05). After treatment, VSP and VRP in both groups were significantly higher than those before treatment (P < 0.05), suggesting that both therapies can effectively restore pelvic floor muscle tension, but the efficacy of the combined treatment was superior to that of the conventional treatment . In contrast, after the intervention, these indices were significantly higher than those before the intervention in the same group . And after the intervention, except for lubrication, there was no significant difference between the two groups. All other indices were significantly higher in the PFMT+ET group than in the CT group   .P > 0.05). After the intervention, the duration of vaginal muscle contraction was significantly higher than that before the intervention, while 1-hour pad test volume, residual urine volume, and frequency of incontinence were significantly lower . In addition, all of these indicators were significantly improved in the PFMT+ET group after the intervention compared with the CT group   .In recent years, the incidence of pelvic diseases in perimenopausal women has seen an increase. Among the diseases, the incidence of PFD after TH is also high, and it will seriously affect the physical and mental health and reduce life quality of patients without timely intervention . PFD canStudies have confirmed that PFMT with or without adjunctive modalities can improve or cure urinary incontinence, fecal incontinence, perinatal and postpartum pelvic floor dysfunction, and sexual dysfunction . In thisIn addition, PFMT combined with estriol was more effective than conventional treatment in improving the female sexual function index in terms of pain, satisfaction, orgasm, sexual arousal, and sexual desire except for lubrication. PFMT combined with estriol also achieved better results of PFD indicators such as persistent time of vaginal muscle contraction, urinary leakage in 1-hour pad test, residual urine volume, and frequency of urinary incontinence, which concurred with the findings proposed by Ye et al. . PossiblAlthough some meaningful observations were reported, there are still some shortcomings that deserve to be described. First, only 95 cases were investigated in this study, which is a small sample size. Second, the lack of follow-up records does not allow for a valid assessment of the long-term treatment effects of PFMT combined with estradiol. Therefore, larger trials and longer follow-up periods are necessary. Additionally, it is worth noting that patients need to pay attention to gradual and measured PFMT; otherwise, the training intensity exceeds the body's tolerance and may lead to damage to the body. And one should also pay attention to the dosage of estriol when administering medication; otherwise, the body may consume too much estriol, which may lead to disruption of the internal environment and disruption of the hormonal balance in the body, leading to serious consequences.The postoperative intervention of estriol vaginal application combined with PFMT in perimenopausal patients with TH can significantly improve vaginal muscle contraction, improve the quality of sexual life, and reduce the degree of pelvic floor muscle dysfunction. Thus, PFMT combined with estriol seems promising in TH-related PFD, and its clinical applicability should be further validated in prospective multicenter studies.


Permanent AF patients presented a higher risk of developing stroke, dementia, and PD compared to patients with paroxysmal AF. Meanwhile, male gender and an increase in age showed an increase in the odds of having cardio-embolic brain complications in patients with paroxysmal AF. Conclusion: Based on the results obtained, it can be concluded that the risk of cardio-cerebral embolic complications is greater in permanent AF patients compared to paroxysmal AF cases. Ischemic stroke and dementia are more frequent in the permanent AF group, but analyzing the data regarding the age of onset paroxysmal AF is critical due to the fact that it involves a younger population. Prompt diagnosis and treatment can help significantly in saving stroke patients.Background: Atrial fibrillation (AF) is the most frequent of all cardiac arrhythmias, with an increasing prevalence in the last 20 years. Cardio-embolic brain complications (CEBC) related to AF often occur or recur, even following appropriate treatment. Method: We conducted a retrospective study and analyzed the presence of stroke, dementia, and Parkinson’s disease (PD) in both paroxysmal and permanent AF patients. The records of 1111 consecutive admitted patients with primary diagnosis of AF at the Municipal Emergency University Hospital, Timisoara, between 2015 and 2016 were examined. Statistical analysis was performed on the patients included in the study based on the inclusion and exclusion criteria. Results: A significant statistical difference was noted among the permanent AF group for stroke (48.75% vs. 26.74%,  Atrial fibrillation (AF) is the most frequently found cardiac arrhythmia, with an increasing prevalence in the last 20 years ,2. CardiCurrent guidelines regarding AF management recommend anticoagulant therapy for preventing CEBC in both paroxysmal AF and permanent AF  in orderOccurrence or recurrence of stroke depends on AF types and regional income ,6,7. In On the other hand, it seems that permanent AF patients have mild cognitive deterioration and dementia compared with different types of AF, regardless of stroke presence, but the data are not so consistent ,15. PermIn the case of Parkinson’s disease (PD), data are mixed. Studies suggest the linkage of cardiovascular risk factors (including AF) with PD, but in a small proportion compared with dementia . FurtherA major benefit of an earlier diagnosis of AF is to delay the development of cardio-embolic brain complications, mainly because of the comorbid association and interrelation in different proportions of AF, cognitive impairment, dementia, and PD ,26,27,28This retrospective study was conducted at the 1st Medical unit of the Municipal Emergency Hospital, Timisoara. We analyzed the patients admitted consecutively with AF diagnostic during the time period of January 2015–December 2016.A total of 1111 cases were analyzed regarding the presence of stroke, dementia, and PD after the onset of AF; the type of AF ; and the medical therapies that can influence the progression of AF. The presence of stroke, dementia, and PD was noted if the diagnosis was made by a neurologist, psychiatrist, or radiologist . The patients were divided into two groups, based on the type of AF they were suffering with. The paroxysmal AF group (group 1) comprised 389 patients, while 722 patients had permanent AF (group 2). Patients having AF at the time of hospital admission were included in the study. The exclusion criteria included the following factors: if the patient had asked for a discharge against medical advice (DAMA), had suffered mortality during the hospital stay, or was not having AF and was admitted for other cardiac or non-cardiac pathologies. The demographic and clinical characteristics, except for the cardiovascular comorbidities of the two groups, are shown in Overweight was defined as a body mass index (BMI) between 25 and 29.9, obesity grade I as BMI between 30 and 34.9, grade II as a BMI value between 35 and 39.9, and obesity grade III as a BMI value ≥ 40. Glomerular filtration rate (GFR) was calculated using the 2012 CKD-EPI formula, and chronic kidney diseases were staged according to KDOQI guidelines .p < 0.05. We used descriptive statistics, figures, and tables to summarize our findings. Results for targeted variables are presented using descriptive statistics  for continuous data (*), and counts with associated percentages for categorical data.Statistical analysis was performed using IBM SPSS Statistics version 20.0 software for Windows and MedCalc version 20.015 with a significance of Patients suffering from paroxysmal AF were younger in comparison to the patients having permanent AF.p < 0.001 in our study.It was found that younger patients were more likely to have paroxysmal AF compared with Permanent AF; mean age was 69.07 years for group 1 and 74.05 years for group 2, with a statistical significance of p values were obtained with independent samples t-test (*) and with Chi-square tests/Fisher’s exact tests (^) for statistical testing between paroxysmal AF and permanent AF patients. Continuous data (*) are summarized as mean (standard deviation), minimum and maximum value, and median and associated quartiles . Quartiles were obtained with Turkey’s method. Categorical data are presented as counts (percentages) (entages) .Neuro-psychiatric changes of any kind were seen in 66.16% of all 1111 investigated patients, irrespective of the time of their first occurrence compared to the date of diagnosis of AF. Details are illustrated in p < 0.001) and dementia  among the two groups. Data regarding stroke, dementia, and Parkinson’s disease are presented in A significant statistical difference was noted for stroke .Obesity per se is a risk factor in the occurrence of stroke in patients with paroxysmal atrial fibrillation, but not for patients with permanent atrial fibrillation .Higher odds for overall neuro-psychiatric changes, stroke, dementia, and PD were observed regarding age and paroxysmal AF and are represented in Regarding the survival without ischemic stroke after AF onset, group 1 showed a longer period of time. No cerebral cardioembolic complications and the mean period of time with no ischemic stroke was 5.1 years for group 1 and 1.3 years for group 2 .2DS2-VASc scores, with scores of 5 and 6 being prominent in stroke patients. Furthermore, even for the acute ischemic stroke and concomitant AF first diagnosis, the mean CHA2DS2-VASc score for the patients was 5.67  for paroxysmal AF and 5.59  for permanent AF.We noted that ischemic stroke incidence increased with the increase in CHAp = 0.000088), stoke (p < 0.00001), and dementia (p = 0.014293). Also statistically significant is the presence of stroke (p < 0.00001) and dementia (p = 0.014146) patients not treated with OAC belonging to the group of patients with permanent AF . Regarding age differences between our two groups for concomitant diagnosis of acute ischemic stroke and first AF, age differences is statistically significant; the paroxysmal AF group has a younger age of 67.8 years vs. 72.5 years .For ischemic stroke onset before AF diagnosis , the meaPatients with paroxysmal AF had 1.900 times the odds in comparison to group 2 permanent AF patients of having dementia  .Analyzing the correlation between the onset of AF before stroke, dementia, and PD, we found that dementia is diagnosed before AF diagnosis, and a higher prevalence is observed in the permanent AF group compared to group 1 .Even if the presence of stroke is significant for the group of permanent AF patients, when we analyzed its occurrence before the diagnosis of atrial fibrillation, we did not find any statistical difference.The majority of the studies performed to date are based on identifying the differences between non-AF and AF patients and their related aspects, while we focused on patients having AF of different types . Furthermore, we analyzed the prevalence of complications, stroke, dementia, and Parkinson’s disease, seen in both forms of AF, and whether there existed a difference or not.Our study revealed that the risk of having stroke, dementia, and PD after the onset of paroxysmal AF is more significant than in permanent AF. Male gender and advanced age increase the odds of cardio-embolic brain complications in patients with paroxysmal AF compared to permanent AF.The prevalence of paroxysmal AF and permanent AF in our study was more significant in women  than in men, contradicting actual data , where iIn our analyses, the relative risk of developing ischemic stroke was comparable with data from the literature ,34, but p < 0.001) than younger patients who have more frequently paroxysmal AF.Age is a significant determinant of AF type. Older patients are more likely to have permanent AF  for paroxysmal AF and 5.59  for permanent AF. Ischemic stroke occurs after AF diagnosis for a higher CHA2DS2-VASc score when we compared it with CHA2DS2-VASc score for patients with concomitant acute ischemic stroke and AF diagnosis. A large majority of current studies have shown us the inaccuracy of the CHA2DS2-VASc score in stroke prediction in AF patients ). Regarding age differences between our two groups, for concomitant diagnosis of acute ischemic stroke and first AF, age difference is statistically significant; the paroxysmal AF group has a younger age of 67.8 years vs. 72.5 years . In Another important aspect is that a large number of patients had a stroke before AF diagnosis, or the diagnosis of AF was made at the same time as the diagnosis of acute stroke and none of those patient were undergoing ACO therapy at that time. For ischemic stroke onset before AF diagnosis, the mean age is statistically significant for paroxysmal AF patients .Our study reveals once again the fact that anticoagulant treatment is underused, including in Romania, the percentage of patients who do not receive anticoagulant treatment, even if they have an indication for it, falling within the percentages mentioned by other published studies ,45,46,47Because of the retrospective character of this study, further follow-up was not possible beyond the established study period, which could have given a better insight into the long-term effects of AF. Another limitation is that we have not evaluated the risk of this complication related to other risk factors . More in-depth analysis on the reasons behind the neurological complications could help to better understand whether AF is the only culprit or if there are other factors involved in the pathogenesis of stroke, dementia, and PD. There was no control group comprised of similar age groups to see the age related senile neurological changes. Based on our study results, it can be statistically concluded that permanent AF seems to be worse for the brain than paroxysmal AF. Ischemic stroke and dementia are more frequent in the permanent AF group. We consider that paroxysmal AF is worse due to the fact that a higher number of younger patients are found in this group. Public awareness programs should be implemented from time to time to educate the general population of the alarming signs and symptoms that will help them identify the initiation of a cerebral hypoperfusion that will rapidly end up as ischemic stroke, which will help them to understand that they should call the emergency services. Such self-awareness programs can dramatically minimize the mortality and stroke related disability rates caused due to the delay in reaching specialized care. Regarding the medical unit in charge, initiation of anticoagulant therapy should be prompt after evaluating precisely the risk of hemorrhage, but at the same time without avoiding anticoagulant use due purely to a phobia of encountering a hemorrhagic event.


Traditional Chinese medicine (TCM) has certain curative effect against acute gouty arthritis (AGA), but it lacks high-quality evidence-based studies. In this randomized controlled trial, we try to evaluate the clinical efficacy and safety of Qinpi Tongfeng Formula (QPTFF) in the treatment of AGA.  One hundred and fourteen patients with AGA (damp heat accumulation syndrome) who met the inclusion and exclusion criteria were randomly divided into treatment group and control group in a ratio of 1 : 1. Patients in the treatment group were treated with QPTFF, and patients in the control group were treated with diclofenac sodium sustained-release tablets for 7 days. The primary outcome measure was the change in visual analog scale (VAS) score for pain from the baseline to day 8. The secondary outcome measures were joint symptom score, TCM syndrome score, total effective rate, pain cure rate, complete pain relief time, patient satisfaction score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum uric acid level. The safety outcome measures were routine blood test, urinalysis, liver function including alanine aminotransferase and aspartate aminotransferase, renal function including blood urea nitrogen and serum creatinine, and the rate of treatment-related adverse events (TRAEs). P > 0.05). The 95% confidence interval of the difference between the eighth and first VAS score for pain of the two groups was  in FAS and  in PPS. The lower bound of both FAS and PPS is greater than the bound value of −0.7. On day 8, there was no significant difference between the two groups in joint symptom score, TCM syndrome score, total effective rate, pain cure rate, complete pain relief time, patient satisfaction score, ESR, and CRP . The serum uric acid level and TRAEs in the treatment group were significantly lower than those in the control group .  105 patients with 53 in the treatment group and 52 in the control group completed the 7-day treatment. There was no significant difference between two groups in demographic characteristics, VAS score for pain, joint symptom score, TCM syndrome score, ESR, CRP, and serum uric acid level before enrollment at baseline  and per protocol set (PPS), Trial Registration. This study protocol was registered in Chinese Clinical Trial Registry (registration number: ChiCTR2100050638). QPTFF could alleviate the symptoms of patients with AGA, which is not inferior to diclofenac sodium sustained-release tablets in analgesic. Moreover, QPTFF overmatches diclofenac sodium sustained-release tablets in decreasing serum uric acid level and TRAEs. Therefore, the results provide reliable foundation for QPTTF in the treatment of AGA.  Gout is a metabolic rheumatism caused by abnormal purine metabolism, increased synthesis, and/or decreased excretion of uric acid, resulting in increased serum uric acid. With the high serum uric acid level, urate will be deposited into crystals to gather in joints, cartilage, and kidney . Urate cAcute gouty arthritis (AGA) is a common acute arthritis with clinical features of severe arthralgia with swelling, recurrence, and poor prognosis . For AGAIn traditional Chinese medicine (TCM), the clinical manifestations of AGA, such as joint swelling and tenderness and local skin redness, constitute the “damp heat accumulation syndrome” of “Bi syndrome” (joint pain) similar to the acute stage of gouty arthritis. The treatment of AGA with TCM has a history of thousand years in China. A preliminary systematic study found thaDeclaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization. Meanwhile, the study followed consort (ChiCTR2100050638).This is a double-blind, double-dummy, multicenter, randomized, noninferiority clinical trial. The study was conducted under the  consort . The proGuidelines for the Combined Diagnosis and Treatment of Gout and Hyperuricemia [Men and women aged 18–70 years were considered for enrollment if met the diagnostic criteria of AGA of the American College of Rheumatology in 2015  as well uricemia . All parPatients within 72 hours of AGA attackPatients with at least one attack of gout in the pastPatients with moderate or above arthralgia, and the visual analog scale (VAS) score for pain is ≥4Patients without taking other oral traditional Chinese medicine or western medicine for AGA 72 hours before enrollmentPatients without taking uric-acid-lowering drugs in recent 2 weeksPatients diagnosed with secondary AGA caused by other diseases or drugsPatients diagnosed with chronic goutPatients with inflammatory arthritis such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and knee osteoarthritisPatients with polyarthralgia (>4 joints)Patients complicated with serious primary diseases such as cardiovascular, cerebrovascular, lung, and kidneyAlanine aminotransferase, aspartate aminotransferase, or serum creatinine greater than 1.5 times upper limit of normal Patients allergic to test drug ingredientsPatients currently preparing for pregnancy, being pregnant, or breastfeedingPatients with active digestive ulcer or bleeding, or who have suffered or suffering from digestive ulcer or bleedingPatients in other intervention studies in recent 1 monthPatients with mental illness or abnormal intelligence, unable to accurately express the condition or take medicine on time, and unable to finish follow-up cooperativelyIn case of intolerable adverse events, complications, or physiological changes, the researcher considered that the trial should be stopped and patients would be treated accordingly after evaluation.The condition of participant did not alleviate or even got worsen within a certain period of time. Although the study was not completed, the researcher should stop the trial and take effective treatment in order to protect the participant. The curative effect of this case was determined to be invalid.The participant proposed to the researcher to withdraw from the experiment voluntarily.The participants who demonstrated poor compliance and were unwilling to continue participating in the study or lost to follow-up. Researchers should try to complete the last laboratory test of all withdrawn or lost cases in order to analyze their efficacy and safety. The reasons for the shedding of all shedding cases in detail and the records of the indicators that met the test requirements should be filled in the case report form (CRF). The unfinished indicators should be also filled in by the last carry forward method.During the study period, participants who used a series of combined medications at will, which will affect the assessments of curative effect, should be excluded and recorded in the CRF.α = 0.025, β = 0.2, the ratio of the treatment group and the control group = 1 : 1, and the boundary value = −0.7. The calculated sample size for the two groups was 102 cases. Considering the potential dropout rate of about 10%, a total of 114 cases were finally included, with 57 cases in each group. According to the situation, 114 drug packaging bags were numbered, so that each center could distribute drugs according to the numbers.The primary outcome measure of this study was the change in VAS score for pain from the baseline to day 8. According to the preliminary clinical trial, the mean values of VAS score changes of QPTFF and diclofenac sodium sustained-release tablets were 3.67 and 3.75, with the standard deviation of 1.22 and 0.97. For sample size estimation, PASS 15.0 software was used and noninferiority design was adopted with one-sided test selected, taking Excel 2013 software was used for stratified randomization for the three centers. There were 74 AGA patients in the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, 20 in the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, and 20 in the First Affiliated Hospital of Nanchang University.Blinding: a trained statistician not involved with the study completed the blinding of the test medications. This study adopted a two-stage blind design. The first stage was the group code corresponding to each drug number, which was group A or group B, and the second stage was the treatment scheme adopted by group A and group B. The two-stage blind data should be placed in an opaque envelope and should not be opened during the study. All researchers who were responsible for recruiting, distributing drugs, testing indexes, and evaluating efficacy, all participants were blind to the randomization. The expert statisticians who were also blind to the randomization would conduct statistical analysis after completing the study.Emergency unblinding: each drug with a number had a corresponding emergency letter, so that the patient could carry out emergency unblinding in case of serious adverse reaction events.The study was designed to be double-blinded and double-dummied. The treatment group used the QPTFF granule + diclofenac sodium sustained-release tablets simulant , while the control group used diclofenac sodium sustained-release tablets + QPTFF granule simulant :Basic treatment: (1) avoiding cold and wet stimulation of joints, (2) no drinking, (3) low purine diet, (4) drinking more than 2000 mL water every day, and (5) prohibiting medications that affect uric acid metabolism.Fraxini (Qin Pi), 10 g Rhizoma Coptidis (Huang Lian), 20 g Semen Plantaginis (Che Qian Zi), 30 g Rhizome Dioscoreae Hypoglaucae (Bi Xie), 80 g Rhizoma Smilacis Glabrae (Tu Fu Ling), 20 g Radix Clematidis (Wei Ling Xian), 30 g Herba Siegesbeckiae (Xi Xian Cao), and 10 g Radix Saposhnikoviae (Fang Feng). QPTFF was taken one bag each time, three times daily, boiled in water for each dose. The simulant of diclofenac sodium sustained-release tablets was manufactured by Tiandi Hengyi Pharmaceutical Company, Changsha, China (batch no. 201101), and was taken 0.1 g each time orally, once daily. Patients in the control group were treated with diclofenac sodium sustained-release tablets provided by Hunan Warner Pharmaceutical Company in Liuyang, China (H200677776), which was taken 0.1 g orally, once daily; QPTFF simulant  was taken one bag each time, three times daily, boiled in water for each dose. The simulant was similar to the original drug in appearance, smell, and taste. All participants were treated for 7 days.Patients in the treatment group were treated with QPTFF as granule, provided by Sichuan New Green Pharmaceutical Technology Development Company, Chengdu, China (batch no. 2107705). QPTFF has 8 components: 30 g Cortex If the pain of participants was severe and intolerable during the study, they would be given colchicine tablets  to assist in emergency pain relief, 0.5 mg each time, three times a day. At the same time, the medication administration would be recorded in the CRF.Record the participant's name, gender, age, height, weight, body mass index (BMI), nationality, course of gout disease, allergy history, smoking history, drinking history, past medical history, and family history of gout.Vital sign: temperature, heart rate, blood pressure, and respiration were recorded on day 1 and day 8Laboratory examination: routine blood test, urinalysis, liver function including alanine aminotransferase and aspartate aminotransferase, and renal function including blood urea nitrogen and serum creatinine were examined on day 1 and day 8Treatment-related adverse events (TRAEs): researchers refer to the incidence of Common Terminology Criteria for Adverse Events version 5.0  to recor(1) Changes in VAS Score for Pain. The pain degree of the participant was evaluated by VAS [d by VAS . Researc(1) Joint Symptom Score. The participant's joint tenderness, redness, swelling, and mobility were evaluated by Likert scale [rt scale  (Table S(2) TCM Syndrome Score. Researchers would evaluate the TCM syndrome score, including the main and concurrent symptoms of AGA patients  Total Effective Rate. The efficacy was evaluated according to the Guiding Principles for Clinical Research of New Traditional Chinese Medicine [Medicine  (efficacMedicine . Recover(4) Pain Cure Rate. Definition of pain cure: within 24 hours during the treatment, the VAS score for pain was 0, and the VAS score was still 0 24 hours after the treatment. The pain cure rate refers to the proportion of cured patients in the total number of patients within 7 days of treatment.(5) Complete Pain Relief Time. Complete pain relief time indicated the duration of the VAS score turning to 0.(6) Patient Satisfaction Score. On day 8, the participant would get an overall evaluation of the treatment, which was rated as 5 points  [ly good) .(7) Laboratory Index. The levels of CRP, ESR, and serum uric acid of participants were measured at baseline on day 8.M . For normal distributed data, the independent sample t-test or paired t-test was used for comparison between groups or within groups before and after the treatment, while data in skewed distribution nonparametric test should be adopted. The repeated measurement data in this study were skewed distribution, so the mixed linear model was used. The counting data were expressed by frequency and composition ratio, and the chi-square test was used for statistics; the Kaplan–Meier survival curve was used to describe the time of complete pain relief, and the log-rank test was used for comparison between groups. P < 0.05 indicated the difference was statistically significant. The change of VAS score was taken as the main efficacy index, and the noninferiority test was carried out according to the confidence interval method. SAS software was used to calculate the 95% confidence interval (CI) of the difference between the changes value of VAS score for pain between the treatment group and the control group before and after treatment. If the lower limit of the CI was greater than the limit value, the noninferiority was established [All outcome measures in this study were analyzed by the full analysis set (FAS) and per protocol set (PPS). In the FAS, for the indicators with missing data, the last observation value carry forward method was used to fill in the data. Safety indicators were analyzed by a safety set. SPSS 22.0 was used to carry out statistical analysis on the data. The quantitative data were described by mean, standard deviation, or interquartile interval ablished . GraphPaAccording to the registered protocol, 114 eligible AGA patients were included in this study from August 2021 to February 2022. In the course of the study, the clinical symptom indexes  were measured. 105 participants completed the 7-day treatment, and 105 were finally included in the PPS, including 53 in the treatment group and 52 in the control group; 89 participants finally finished the laboratory indexes and were included in the PPS, including 45 in the treatment group and 44 in the control group .P > 0.05), as shown in P > 0.05). There was no significant difference in temperature, heart rate, systolic blood pressure, diastolic blood pressure, and respiration between the two groups (P > 0.05). There was no significant difference between the two groups in VAS score for pain, joint symptom score, TCM syndrome score, ESR, CRP, and serum uric acid level (P > 0.05), as shown in There was no significant difference between the two groups in gender, age, course of gout disease, weight, height, and BMI (∗ time point (P > 0.05), and the overall curative effect difference between the two groups was not statistically significant (P > 0.05), as shown in P > 0.05), as shown in The VAS score for pain of the two groups decreased gradually, and the changes are shown in Figures P < 0.05). After the treatment, there was no significant difference in the joint symptom scores between the treatment group and the control group (P > 0.05), as shown in The joint symptom scores of the two groups after the treatment were better than those before the treatment . After the treatment, there was no statistically significant difference between the TCM syndrome scores of the treatment group and the control group (P > 0.05), as shown in In FAS and PPS, the TCM syndrome scores of the two groups after the treatment were better than those before the treatment and the difference was statistically significant (P > 0.05). In PPS, the total effective rate was 96.23% in the treatment group and 96.15% in the control group, and there was no significant difference between the two groups (P > 0.05), as shown in In FAS, the total effective rate was 89.47% in the treatment group and 87.72% in the control group, and there was no significant difference between the two groups (P > 0.05). In PPS, the pain cure rate was 35.84% in the treatment group and 38.46% in the control group, and there was no significant difference between the two groups (P > 0.05), as shown in In FAS, the pain cure rate was 35.09% in the treatment group and 38.60% in the control group, and there was no significant difference between the two groups (P=0.701). In PPS, the median time of complete pain relief time in the treatment group and the control group was 7.65 days. The survival curve of the two groups is shown in P=0.85).In FAS, the median time of complete pain relief time in both the treatment group and the control group was 7.65 days . Using tP > 0.05)  see .P < 0.001). After the treatment, there was no statistically significant difference in the levels of ESR and CRP between the treatment group and the control group (P > 0.05), as shown in Tables P < 0.001), and there was no significant difference in the level of serum uric acid in the control group before and after the treatment (P > 0.05). After the treatment, the level of serum uric acid in the treatment group was significantly lower than that in the control group (P < 0.05), as shown in In FAS and PPS, the levels of ESR and CRP in the two groups after the treatment were lower than those before the treatment and the differences within the two groups were statistically significant (P < 0.05), as shown in During the treatment, routine blood test and urinalysis did not show abnormalities in the two groups. Only 23 patients had elevated leukocytes stimulated by inflammation before the treatment, but they all returned to normal level after the treatment. Another 9 patients had elevated platelet count before the treatment, but decreased after the treatment. There was no abnormal increase or decrease in vital signs in the two groups after the treatment. The TRAEs were 7.02% in the treatment group and 26.32% in the control group. The TRAEs of the treatment group were significantly lower than those of the control group  between the two groups is greater than the lower limit . There was no significant difference in complete pain relief time and pain cure rate between the two groups, which suggested that the analgesic effect of QPTFF was not inferior to that of diclofenac sodium sustained-release tablets. The results of secondary outcome measures showed that both treatments had a great improvement in the joint symptom score, TCM syndrome score, ESR, and CRP, but without significant difference, indicating that QPTFF and diclofenac sodium sustained-release tablets could significantly improve the patients' symptoms and inflammatory indicators with equal effects. However, QPTFF had more advantages than diclofenac sodium sustained-release tablets in reducing the serum uric acid level. After the treatment, the satisfaction survey was carried out on the patients, and the results showed that the subjective feeling of the patients in the two groups was equal.In terms of safety evaluation, the rate of TRAEs in the treatment group was significantly lower than that in the control group and the patients in the treatment group had no liver and kidney function injury, but discomfort in the stomach. To timely monitor the changes of liver and renal function, we set the abnormal liver and renal function as higher than the upper limit of the normal, or abnormal liver and renal function before treatment, while further increased after treatment to protect the patient's health. Although the reported percentage of abnormal liver and renal function was higher in the control group, there was no serious liver and renal injury occurred in the patients. The side effects of nonsteroidal drugs on the digestive system have been widely concerned by clinical workers. Clinical studies have shown that they will increase the risk of digestive tract, cardiovascular, and kidney disease . AlthougTaiping Shenghui recipe (AD 992). This compound contains Cortex Fraxini (Qin Pi), Rhizoma Coptidis (Huang Lian), Semen Plantaginis (Che Qian Zi), Rhizome Dioscoreae Hypoglaucae (Bi Xie), Rhizoma Smilacis Glabrae (Tu Fu Ling), Radix Clematidis (Wei Ling Xian), Herba Siegesbeckiae (Xi Xian Cao), and Radix Saposhnikoviae (Fang Feng). QPTFF has the functions of clearing heat and detoxification, removing dampness and turbidity, dredging arthralgia, and relieving pain. The total coumarin of Qinpi in Cortex Fraxini can reduce uric acid by inhibiting the activity of xanthine oxidase [Cortex Fraxini extract can reduce the level of urate anion transporter 1 (URAT1), so it has the effect of reducing uric acid [Rhizoma Smilacis Glabrae, such as colchicine, syringic acid, and catechin, can inhibit the expression of inflammatory factors and have strong anti-inflammatory effects [Rhizoma Smilacis Glabrae can reduce the serum uric acid concentration of mouse hyperuricemia model by inhibiting xanthine oxidase activity [Rhizoma Coptidis, which could inhibit the activation of NLRP3 inflammatory bodies and prevent IL-1β to resist inflammation [Rhizoma Coptidis can reduce the serum uric acid level and protect renal function by inhibiting the activation of NLRP3 inflammatory bodies and the abnormal expression of URAT1 [Herba Siegesbeckiae, which have anti-inflammatory and analgesic effects [Herba Siegesbeckiae can also inhibit the activity of xanthine oxidase and reduce serum uric acid [Rhizome Dioscoreae Hypoglaucae has anti-inflammatory and analgesic effects [Rhizome Dioscoreae Hypoglaucae can promote the excretion of uric acid by regulating the levels of organic anion transporter 1, murat1, and organic cation transporter 2 and has the effect of reducing uric acid [Semen Plantaginis, such as luteolin, mullein glycoside, golden sage grass flavin, so it has the effect of reducing uric acid [Plantain polysaccharide may have renal protective effect by downregulating the expression of NLRP3, ASC, and caspase-1 protein and inhibiting the release of downstream inflammatory factors [Radix Clematidis inhibits NF-κB and MAPK pathways in macrophages to reduce the production of proinflammatory factors, to function in anti-inflammatory and analgesic [Radix Saposhnikoviae has anti-inflammatory and analgesic effects by regulating the expression of p53 and inhibiting the release of inflammatory factors [Radix Saposhnikoviae can reduce blood uric acid by inhibiting the activity of xanthine oxidase [QPTFF is optimized and improved from Qinpi powder in the ancient Chinese book  oxidase . Cortex ric acid . Aesculeric acid . The com effects . Rhizomaactivity . Berberiammation . Berberiof URAT1 . There a effects . The extric acid . Rhizome effects , 44. Theric acid . There aric acid . Plantai factors . Radix Cnalgesic . Polysac factors . The ext oxidase . TherefoHowever, our study still has some limitations. This study only uses common efficacy indicators for observation, without the observation of the changes of immune indicators and images in AGA. Although the sample size of this study was estimated by the PASS 15.0 software, it was only the minimum sample size required by clinical practice, and there were only 3 hospitals in the study. In the future, more high-quality multicenter, large-sample randomized controlled trials should be carried out to observe the changes of immune indicators and images with AGA.QPTFF can improve the symptoms and signs of patients with AGA, as well as the inflammatory indexes and serum uric acid level. Its analgesic effect is not inferior to diclofenac sodium sustained-release tablets, but it has more advantages in reducing the serum uric acid level and the rate of treatment-related adverse events. Therefore, QPTFF is an effective clinical treatment for AGA.


Diagnostic ultrasound has long been a part of a physician’s armamentarium, but transcranial focused ultrasound (FUS) is an emerging treatment of neurological disorders. Consequently, the literature in this field is increasing at a rapid pace.This analysis was aimed to identify the top-cited articles on FUS to discern their origin, spread, current trends highlighting future impact of this novel neurosurgical intervention.Web of Science database on 28th May 2021 and identified the top 100 cited articles. These articles were analyzed with various scientometric parameters like the authors, corresponding authors, country of corresponding author, journal of publication, year of publication. Citation based parameters including total citations, mean citations per article and mean citations, citation count, and the citation per year, citations per year and co-authors per document were studied as well in addition to Hirsch h-index, g-index, m-index, Bradford’s Law, Lotka’s law and Collaboration index.We searched the n = 11), and most articles originated from the United States, followed by Canada. Among individual institutions, the University of Toronto was the most productive.The 100 top-cited articles were published between 1998 and 2019 in 45 different journals. The average citations per document and citations per document per year were 97.78 and 12.47, respectively. The most prolific authors were Hynynen K , Elias WJ (Neurosurgery—Virginia), Zadicario (InSightec). The Journal of Neurosurgery published the most top-cited articles  contributing to more than half of these articles. Diagnostic ultrasound has been a part of a physician’s armamentarium for the last seven decades. Focsused ultrasound (FUS) has emerged as a therapeutic option in the last few decades to successfully ablate soft tissue tumors such as uterine fibroids, breast carcinoma, and bone metastases ,b. TechnBibliometrics is a methodological approach from the library sciences that statistically analyses the citation counts of books, articles, and other publications to determine the influence and impact of the scientific publications. Scientometrics is a subfield of bibliometrics that studies science publications by using bibliometric methods to find author, article, and journal-level metrics . It provides a broad overview of the field’s direction, complements the expert peer review process, and is transparent and objective. Many scientometric analyses have been published in neurosurgery to find the 100-most cited articles on topics like endoscopic third ventriculostomy, ossified posterior longitudinal ligament, pallidotomy, and cervical spondylotic myelopathy . HoweverWeb of Science database was performed on 28th May 2021. The keywords used for literature search were—“MR guided focused ultrasound,” “MRgFUS,” “Magnetic resonance-guided focused ultrasound,” “Ultrasound Thalamotomy,” “Ultrasound Thalamotomy for Essential Tremor,” “Ultrasound Subthalamotomy, “focused ultrasound tremor,” “focused ultrasound tremor,” “ultrasound Parkinson,” “focused ultrasound ablation,” “transcranial focused ultrasound,” “focused ultrasound neuromodulation” and “focused ultrasound blood brain barrier opening.” The search results were screened and arranged in descending order of the number of citations, and articles were selected as per the following inclusion and exclusion criteria. FUS studies on transcranial FUS for neurological disorders, comparative study of FUS with DBS or radiofrequency (RF) for movement disorders, blood-brain barrier permeability, animal or cadaver research, targeted therapeutics and radiological aspect of FUS were included. FUS articles on non-cranial pathology were excluded.A systematic search of the The articles were arranged in descending order according to the number of citations. The various parameters analyzed were the title of the articles, authors, corresponding authors, country of corresponding author, journal of publication, year of publication. Citation based parameters including total citations, mean citations per article and mean citations, citation count, and the citation per year, citations per year and co-authors per document were studied as well. The following statistical parameters were considered during the analysis:Hirsch h-index: authors number of publications and number of citations, reviewed in other articles.g-index: is a variant of h-index which gives credit for the most cited papers. It is the highest rank where the sum of the citations is larger than the square of rank.m-index: is another variant of the h-index that displays h-index per year since first publication.Bradford’s Law: estimates the exponentially diminishing returns of searching for references in science journals was also studied.Lotka’s law: which denotes the distribution of the number of articles published by the number of authors.Collaboration index: it assigns a weighted credit to each author in a multi-author paper to capture a researcher’s scientific caliber better.The statistical analysis was performed using R software version 4.0.3  .The literature search yielded 2,500 articles, and we selected the 100 most cited articles which met the study inclusion and exclusion criteria (n = 41). Thirty-six studies were related to blood brain barrier (BBB) disruption and only three studies of these were human studies. Twenty-five studies focused on the role of FUS in patients with movement disorders and all were human studies. Three articles discussed the role of FUS in patients with pain, and a similar number of articles discussed the role of FUS for oncological indications in humans. Eleven articles discussed the technical aspects, while one clinical article described the use of FUS in patients with obsessive-compulsive disorders (OCD).These articles can be divided into three topics depending on the pathology type in which MRgFUS use has been described in the article. Equal numbers of articles involved human studies and animal studies . There were 85 original and 15 review articles. The average number of years from the date of publication was 7.22. Interestingly, most of these articles were published recently: 2017 (15 articles), 2018 (12 articles), and 2014 (10 articles) .Average citations per document were 97.78, while average citations per year per document were 12.47 . MaximumJournal of Neurosurgery had a maximum of 11 publications, followed by the Journal of Controlled Release (7), Movement Disorders (6 articles), and Neurosurgery (6 articles). Other journals that published at least one of these articles included Stereotactic and Functional Neurosurgery, the Journal of Neurology, Neurosurgery and Psychiatry, and the Journal of Magnetic Resonance Imaging.Journal of Neurosurgery, Journal of Controlled Release, Movement Disorders, Neurosurgery and Physics in Medicine and Biology lie in Zone 1.Radiology were cited the most , followed by New England Journal of Medicine (761 citations) and Journal of Neurosurgery (736 citations). The articles published in these journals were 4, 2, and 11, respectively. the Journal of Neurosurgery at the top. Journal of Neurosurgery published the first article in 2012, and there has been a rapid increase in the published articles since.These top 100 cited articles included 481 authors who made 833 appearances in these 100 articles. The number of co-authors per document was 8.33, with a collaboration index of 4.81. None of these articles were published by a single author.n = 45) published from the United States. It was followed by Canada (19 articles) and China (10 articles). There were significant international collaborations in these articles, as shown by the orange bars in These top 100 cited articles were authored by corresponding authors from 11 countries, showing the limited availability of this technology. MRgFUS is one of the most evolving field in the neurosurgery This scientometric analysis of the MRgFUS revealed some interesting and intriguing trends. First, these articles were published over the last 22 years, from 1998 to 2019. Obviously, it takes a few years for any article to garner many citations to feature in the top 100 cited articles and more importantly adoption in the clinical field given novelty of the technology. However, articles published recently, as recent as in 2019, appeared in this top 100 list. This reflects the rapid evolution and the acceptance of the field, not only by clinician but also the patients. As this technology is evolving and explored in newer neuropsychiatric indications, the scientific publications and their citations are going to be more voluminous and robust in near future.Secondly, only 11 countries contributed to these top 100 cited articles, with the top 2 countries (the United States and Canada) contributing to more than half of these articles. As MRgFUS is a new technology and its availability is yet limited. There was no article from low to middle-income countries, perhaps due to the high cost of initial set up. The low acceptance of a surgical procedure for non-life-threatening diseases may also contribute to the limited interest of many countries. Although the average citations per document of these articles were less when compared with the top 100 cited articles on other pathologies, the average citations per document per year were higher . This ren = 25) described the use of MRgFUS in various movement disorders, with essential tremor being the commonest pathology. The other rare pathologies where the use of MRgFUS has been described in these studies are Parkinson’s disease, dystonia, and OCD.The analysis revealed that 41 articles were based on animal or cadaveric studies to study the preclinical aspects of focused ultrasound. It again reflects the novelty of the technology and value of translational impact in clinical neurosurgery. Amongst the human studies, most of the articles  and 18.2 to 2.8 (P = 0.001), respectively in 15 ET patients treated with FUS thalamotomy. This pilot trial was followed by a multicentric randomized controlled trial, published in NEJM in 2016, comparing the efficacy of unilateral focused ultrasound thalamotomy with a sham procedure in 76 patients with ET  and Zadicario (12 articles). The second highest contributor to these articles is Elias WJ, a Professor of Neurological Surgery at the University of Virginia. The third highest contributor was Eyal Zadicario, who is a part of the InSightec (manufacturer) team. Hynynen K has contributed to FUS research for more than three decades and is the lead author of the highly cited article in this list.There are some inherent drawbacks of bibliometric analysis. The reasons why a paper is cited multiple times may be diverse and may not accurately reflect the influence of the study in question . Sole reMRgFUS is one of the fastest evolving field in neurosurgery, specifically functional neurosurgery with increasing studies in recent years. As novel indications are studied, it is crucial to identify the most important topics and contributors to the field as scientific literature expands to guide clinician and research in the field. Most of the top 100 cited articles comes from North America and Europe, with the United States and Canada contributing to more than half of the articles on MRgFUS. The top 100 cited articles also highlight the access of MRgFUS to developed countries and healthcare disparity in access of MrgFUS to developing countries.KG: conceptualization, methodology, software, writing, rewriting and editing, data curation, writing—original draft preparation, visualization, investigation, software, and validation. MR: conceptualization, writing, rewriting and editing, writing—original draft preparation, visualization, investigation, supervision, software, and validation. VK: conceptualization, methodology, rewriting and editing, and supervision. MS and AR: methodology, rewriting and editing, and supervision. All authors contributed to the article and approved the submitted version.


Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory. Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders and has prevalence in children of 5–7%, of which around two-thirds report persisting problems in adulthood , 2. A maAlterations in brain morphometry have been widely reported in both children and adults with ADHD , 10 and We used two distinct analytic approaches to investigate this topic. First, we conducted a standard univariate analysis of FreeSurfer-based volume segmentations of the structural brain scans of subjects with ADHD with and without comorbidities for testing our specific hypotheses. Second, we employed a machine learning (ML) algorithm trained to classify subjects with ADHD in a larger dataset and used it to calculate the ADHD brain risk score  of the We address three separate research questions by both types of analyses: 1) is there a general effect of comorbidities on structural brain morphometry and/or predictive accuracies of the ML algorithm? 2) Is there a cumulative effect of comorbidities? 3) Is there a specific effect of each of the comorbidities?We hypothesized that the subjects with ADHD and comorbid disorders will show smaller subcortical brain volumes and lower cortical thickness, particularly in the frontal-striatal pathways than the patients with ADHD only . We hypoThe study includes 133 subjects with ADHD with and without the comorbid presence of depression, obesity, or SUD . The recruitment took place at Donders Center for Cognitive Neuroimaging, Nijmegen, Netherlands and Goethe University, Frankfurt am Main, Germany.via the short Wender-Utah-Rating scale . Adult e [WURS; , which uThe project was carried out in accordance with the provisions of the Declaration of Helsinki and the European Guidelines on Good Clinical Practice, and was approved by the Ethics Committee of the Medical Faculty of the J.W. Goethe University Frankfurt am Main (reg. no. 256/16) and in Nijmegen by Radboud University (reg. no. 2018-4364).http://enigma.ini.usc.edu/protocols/imaging-protocols/) based on automatic outlier detection and visual inspection of segmentation quality.Structural T1 MPRAGE sequences were acquired on a Siemens PrismaFit scanner (Nijmegen) or a Siemens Trio Syngo scanner (Frankfurt). T1 scans were segmented by FreeSurfer cortical and subcortical segmentation. Quality Control (QC) was performed using the standardized ENIGMA QC pipeline (http://enigma.ini.usc.edu/protocols/imaging-protocols/). The automated protocols, based on FreeSurfer (version 5.3) segmentations, are fully validated and allow for maximal uniformity and comparability across sites. For each participant, left and right subcortical volumes, cortical thickness, and cortical surface area measures were calculated. Quality control depended on the visual inspection of all volume segmentations. Poorly segmented regions were removed from further analyses.In order to investigate brain morphometry, all structural MRI scans were segmented into subcortical volumes, cortical thickness, and cortical surface area by FreeSurfer segmentation. Structural T1-weighted MRI scans acquired at the two contributing sites were segmented using standardized and publicly available ENIGMA imaging protocols (p = 0.002). Full details of the model training and operation are available in Zhang-James et al.  data from 4,183 subjects (adults and children with and without ADHD) from 35 participating sites . Images were processed using the consortium's standard segmentation algorithms in FreeSurfer (V5.1 and V5.3). Details about the processing of the training data sample are provided in Zhang-James et al. . FreeSurFor the current study, the algorithm was applied to our new comorbidity cohort, rendering a BRS for each subject, indicating the likelihood that the subject was affected by ADHD. Average BRS scores were used in the current study to test whether predictive accuracies for the ADHD diagnostic status would differ between subjects with ADHD and comorbid diagnoses of SUD, obesity, or depression.The machine learning classifier reported by Zhang-James et al.  was usedThe final ensemble multilayer perceptron (MLP) neural network models reported in Zhang-James et al.  were tesThe primary outcome measure in the current study was therefore the BRS for each subject, indicating a likelihood that each subject would be classified as affected by ADHD. Given that all our subjects have an ADHD diagnosis (both in the comorbid and non-comorbid groups), correct prediction would mean the algorithm classifies all the subjects as “affected”.t-tests and the third one as F-test.As stated in the introduction, we formulated three hypotheses to test for the effects of comorbidity on structural brain morphometry, as operationalized by FreeSurfer segmentations of subcortical volumes, cortical thickness, and cortical surface area. First, we compared patients with and without comorbidity. Second, we looked for a linear effect of comorbidity . Third, we compared by F-test contrast all eight subgroups of different combinations of depression, SUD, or obesity. All tests included age, gender, and site as covariates. Intracranial volume (ICV) was added as an additional covariate in all the models, with subcortical volume as the dependent variable. The first two tests were defined as We calculated differences in medication use between the comorbidity subgroups with a univariate general linear model in R (R Core 27). Comorbidity  was used as a dependent variable, whereas medication type  was used as an independent variable with age, sex, and site as covariates.In accordance with the three research questions, three sets of models were run in R. Each model used each segmentation of subcortical volume, cortical thickness, and surface area as separate independent variables. The first model set tested for differences between participants with ADHD and no comorbidities and those with any comorbidity. The second model set tested for group differences between participants with ADHD and all comorbidities (cumulatively). The third model set tested for individual differences among subjects with ADHD, ADHD + depression, ADHD + obesity, and ADHD + SUD.p =0.022), left bank of the superior temporal sulcus , and middle temporal sulcus . Similarly, the model testing differences between solely ADHD and ADHD + all cumulative comorbidities showed uncorrected group differences in the right and left rostral middle frontal , superior frontal , right pars triangularis , lateral orbitofrontal  and left pars opercularis , and caudal middle frontal , indicating lower cortical thickness in frontal areas associated with more comorbidities. These effects did not survive multiple comparisons corrections with a stringent pFDR-correction.The summarized results of the models are depicted in No effects of the different comorbidities on medication use were observed. As an exploratory follow-up analysis, medication use  was also subsequently added as a predictor in all ROIs that showed an uncorrected significant effect as depicted in p < 0.001). However, no differences were observed between any of the comorbidity groups, so the addition of comorbidities did not influence the accuracy of this prediction. Neither any, all, or each of the comorbidities were associated to BRS : t = 0.879, p = 0.381, Cohen's d = 0.15, Cohen's d CI = −0.3–0.62; every: f = 0.04, p = 0.986). The post hoc power analyses indicate that the power achieved for the F-test was 1-β = 0.05, limiting the interpretability of the lack of effects. BRS was not associated with site or sex, and neither was the BRS correlated with childhood symptoms of ADHD (WURS-k) -factor  in the dSimilarly, the ML algorithm had a predictive accuracy of 0.57, indicating an above-chance level for a correct ADHD diagnosis across all the subjects. However, this did not differentiate between subjects with solely ADHD or subjects with ADHD and comorbidities. Therefore, an ML model trained to differentiate between subjects with ADHD and healthy controls in the ENIGMA-ADHD dataset does not differentiate between subjects with just ADHD and ADHD + comorbidities. This indicates that the features used by this data-driven algorithm to predict ADHD status are not the same features that are altered in subjects with comorbidities. Therefore, using this approach, we find no evidence that the underlying morphometric features underlying ADHD and comorbid disorders are similar.As the ML model was based at least in part on adolescent brains, this might indicate that comorbid disorders and their brain changes that come later in life are not captured by the ML model because it represents a different developmental trajectory. In addition, one could argue that the disorders are not simple extensions of a dysregulated ADHD-developmental trajectory; therefore, our ML model does not pick up different subgroups.post hoc power analyses also indicate low to moderate power for the FreeSurfer analyses (1-β = 0.1–0.2). Therefore, a more extensive sample may aid in uncovering subtle severity-related effects on brain structure.Several further limitations should be considered when discussing our study. First, the limitations of the ML model described by Zhang-James et al.  apply toAn innovative part of our study is the use of an ML-model for generating a predictive ADHD brain risk score. This has parallels in recent studies trying to use the ENIGMA dataset as a weighting prior for a brain risk summary measure, e.g., in schizophrenia  but not To conclude, it is notable that neither the morphometric ML-model nor the univariate FreeSurfer-Segmentation models were effective in predicting ADHD and comorbid disorders. However, we do not think that the current results should be interpreted as definitive evidence that there are no effects on individuals with ADHD depending on type or number of comorbid disorders. Future studies might further investigate specific tasks, e.g., reward-learning, and look for relationships with ADHD symptoms. For example, there are alternate approaches with specific tasks, e.g., functional connectivity that may prove better. Indeed, a recent article by our group demonstrated that striatal rs-fMRI-connectivity is able to distinguish between the number of comorbidities aka the disorder “load” , indicatThe 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 Ethics Committee of the Medical Faculty of the J. W. Goethe University Frankfurt am Main (reg.no. 256/16) and in Nijmegen by the Radboud University (reg.no. 2018-4364). The patients/participants provided their written informed consent to participate in this study.DR and OG were involved in data collection, analysis, conceptual development, and writing of the manuscript. AR and JB were invovled in writing the grant application, conceptual development, and proofreading of the mansucript. YZ-J and SF were involved in the development of the machine learning algorithm, statistical analyses, conceptual interpretation, and proofreading of the manuscript. All authors contributed to the article and approved the submitted version.Financial support for this study was received from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement 667302 (Comorbid Conditions of ADHD).AR has received a research grant from Medice and served on advisory board and/or speaker's bureau for Medice, Shire/Takeda, Janssen, Servier, and Neuraxpharm. OG has served on advisory board and/or speaker's bureau for Medice Arzneimittel Pütter GmbH and Shire/Takeda and has served on advisory board and/or speaker's bureau for Medice Arzneimittel Pütter GmbH. JB declares that he has been, for the past 3 years, a consultant /member of the advisory board of/and/or speaker for Janssen Cilag BV, Eli Lilly, Medice, Shire, Roche, and Servier. 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.


Foetal kidney length (FKL) measurements and comparisons to normal charts can be used to assess the development of the foetal kidneys throughout the entire course of pregnancy. This study was designed to assess FKL between 20 — 40 weeks' gestation, establish reference ranges for FKL and determine the relationship between FKL and gestational age (GA) in normal pregnancy.This descriptive, cross-sectional study was conducted between March-August 2022, at the Obstetric Units and Radiology Departments of the two tertiary health facilities, one secondary facility and one radio-diagnostic facility in Bayelsa State, Southern Nigeria. Transabdominal ultrasound scan was used to evaluate the foetal kidneys. The relationship between foetal kidney dimensions and GA was explored using Pearson's correlation analysis. Linear regression analysis was done to define the relationship between GA and mean kidney length (MKL). A nomogram predicting GA from MKL was constructed. Level of significance was set at p<0.05.There was a very strong significant correlation between foetal renal dimensions and GA. The correlation coefficient between GA and mean FKL, width and anteroposterior diameter were 0.89 (p=0.001), 0.87 (p=0.001) and 0.82 (p=0.001), respectively. A unit change in mean FKL corresponded to a 79% change in GA (ɼ2), showing a very strong association between mean FKL and GA. The regression equation: GA = 9.87 + 5.91 x MKL, was derived for estimation of GA for a given MKL.Our study revealed a significant relationship between FKL and GA. The FKL can therefore be reliably used to estimate GA. The definitive foetal kidney begins to develop in the first trimester as a fusion of the ureteric bud and metanephric mesoderm. Development of the kidney begins at seven weeks, and by 11 weeks' gestation, the kidney begins to function properly. As early as 9 to 12 weeks' gestation, prenatal ultrasonography (USS) can detect the foetal kidneys, which have a lobular appearance and are located in the paraspinal area , crown-rump length (CRL), biparietal diameter (BPD), head circumference (HC), femur length (FL) and abdominal circumference (AC), used for estimating the GA of the foetus. However, none has been reported to be the most accurate or reliable for estimating GA. In fact, Benson and Doubilet reported that the accuracy of ultrasound foetal biometric measurements decreases as pregnancy advances  Other auThe need for an accurate estimation of gestational age, especially in a high-risk pregnancy for obstetricians and paediatricians alike, cannot be overemphasized. It will enable adequate and comprehensive care to ensure safe maternal and foetal outcomes. Transvaginal sonography, which may be used between 14 and 17 weeks of gestation, and transabdominal ultrasound scan USS, which can be used from 18 weeks of gestation and upwards, are both reliable methods for measuring the foetal kidney .Literature on the relationship between FKL and GA of pregnancy is sparse in our setting. This study therefore sought to assess FKL between 20 – 40 weeks' gestation, establish reference ranges for FKL dimensions, and determine the relationship between FKL and GA in normal pregnancy among a sample of pregnant women in Southern Nigeria.Study setting: This descriptive, cross-sectional study was conducted at the Obstetric Units and Radiology Departments of the Federal Medical Centre, Yenagoa, Niger Delta University Teaching Hospital, Okolobiri, Diete Koki Memorial Hospital, Yenagoa, and Silhouette Radio-diagnostic Consultants, Yenagoa, all in Bayelsa State, South-South Nigeria. The first two study centres are tertiary health facilities that provide specialised gynaecological services to women in Bayelsa State and serve as referral centres for other hospitals in Bayelsa State, and surrounding Rivers and Delta States, both in South-South Nigeria. The third study centre is a secondary health institution. The fourth study centre is the biggest Radio-diagnostic Institution in Bayelsa State, Nigeria. The study was conducted from March – August 2022.Ethics: Ethical approval for this study was obtained from the Research and Ethics Committee of the Federal Medical Centre, Yenagoa, Bayelsa State, Nigeria (FMCY/REC/ECC/2022/628).Sample size: The sample size of 423 for this study was calculated using the Fisher's formula , with special interest and expertise in foetal renal scans. With the patient lying supine, and the abdomen and pelvis exposed, adequate ultrasound gel was applied to the lower anterior abdominal wall/pelvis. The gel served to remove air from the skin, and for ease of transducer movement. A real-time, grayscale, 3.5 MHz curvilinear array transducer of a 2012 Philips HD11 ultrasound machine was used to obtain measurements of all foetal biometric parameters. The probe was moved back and forth on the skin, and in orthogonal planes, with gain adjusted, as required, for good image quality. Estimated gestational age, foetal biometric parameters and estimated foetal weight (EFWT) were determined using the Hadlock's method, which included foetal BPD, HC, FL and AC measurements taken at specific reference points  was recorded. The adrenal glands were excluded from these measurements.Data analysis: Data from the study proforma was checked daily for completeness and correctness, and were entered directly into a statistical software, Statistical Product and Service Solutions version 25.0 , which was used for data cleaning and analysis. Categorical variables (parity and age-group) were summarised using frequencies and percentages, while continuous variables  were summarised using mean and standard deviation after a normality (Shapiro-Wilk) test revealed that the variables were normally distributed. The mean kidney dimensions were calculated by dividing the sum of the right and left kidney dimensions by 2. The relationship between the kidney dimensions and estimated gestational age, maternal height and weight was explored using the Pearson's correlation analysis. The mean kidney length had the strongest correlation with the estimated gestational age; hence, it was used in a logistic regression analysis in defining the relationship between estimated gestational age and mean kidney dimension. The equation was thereafter used in predicting gestational ages at different kidney lengths, thereby, producing a nomogram. Level of significance was set at p<0.05.Sociodemographic and obstetric characteristics of study participants: The mean age of the women was 29.03 ± 6.35 years. The median parity was 1, with a range of 0 to 7. Mean body mass index and gestational age were 27.75 ± 4.12 kg/m2 and 31.8 ± 5.5 weeks, respectively  showing a very strong association between mean kidney length and GA. There was significant statistical correlation between maternal height and FKL. Maternal weight on the other hand, did not show any significant statistical correlation with FKL . This correlation is in tandem with the reports of other authors  was slightly longer than the left FKL (3.66 ± 0.88 cm). This finding is in contrast with the reports of Abonyi et al.  and Fitzet al. , where t  to 40 weeks (kidney length of 5.0 cm). These reference ranges are very similar to the values reported from other centres within Nigeria . HoweverThis study is limited by the fact that it is regional-based, and its findings and reference ranges may not reflect those obtainable from other regions of the world. Some of our patients were obese. Obesity limits the optimal visualisation of the kidneys and subsequent assessment of their lengths. However, with our high-resolution ultrasound scan machine, we were able to surmount this limitation. This limitation notwithstanding, our study provides crucial data on the relationship between FKL and GA in normal pregnancy among a sample of pregnant women in our region. The strength of our paper lies in the fact that it is a multicentre study. Ultrasound scans were performed by only four Consultant Radiologists (one for each centre), with special interest and expertise in foetal renal scans, limiting inter-observer differences, and increasing the reliability of our findings.In conclusion, our study revealed a strong correlation between FKL and EGA. The FKL increases with advancing gestation. The FKL can therefore be used to estimate GA. The nomogram from this research will serve as a reference chart for our local population.