The number and health burden of Parkinson’s disease increase rapidly in China. It is estimated that China will have nearly half of the Parkinson’s disease population in the world in 2030. In this review, we present an overview of epidemiology and health economics status of Parkinson’s disease across China and discuss the risk factors of Parkinson’s disease and related complications. From the view of clinical research, we also discuss the current status of clinical trials, diagnostic biomarkers, treatment of Parkinson’s disease, tertiary network and post-occupation education in Chinese Parkinson’s disease clinics.The online version of this article (10.1186/s40035-019-0162-z) contains supplementary material, which is available to authorized users. China, a multiethnic developing country with the largest population of the world, is stepping into an aging era . It is eSince 1978, the year of “reform and opening”, economy has boomed in China. The researches in PD have also developed rapidly both in clinical and basic science, with the number of publications increasing from zero to the second largest country in the world. , a database of macroeconomics, the gross domestic product (GDP) per capita in Shanghai in 2004 was 5,708.00 USD  and GDP per capita in Tianjin in 2015 was 18,472.32 USD . Many anti-PD drugs have been covered in the government health insurance, and deep brain stimulation (DBS) has been covered partly in a few cities recently.In the year of 2004–2005, the overall mean annual cost of PD in Shanghai was 925 USD, and the direct medical care cost was 519 USD (56.1%) . In the Common risk factors have been found, such as rapid eye movement sleep behavior disorder (RBD), olfactory dysfunction, constipation, family history of PD and pesticide exposure . In addiSeveral studies focused on risk factors for motor and non-motor complications of PD. Young age of onset, severe depressive symptoms, female, RBD, autonomic dysfunction and muscle cramps were risk factors of anxiety in PD patients . Tumor hThe number of PD scientific publications is being a steady increased in China Fig. , exceediClinicalTrials.gov, there are 110 studies in China registered on this website, 56 of them in mainland, 2 in Hong Kong and 52 studies in Taiwan. Due to historical reasons, the development of clinical trials are uneven among mainland China, Hong Kong, Macau, and Taiwan. The number of clinical trials that we took part in was much less than that in developed countries, such as United States, Canada, United Kingdom and Japan. ClinicalTrials.gov is not widely used in mainland China. With the socioeconomic and medical care developments in past 40 years, clinical trials in China have been paid more attention than before. More and more Chinese hospitals have been invited to participate high-quality international multicentral clinical trials  in Chinese Han population were identified and replicated quickly. However, how these genetic risk loci contribute to the adult-onset PD pathogenesis remains largely unknown. In Table The regulations of several non-coding RNAs, such as down-regulation of miR-15b, up-regulation of miR-24, have been validated as biomarkers of PD –57. Besi99mTc-TRODAT-1 single photon emission computed tomography (SPECT) [18F-fluorodeoxyglucose positron emission tomography imaging (18F-FDG-PET) [131I-MIBG) [Besides rapid eye movement sleep behavior disorder, constipation and hyposmia, clinical biomarkers are paid attention by Chinese neurologists. Radiological methods, such as  (SPECT) , 18F-fluFDG-PET) , functioFDG-PET)  and Iodi1I-MIBG)  have bee1I-MIBG) . Transcr1I-MIBG) .However, the validation, sensitivity and specificity of these biomarkers among different ethnicities and the combination of these biomarkers are warranted. Biomarkers in prodromal stage are needed, as well as a nationwide multi-center Chinese prodromal PD cohort.Most drugs for PD are available except for apomorphine and Levodopa-carbidopa intestinal gel, inhalation form of L-dopa, droxydopa, pimavanserin, safinamide, extended release amantadine in mainland China. The Chinese PD and Movement Disorders Society (CMDS) published guidelines of PD and PDD treatment in 2006, and updated in 2009 and 2014 –71. TreaIn 1950s, stereotactic surgeries such as posteroventral pallidotomy (PVP) and unilateral subthalamotomy were adopted in clinical treatment of PD. However, they were abandoned because of severe adverse effects since 1968, the year of levodopa introduction in China . With thIn traditional Chinese medicine (TCM), PD can be categorized into three syndromes based on the main symptoms. Most tremorous PD belongs to “tremor syndrome”. . TreatmeRehabilitation is considered as a complementary therapy in PD. It can improve the functional abilities and decrease complications. Physical therapy, occupational therapy and speech therapy are major parts of rehabilitation. Traditional Chinese activities, such as Qigong, Tai Chi and Baduanjin, have been drawn attention because of their benefits, probably due to rehabilitation effect. Tai Chi could improve motor function, balance and gait in PD . Blood HA survey conducted in Shanghai revealed that the median time from the onset of motor symptom to the first clinical visit was 1.0 month (0–51.5 months) . The medA study aiming to compare UK-Criteria versus MDS-PD Criteria in the clinical diagnosis of Parkinson disease in a single center was conducted . In thisLike other chronic diseases such as diabetes, hypertension and cerebral vascular disease, it is important to educate physicians and patients for PD management. Health education is an effective way for local physician and patients to acquire knowledge of PD, which could improve the early diagnosis and management of PD . Tan et Palliative care has a late start in China. There is no currently available palliative care for PD in China. Caregivers often regard palliative care as hospice care . BesidesThe health system of China, i.e. the tertiary network, is different from the health system of western countries. The primary hospitals, which are mainly located in communities, are for prevention, diagnosis and treatment of common illness. The secondary hospitals serve for several communities and are in charge of teaching and researching. The tertiary hospitals are for the diagnosis and treatment of difficult cases and are in charge of teaching and researching. As patients are self-referred in Chinese health system and there is an inequivalent development between the gross economic growth and the service of hospitals, patients prefer to choose tertiary hospitals for the first clinical visit rather than primary or secondary hospitals. Dual referral system of this network is not well developed. Experienced neurologists are overworked in tertiary hospitals . In contClinics to specific diseases have been set up to help the patients see specialists. The first PD clinics, started in seven hospitals in China, including Beijing Hospital, Ruijin Hospital and other 5 hospitals in 1978. Later, the Chinese Movement Disorder Study Group was established. Specialists in PD clinics are experienced doctors in the PD diagnosis and treatment. Besides, it is much easier to perform health education to PD patients and caregivers in the PD clinics. Clinics of neuromodulation and neurorehabilitation were set up recently. In April 2007, club of PD patients were organized by Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, for the purpose of better education and management .Wearable devices improved the quality of PD patients’ life and helped PD diagnosis to some extent. Researches on wearable devices in China have just started. In PD clinics, more and more wearable devices could be applied. PD-Monitor applied with evolutionary algorithm could differentiate early stage PD patients with normality . Spoons The Chinese PD and Movement Disorders Society was established in 2002, which is affiliated to Chinese Medical Association (CMA). The diagnostic criteria and therapeutic guidelines of PD have been published by this society, including Chinese diagnostic criteria of PD , guideliBesides adaptive reading literatures, guidelines and expert consensus, many meetings and post-occupation educational classes were organized every year to update the knowledge of PD. There are 3 meetings related to PD held by national association, i.e. annual conference of the CMDS, annual conference of Chinese Neurology Society, annual conference of Chinese Neurologist Association , 109. SeThere are only about 150 board-certified movement disorder specialists in CMDS currently among nearly 100,000 neurologists in China. Thanks to the development of Internet, online learning courses have been a common way for practitioners who do not have enough grant for attending the meetings. The biggest medical forum, Dingxiangyuan, provides a lot of open online courses for PD. Mobile learning via applications such as WeChat has been introduced recently and soon becomes popular among doctors.Since 1978, the development of clinical research and bedside work of PD in China is fascinating. The amount of publications increases from zero to the second place in the world. The bedside work develops from personal experience to standardized diagnosis and treatment. By 2030, there will be a half of worldwide PD patients in China. There are more and more doctors paying attention to PD. Clinical researches provide important data for amending health policies of PD, such as cost for DBS could be reimbursed in health insurance for PD. However, several problems remain to be solved. Huge burden of tertiary hospital doctors, lack of experienced doctors in primary and secondary hospitals in PD, and the lack of dual referral system in tertiary network are the current major issues. Lack of standardized PD database is another issue. Chinese expert consensus on clinical database construction of PD and movement disorders brought up by CMDS has been published recently to standardize the construction on clinical database . Due to Additional file 1:Table S1. Epidemiology of PD in China. Table S2. Status of Clinical Trials. Data S3. Meta analysis of genetic variants for Parkinson’s disease in Chinese population. (DOCX 38298 kb)


Huazhuo Jiedu Shugan decoction (HJSD), a traditional Chinese medicine (TCM), has been used to treat epileptic seizures for many years. Some ingredients in these herbs have been demonstrated to be effective for the treatment of brain damage caused by epilepsy.  The object of the study is to determine the effects of HJSD on cognitive and emotional disorders in a rat model of epilepsy.  After a predetermined time period, rats were intraperitoneally injected with pentylenetetrazol and observed in different phases of convulsions. The cognitive and emotional changes in the epileptic rats were assessed using behavioral and immunohistochemical tests. P < 0.01). Compared with the control group, the epilepsy group displayed marked worse performance on the animal behavior tests (P < 0.05) and the HJSD-H group displayed improved behavioral performance (P < 0.05). After HJSD-H treatment, the expression of adenylate cyclase (AC), cyclic adenosine monophosphate (cAMP), cAMP-response element binding protein (CREB), and neuropeptide Y (NPY) immunoreactive cells markedly increased in the hippocampus, compared with that of the epilepsy group (P < 0.05).  Compared with the epilepsy group, the seizure grade was reduced and seizure latency was prolonged following HJSD-H treatment ( The current results demonstrate that HJSD treatment in epileptic rats markedly inhibits epileptic seizures and improves cognitive and emotional disorders, which may be related to the regulation of AC-cAMP-CREB signaling and NPY expression in the hippocampus. The effects of the HJSD treatment may provide a foundation for the use of HJSD as a prescription medicinal herb in the TCM for the treatment of epilepsy. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition . In addiThe cognitive impairments and emotional disorders caused by epilepsy are related to abnormal neuronal discharge, neuron dysfunction, synaptic recombination, and disorders caused by epilepsy. The cognitive impairments associated with epilepsy seriously influence the quality of life in patients, and about 50% of patients with epilepsy have varying degrees of cognitive impairment. Complex partial epilepsy, temporal lobe epilepsy, generalized convulsive epilepsy, and even absence epilepsy can all result in cognitive impairments . EpilepsTo date, first-line antiepileptic drugs (AEDs) have taken precedence in the treatment of epileptic seizures. Long-term application of AEDs, however, can cause resistance to these drugs, decreasing their clinical effects, or causing cognitive impairments and emotional disorders . ResearcSixty male Sprague Dawley rats  were used in the study. Rats were acquired from the Animal Experiment Center of Hebei Medical University in Hebei, China (license number SCXK 2018-004 and certificate number 1808129). Three rats were housed per polysulfone cage at ambient temperature (22–25°C) and relative humidity (60 ± 5%). Animals were free-fed a rat pellet artificial diet  and tap water. The rats were adapted to laboratory conditions 7 days before experimentation.All experiments were conducted between 8:00 AM and 2:00 PM, and all animal experiments were conducted according to the guidelines of the National Institutes of Health's Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize the suffering of animals and reduce the number of animals used. All experimental procedures were carried out after being approved by the Laboratory Animal Administration and Ethics Committee of Hebei Academy of Chinese Medicine Sciences .Scutellaria baicalensis (Huang qin) 12 g, Gynostemma pentaphylla (Jiao gu lan) 12 g, Radix bupleuri (Chai hu) 12 g, Rhizoma acori graminei (Shi chang pu) 9 g, lotus petiole (He geng) 9 g, and basil (Luo le) 6 g.The total amount of crude drugs in HJSD is 60 g, among which the drug composition and dose are The HJSD and sodium valproate tablets  were purchased from the Affiliated Hospital of Hebei Academy of Chinese Medicine Sciences. Pentylenetetrazol , anti-AC rabbit polyclonal antibody , rabbit anti-cAMP polyclonal antibody , CREB (48H2) Rabbit mAb , and anti-NPY antibody  were purchased from Hebei Bio-high Technology Co. Ltd., China. All other chemicals were sourced from the Hebei Academy of Chinese Medicine Sciences and were of analytical grade.The rats were randomly divided into six groups (10 rats in each group) as follows: the control group, the epilepsy group, the VPA group (300 mg/kg/day), the HJSD high-dose group , the HJSD medium-dose group , and the HJSD low-dose group . The volume for HJSD treatment  was 5 ml/kg. HJSD and VPA were administered by gastric gavages between 9:00 AM and 10:00 AM during the treatment period. These doses are generally consistent with and cover the clinical dose of HJSD and the intragastric dose of the animals referred to in previous animal studies . VPA of An epilepsy model induced by PTZ was used in this study. Seizure grade and incubation period, animal behaviors, and immunohistochemical staining were also evaluated. The experimental design is illustrated in The modified PTZ kindling model was established by intraperitoneal injections (IP) of a subconvulsant dose of PTZ once daily until complete kindling was achieved in rats for 28 consecutive days , 21. ForAll animal behaviors were tested and documented using the SLY-ETS animal behavioral activity record analysis system .The Morris water maze (MWM) test was performed to measure learning and memory in epileptic rats. The experiment was conducted according to the methods described in Cao et al. . BrieflyBriefly, the radial arm maze (RAM) was designed to assess spatial learning and memory in rats. According to the method of Wang et al., before the RAM test, the rats were habituated . In ordeThe Y-maze (YM) was mainly used to assess discrimination learning, working memory, and the reference memory test of rats according to the method of Mohammadi et al. . BrieflyThe elevated plus maze (EPM) measured the anxiety of the rats based on the contrast between exploratory behavior and the tendency to avoid open, well-lit, and elevated spaces as described previously. The test was conducted according to the method described in Marques-Carneiro et al. . BrieflyBehavior using the open field maze (OFM) test evaluated spontaneous activity and emotionality. Less activity in the OFM test is thought to represent a higher level of anxiety and vice versa. According to the method of Fan et al., undisturbed rats were recorded by a camera placed above the center of the OFM for 10 minutes . The ratn = 3 for each group). Brain tissue sections were deparaffinized in xylene, rehydrated in a graded series of ethanol for 5 min, and then incubated with H2O2 . For antigen retrieval, the sections were heated in a microwave oven with 10 mmol/L sodium citrate buffer (pH 6.0) for 10 min at 92–98°C. The sections were then incubated with goat serum  for 30 min at room temperature [All rats were sacrificed 28 days after being considered kindled, and the last PTZ administration  was made the day before the rats were killed  and the LSD method test. All statistical analyses were performed using SPSS 23.0 software . n = 54). The kindled epileptic rats were arbitrarily divided into 5 groups. The drug-resistant animals did not appear in this study.The behavioral seizure grade was assessed in the epileptic rat model. During the administration of PTZ, the number of rats killed was 4 and the survival rate of the rats was 92.6%  was reduced while the seizure latency  was prolonged in rats of the HJSD-H group after therapy.As shown in F5,42 = 2.591, P < 0.01) was reduced, and the escape latency  was longer in rats from the epilepsy group. Compared to the epilepsy group, the platform area crossing times was longer, and the escape latency was shortened in rats from the HJSD-H group .As shown in F5,36 = 5.045, P < 0.05) increased while the residence time of the correct feeding arms  was shortened in rats from the epilepsy group. Compared to the epilepsy group, reference memory errors were reduced, and the residence time on the correct feeding arms increased in rats from the HJSD-H group .As shown in F5,42 = 1.074, P < 0.01). After the HJSD-H therapy, the number of evasive errors  was reduced.As shown in F5,30 = 1.396, P < 0.05) was reduced among rats in the epilepsy group. Compared to the epilepsy group, the number of entries into the open arms was increased in rats in the HJSD-H group (P < 0.05). Compared to the control group, the time spent in the open arms was shortened in rats from the epilepsy group . HJSD markedly prolonged the time spent in the open arms for the epilepsy rats (P < 0.05).As shown in F5,30 = 3.642, P < 0.01) and central traveled , the duration , and entries into the center  were reduced in rats form the epilepsy group. The distance of total traveled and central traveled were lengthened, the duration was prolonged, and the number of entries into the center of the OFM increased for rats in the HJSD-H group compared to those in the epilepsy group .As shown in F5,444 = 6.557, P < 0.01). After treatment with HJSD-H, the expression of AC markedly increased (P < 0.01). In CA3 neurons, the expression of AC in the epileptic group was decreased compared to the control group . After treatment with HJSD-H, the expression of AC was found to be markedly increased (P < 0.01). In DG neurons, the expression of AC in the epileptic group was markedly decreased compared to that of the control group . After treatment with HJSD-H, the expression of AC markedly increased (P < 0.01).As shown in F5,444 = 3.090, P < 0.01). After treatment with HJSD-H, the expression of cAMP was found to increase (P < 0.05). In CA3 neurons, the expression of cAMP was reduced in the epileptic group compared to that of the control group . After treatment with HJSD-H, the expression of cAMP markedly increased (P < 0.01). In DG neurons, the expression of cAMP was markedly decreased in the epileptic group compared to that of the control group . After treatment with HJSD-H, the expression of cAMP markedly increased (P < 0.01).As shown in F5,444 = 3.993, P < 0.01). After treatment with HJSD-H, the expression of CREB markedly increased (P < 0.05). In CA3 neurons, the expression of CREB was markedly decreased in the epileptic group compared to that of the control group . After treatment with HJSD-H, the expression of CREB markedly increased (P < 0.01). In DG neurons, the expression of CREB was markedly decreased in the epileptic group compared to that of the control group . After treatment with HJSD-H, the expression of CREB markedly increased (P < 0.01).As shown in F5,444 = 3.862, P < 0.01). After treatment with HJSD-H, the expression of NPY was increased (P < 0.01). In CA3 neurons, the expression of NPY in the epileptic group was reduced compared to that of the controls . After treatment with HJSD-H, the expression of NPY was found to be markedly increased (P < 0.01). In DG neurons, the expression of NPY in the epileptic group was markedly decreased compared to that of the control group . After treatment with HJSD-H, the expression of NPY markedly increased (P < 0.01).As shown in Administration of PTZ resulted in chemical kindling and a chronic and progressive rise in the irritability of the central nervous system, as well as a decrease in the threshold for seizure occurrence . PTZ kinIn this study, a variety of behavioral tests were used to demonstrate the cognitive decline and emotional behavior changes in PTZ-induced epilepsy models. The MWM test is a type of dimensional learning and memorization method directly related to hippocampal function , 34, andCompared with the epilepsy group, the degree of improvement in learning memory and cognitive ability in the HJSD treatment group was significantly improved. In terms of the behavioral performance of rats, the number of the platform crossings increased and the latency of escape shortened in MWM, the residence time of correct feeding arm increased, and the number of reference memory errors decreased in RAM. Also, the number of evasive errors decreased in YM. In addition, the results of this study showed that compared with the epilepsy group, the behavior of the rats in the HJSD treatment group was as follows: in EPM, the time and number of open arms increased; in OFM, the number, time, and distance of entering the center increased and the total distance traveled also increased, which indicates that HJSD may improve the fear and anxiety emotional responses and locomotor abilities of epileptic rats. In these experiments, HJSD played a major role in improving behavioral abnormalities.Scutellaria baicalensis) and saikosaponin (Radix bupleuri) have significant effects on convulsions, neuroprotective mechanisms, and brain injury caused by epilepsy [α-Asarone (the Acori graminei rhizoma) has been used to improve various disease conditions including stroke and convulsions [Ocimum basilicum has been shown to be significantly effective in reducing the latency and frequency of seizures [HJSD has been used to treat epileptic seizures for many years. Some ingredients in HJSD have been demonstrated to be effective for the treatment of brain damage caused by epilepsy, for example, baicalin . Once formed, cAMP diffuses to act on its effector proteins, of which, cAMP-activated protein kinase (PKA) seems to be the most important (or at least the most studied) in the context of epilepsy, as indicated from the published literature. The role of cAMP signaling can be divided into short-term and long-term effects on epileptogenesis. The short-term effects include the immediate effects, such as channel or receptor phosphorylation, which instantly changes epileptic factors that include neuronal excitability. The long-term effects of cAMP signaling entail protein expression-based changes in epileptogenesis, such as those mediated by CREB. The long-term effects of cAMP signaling also play a major role during epileptogenesis although many of the changes observed are still poorly understood . The CREOur experimental results have showed that the number of immunoreactive cells of AC, cAMP, and CREB in the epilepsy group is significantly reduced compared with that of the control group. However, conflicting results have also been reported. Some report that there is an increase in the expression of AC or an increase in the level of cAMP in the epilepsy group –50. The in vivo and in vitro [Recently, many researchers believed that NPY has an antiepileptic effect and is important in the physiological regulation of cognitive function in epileptic disease models. NPY plays an important role in depression, anxiety, and other pathological disorders. Its expression is mainly in the limbic system, which is related to emotional responses, especially in the caudal putamen, hippocampus, and other brain tissues of the back . NPY is in vitro , 54. Botin vitro , 56.Our results showed that NPY expression in the epileptic rats was significantly lower than the control group, and the HJSD-H group was significantly higher than that in the epilepsy group. This result showed that HJSD could improve the expression of NPY in the brain of epileptic rats so that it may continue to play an antiepileptic role, and there was no statistical difference in the expression of NPY between the HJSD group and the VPA group. But the results of Vezzani and Sperk  showed tThis study has provided a mechanism for the antiepileptic effect of HJSD and the improvement of cognitive and emotional disorders by observing hippocampal CA1, CA3, and DG regions, as well as immunohistochemical and behavioral test results. However, further studies are needed to determine the effect of HJSD on the differences (or changes) of the dorsal and ventral hippocampus areas and gene expression can also be used to pinpoint the target of the drug action in detail.In conclusion, our results demonstrate that HJSD treatment in epileptic rats may significantly inhibit epileptic seizures and improve cognitive and emotional behavior disorders. The antiepileptic effect of HJSD-H was similar to VPA. These experimental results suggest that HJSD might significantly inhibit epileptic seizures by enhancing the AC-cAMP-CREB signaling pathway and NPY expression in the hippocampus. Understanding the regulation of AC-cAMP-CREB signaling and the expression of NPY is expected to elucidate the efficacy of TCM in the treatment of epilepsy and should provide the basis for the development of new Chinese medicines.


Background and Purpose: Hyperhomocysteinemia (Hhcy) is a well-known risk factor for ischemic stroke. However, the role of Hhcy in the clinical outcome of ischemic stroke has not been fully elucidated. In addition, previous studies have found that Hhcy was implicated in the disruption of the blood-brain barrier, which may increase the risk of hemorrhagic transformation (HT) after thrombolysis. Thus, the aim of this study was to investigate the effect of Hhcy on the clinical outcome and HT after thrombolysis in ischemic stroke patients.Methods: Patients who were diagnosed with ischemic stroke and received intravenous thrombolytic therapy between January 2016 and September 2018 were included in this study. Multivariate logistic regression analysis was used to assess the association between Hhcy, clinical outcome, and HT after thrombolysis. Furthermore, the potential interaction between Hhcy and hypertension on the clinical outcome and HT after thrombolysis was also assessed.Results: Of 568 patients, 455 (80.1%) had Hhcy, 66 (11.6%) had HT, and 219 (38.6%) had poor outcome. Patients with Hhcy had a higher incidence of poor outcome than the patients with non-Hhcy . However, there was no significant difference in the incidence of HT  between patients with Hhcy and non-Hhcy. After adjustment for major covariates, multivariate logistic regression analysis disclosed that Hhcy was independently associated with increased risk of poor outcome  but was not associated with the risk of HT . In addition, we found no significant interaction between Hhcy and hypertension on the clinical outcome (p = 0.513) or HT (p = 0.170) after thrombolysis.Conclusion: We found that Hhcy was an independent risk factor for poor outcome, but not an independent risk factor for HT after thrombolysis in ischemic stroke patients. In addition, there was no significant interaction of Hhcy and hypertension on the clinical outcome or HT after thrombolysis. Ischemic stroke accounts for 80–85% of all strokes and is one of the leading causes of mortality and disability in China . IntraveHyperhomocysteinemia (Hhcy) is a condition in which the plasma levels of homocysteine and related metabolites are elevated. Accumulating evidence has demonstrated that Hhcy is an independent risk factor for ischemic stroke . HoweverThis study was approved by the Ethics Review Committee of the First Hospital of Jilin University, and written informed consent was obtained from all participants or their direct relatives.We consecutively recruited patients who were diagnosed with ischemic stroke and received intravenous thrombolysis with rtPA in our department between January 2016 and September 2018 for this study. The diagnosis of ischemic stroke was based on the clinical manifestations and signs, brain computed tomography (CT), and/or magnetic resonance imaging (MRI), as well as routine laboratory tests. Intravenous thrombolytic therapy was administrated within 4.5 h of onset for patients with ischemic stroke according to the recommendations of current guidelines and the decision of the treating physician . After tDemographics, vascular risk factors, previous history of drugs, as well as clinical and follow-up information of participants were prospectively collected and recorded in a well-established database. All information was obtained by trained staff through a standard questionnaire. Cigarette smoking was defined as having smoked at least 1 cigarette per day for 1 year or more . AlcoholThe clinical outcome was assessed at 3 months by modified Rankin Scale (mRS) with a score ranging from 0 (no symptoms) to 6 (death). We defined mRS scores ≥3 as a poor outcome and mRS scores ≤ 2 as a favorable outcome. HT was defined as any visible hemorrhage on brain CT or MRI 22–36 h after thrombolysis. sICH was defined as a HT that led to death or neurological deterioration with an increase of 4 or more on the National Institute of Health Stroke Scale (NIHSS) scores .t-test or Mann–Whitney test for continuous variables and the chi-squared test or Fisher's exact test for categorical variables. For exploring the effect of Hhcy on the clinical outcome and HT after thrombolysis, we first conducted univariate analysis to compare baseline factors associated with clinical outcome and HT. The variates with a p-value < 0.1 in the univariate analysis were included in multivariate logistic regression models as the major covariates. Then, we conducted multivariate logistic regression analysis to assess the association between Hhcy, clinical outcome, and HT after thrombolysis, and odd ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the risk of poor outcome and HT. Furthermore, we also assessed the potential interaction between Hhcy and hypertension on the clinical outcome and HT after thrombolysis. All statistical tests were two-tailed, and p < 0.05 was considered statistically significant.The data were analyzed by Statistical Program for Social Sciences version 22.0 . Continuous variables were expressed as means and standard deviation if the data was normally distributed, and vice versa by median and interquartile range. Categorical variables were expressed as frequency and percentage. The intergroup difference was compared using Student's A total of 618 patients were screened for this study, of which 23 patients were lost for follow-up, 12 patients missed the data of brain CT/MRI after thrombolysis, and 15 patients did not receive the examination of plasma homocysteine. Finally, 568 patients (418 men and 150 women) were included, and the overall characteristics of participants are shown in p = 0.022). However, there was no significant difference in the incidence of HT  and sICH  between the two groups.The patient characteristics between Hhcy group and non-Hhcy group are compared in the p = 0.513).As shown in p = 0.170).This study included a cohort of ischemic stroke patients with intravenous rtPA thrombolysis and attempted to determine the effect of Hhcy on the clinical outcome and HT after thrombolysis. We found that Hhcy was an independent risk factor for poor outcome, but not an independent risk factor for HT after thrombolysis. In addition, we found no significant interaction of Hhcy and hypertension on the clinical outcome or HT after thrombolysis.Although a small number of studies have already been published, the role of Hhcy in the clinical outcome of ischemic stroke after thrombolysis remains controversial. Ribo et al. first explored this issue in two prospective studies of small sample sizes  and found that plasma homocysteine levels were not associated with the clinical outcome after thrombolysis in ischemic stroke patients , 16. How202 that can induce necrotic cell death (The mechanisms of Hhcy's effect on the clinical outcome of ischemic stroke after thrombolysis are not clear. However, experimental studies have provided some insights into the mechanisms of Hhcy-induced brain injury. It was found that Hhcy can induce excitotoxicity via the glutamate receptor . In addill death .Previous research has found that HT after thrombolysis was associated with rtPA-induced coagulopathy, ischemic injury, reperfusion injury, and disruption of the blood-brain barrier, and the breakdown of blood-brain barrier played a critical role in the development of HT , 17, 31.In China, Hhcy is a common comorbidity in hypertensive patients with a proportion of up to 75% . PreviouThere are some limitations in the present study. First, this study was a retrospective analysis with a limited sample size. Second, the levels of plasma homocysteine were measured after thrombolysis, which might affect the correlation between Hhcy and HT. Third, Hhcy may be caused by genetic factors, physiologic factors, lifestyle factors, various diseases, and drugs . HoweverWe found that Hhcy was an independent risk factor for poor outcome, but not an independent risk factor for HT after thrombolysis in ischemic stroke patients. In addition, there was no significant interaction of Hhcy and hypertension on the clinical outcome or HT after thrombolysis.The datasets generated for this study are available on request to the corresponding author.This study was approved by the Ethics Review Committee of the First Hospital of Jilin University, and written informed consent was obtained from all participants or their direct relatives.YL, XS, and YiY were responsible for study design. HJ, Z-NG, L-YZ, JC, YaY, YW, JL, and Q-YH performed the data collection. PZ conducted the data analysis. YL drafted the manuscript. HJ, Z-NG, and PZ helped revise the article. All authors were responsible for data interpretation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Preeclamptic women were selected from the same cohort. Pregnant women were followed during three periods of pregnancy and postpartum. The results showed a significant increase in the values of TyG and TG/HDL-c (p < 0.01) as pregnancy progresses, without significant differences between healthy and preeclamptic women. TyG and TG/HDL-c indices are significantly low in nonpregnant and three months' postpartum women when compared with each gestational period studied. TyG and TG/HDL-c indices are positively correlated with HOMA-IR in the early and middle pregnancy (p < 0.05). Multiple linear regression using the TyG and TG/HDL-c indices as dependent variables showed that TyG index was significantly associated with HOMA-IR, gestational age, HDL-c, TC, LDL, fasting insulin, and mean BP (p < 0.001); meanwhile, TG/HDL-c index was only associated with HOMA-IR (p < 0.0242) and gestational age (p < 0.001). In conclusion, the TyG and TG/HDL-c indices could be useful in monitoring insulin resistance during pregnancy.Metabolic changes have been correlated with adverse pregnancy outcomes. The aim of the present study is to determine the TyG and TG/HDL-c indices in a cohort of healthy pregnant ( Pregnancy is a state of multiple and critical changes in the morphology and physiology of women, which play a fundamental role in meeting the mother's basal needs and the requirements of the developing fetus . Among tIn nonpregnant patients with a body mass index (BMI) in the range of overweight or obesity, insulin resistance is a predisposing factor to generate metabolic syndrome and related diseases such as dyslipidemia, hypertension, and diabetes . In pregHypertriglyceridemia and hypercholesterolemia are physiological conditions in the second trimester of gestation . Two groIdentification of preconceptional cardiovascular risk is limited but it is important, using methods that are easily applicable and accessible for physicians, cost-effective, and with adequate diagnostic performance , 8. In tThe present study was approved by the Ethics Committee of the School of Medicine of the Universidad Nacional de Colombia, in accordance with the ethical guidelines established by the Declaration of Helsinki. All study participants accepted their voluntary participation through the signing of an informed consent. The women included in the study were attended by health care personnel from the Department of Obstetrics and Gynecology of the School of Medicine of the Universidad Nacional de Colombia, in Engativá Hospital in the city of Bogotá, D.C.n = 142) followed during three periods of pregnancy, early , middle , and late  and at three months postpartum who attended visits between May 2012 and November 2015. In addition, a group of healthy nonpregnant women (n = 56) was included in the study.The present is a prospective cohort study. It included a group of healthy pregnant women  , followi2), not currently breastfeeding, nonsmokers, without previous history of psychoactive substance or habitual alcohol use, and not using medications that alter glucose tolerance .Additionally, 18 pregnant women who developed nonsevere preeclampsia belonging to the same cohort were selected. The diagnosis of preeclampsia was made in accordance with the recommendations of the American College of Obstetricians and Gynecologists . Finallyg for 10 minutes at 4°C. Serum was stored at −80°C until analysis.In each period of pregnancy and in nonpregnant women, blood was taken after 10–12 hours of fasting, between 7:00 and 8:00 am. Nonpregnant women were studied during the two phases of the menstrual cycle, follicular phase (3rd to 5th day of cycle) and luteal phase (20th to 22nd day of cycle). Additionally, in nonpregnant women, at each phase of the menstrual cycle, two blood samples were taken between 9 am and 12 m, with a half-hour interval, in order to report the average progesterone concentration . BD Vacu0) + log(G0)], including the fasting plasma glucose and insulin levels of our groups of study  when compared with women of normal gestation . AdditioIt has been shown that the TyG index is a surrogate marker of the degree of insulin resistance and predicts the risk of developing diabetes in men and women, both in obese and nonobese subjects . Unger eIn the present study, the values of TyG and TG/HDL-c were determined in a prospective cohort study during three periods of gestation, which once again confirm the concept of Mouzon and Lassance , who sta


Background: Thyroid function is closely associated with neuropsychological functions, including mental state and cognitive functions. Although thyroid function is routinely examined in persons with depressive symptom, the association between subclinical hypothyroidism (SCH) and depression remains inconclusive.Objective: This systematic review and meta-analysis aimed to evaluate the risk of depression in persons with SCH.Methods: The PubMed, Embase, and Web of Science databases were searched up to August 2018. The primary outcome was the prevalence of depression, as evaluated by various types of self-reported depression scales. Odds ratios (ORs) were calculated to compare the risk of depression between persons with SCH and those with euthyroidism.Results: Twenty-one studies were included in the systematic review, with a total of 103,375 subjects from 7 studies being pooled for the meta-analysis to evaluate the risk of depression. The meta-analysis showed that persons with SCH had a significantly elevated risk of depression than persons with euthyroidism . No publication bias was found, as indicated by Egger's test  and Begg's test . In addition, the funnel plot showed a symmetric distribution.Conclusions: This meta-analysis demonstrated that SCH was positively associated with the risk of depression, especially in persons above 50 years of age, suggesting it is necessary to pay close attention to depressive symptoms in persons with SCH. Thyroid function is closely associated with neuropsychological functions, including mental state and cognitive functions . SubclinIn recent years, an increased number of studies investigated the association between SCH and depression , 6. HoweThis meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)  and the SCH participants were diagnosed according to the specific diagnostic criteria in each included study  and the The PubMed, Embase, and Web of Science literature databases were searched, without restriction of language, for publications up to August 2018. In order not to miss potential studies, we use “hypothyroidism” as a keyword instead of “subclinical hypothyroidism” to expand retrieval results because some articles may use similar terms like “mild hypothyroidism” or “slight hypothyroidism.” This searched keyword was combined with “depression” and “depressive symptom” in the “title and abstract” column. The complete search items were “[(hypothyroidism) AND (depression OR depressive symptom)]” in PubMed and Web of Science, and hypothyroidism AND (depression OR “depressive symptom”) in Embase.Selected studies were eligible if they met the following criteria: (1) SCH was confirmed by elevated TSH levels and circulating thyroid hormones within the normal range; and (2) the study was a cross-sectional, case-control, or cohort study. Studies were excluded if: (1) the title and/or abstract were not appropriate for the objective of this review; (2) the use of antidepressant drugs was not allowed in a specific period before each trial; and (3) the article was a review, case report, non-human study, or an abstract or conference proceeding, or if it contained unpublished data. Two reviewers screened potential articles independently and a third reviewer made the final decision when discrepancies were found with a specific study.Data, including study name, characteristics of the study population , main conclusion(s), diagnostic criteria, number of SCH participants with depression and the total number of SCH patients, the number of euthyroid participants with depression, the total number of euthyroid participants were extracted. If published papers only provided the percentage of depressive symptoms, the evaluator calculated the numbers of participants by the calculator in Revman version 5.3 .The literature quality evaluation was conducted by means of the Newcastle-Ottawa Quality Assessment Scale . Two revOdds ratio (OR) and 95% confidence intervals (CIs) were calculated for the outcome of depression, in which the prevalence of depressive symptoms in SCH participants and a normal population was assessed. The reason for the choice of OR was due to the retrospective design of this meta-analysis based on published studies that varied in design, subject populations, primary outcome measures, and research quality .I2 statistic. Due to the potential clinical heterogeneity, a random-effect model was chosen to synthesize data instead of a fixed-effect model. Heterogeneity was considered significant if the I2 value was over 25%. All reported test results were two-tailed and a P value < 0.05 was considered statistically significant. All data analyses were performed with Revman 5.3.A forest plot was used to present the pooled OR value, and heterogeneity was evaluated using the n = 13); inadequate information presented (n = 10); not related to our study topic (n = 32); conference abstract (n = 2); outdated method for SCH diagnosis (n = 1). A total of 21 studies were included in the qualitative analysis. Among these studies, 14 studies presented the mean scores of depression scales of each group or only provided the regression results without details, which hinders access to data analysis. Finally, seven studies were eligible and included in the final quantitative analysis .A flow chart of the meta-analysis is shown in The characteristics of 21 studies were presented in The quality of the literature for the analyzed studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale. Overall, the quality for each study was found to be “good” as indicated by 6-plus scores. The main drawback of these studies was that participants in some cohorts were not representative and outcome assessment was self-reported (questionnaires); however, this is typically inevitable for these types of studies. For cross-sectional studies, the common deficiency was the lack of a direct description of response rates and the completeness of data collection that could be determined. The case-control study by Yu et al.  also lact = −0.49, P = 0.647) or Begg's test , and the funnel plot showed a symmetric distribution (I2 = 75%) was detected and not diminished after a sensitivity analysis by removing a single study at a time in an iterated manner.No publication bias was found from Egger's test (ribution . ObviousP = 0.02), and the prevalence of depression in SCH participants  was slightly higher than that of the control group  (P = 0.11)  . Conside = 0.11) .This systematic review and meta-analysis demonstrated that the prevalence of depression is slightly higher in persons with SCH, especially in persons above 50 years of age, suggesting subclinical hypothyroidism might be a risk factor for depression.Previously, many studies investigated the relationship between SCH and depression; however, these studies showed conflicting conclusions. Recently, a large cohort study conducted by Kim et al. analyzed a total of 92,206 young to middle-aged adults and found no link between SCH and depression , 32, theAnother interesting phenomenon was observed in terms of age stratification. In our qualitative analysis, we found that 22% (2/9) of the included studies, which enrolled participants aged over 60 years, showed a positive correlation between depression and SCH , 22, 25;Fourteen studies were excluded in our final meta-analysis because they utilized mean depressive scores or other methodologies to present their results in the final publication, making it impossible to meta-analyze these data. Among these studies, Park et al.  enrolledAlthough some studies reported that L-T4 treatment has the benefit of improving depressive symptoms, the pathophysiological role of thyroid hormones in depression remains unclear –40. A biThis meta-analysis demonstrates that there is a higher prevalence of depression in persons with SCH, raising some suggestions for clinical practice. First, timely screening and intervention of depressive symptoms are of great importance in persons with SCH. Second, our findings strongly support the routine examination of thyroid function in participants with depression in the clinic. Third, L-T4, which is the suggested treatment for hypothyroidism, may be effective in improving depressive symptoms in participants with SCH if the association between the presence of SCH and depression will be proved. Therefore, well-conducted and large-scale random controlled trials are expected to verify the therapeutic effect on depressive symptoms by L-T4 , 42–44.To the best of our knowledge, this is the first systematic review and meta-analysis aimed to verify the association between subclinical hypothyroidism and depression. The total number of the cases and controls was sufficiently large to support our conclusions. However, several limitations should be taken into consideration. First, the age of subjects in the included studies was not restricted to a specific range. Second, the included reports were designed as observational studies  with different data collection methods (retrospective and prospective). Third, there may be possible bias due to the heterogeneity of the analyzed studies in terms of the definition of SCH and the evaluation of depression. Nonetheless, it is recommended that each laboratory should establish their own cut-off value to evaluate SCH based on the age, region, ethnic factors. Thus, the heterogeneity pertaining to the different cut-off value of TSH for the diagnosis of SCH is acceptable. In addition, SCH may result from antithyroid treatment in patients with Graves' disease. In such patients, neurological disturbances may stem from either the hyperthyroid state or the iatrogenic hypothyroidism that ensues from antithyroid treatment . Future In conclusion, our study demonstrated that depression is positively associated with SCH, suggesting that it is necessary to for clinicians to pay special attention to depression symptoms in patients with SCH. Future studies should focus on whether depression or other neuropsychological conditions could be improved by treating thyroid dysfunction and any potential mechanism.RT, JW, and LY: data analysis. XD and YZ: data extraction. JP, HY, and LM article screening. XC and ZC: paper writing and review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The malignant transformation of laryngeal papillomatosis (LP) into squamous cell carcinoma (SCC) can occur in up to 4% of LP cases. The low-risk HPV types 6 and 11 are those that are most commonly related to LP; however, high-risk HPV types may be present. The present study reviews the literature on cases of malignant transformation of LP in adults and reports a clinical case. in situ hybridization (CISH) test, both lesions showed a positive result for high-risk HPV types 16 and 18 and negative for low-risk HPV types 6 and 11. The final diagnosis was SCC arising from LP. The patient underwent surgical treatment. After 36 months of follow-up, no signs of recurrence were observed.  A 47-year-old male patient exhibiting hoarseness for 4 months presented an exophytic lesion in the right palatine tonsil and a digitiform-like lesion in the right vocal fold. The biopsy revealed a well-differentiated SCC in the vocal cord, which showed a transition zone with a squamous papillomatous lesion. By using the chromogenic  The literature review revealed 25 cases of malignant transformation into SCC of LP with adult onset. Of these, only 9 cases were assessed by CISH and/or PCR for HPV identification, of which 7 were positive. The current study focuses on the eighth case, suggesting the involvement of the high-risk HPV types in its pathogenesis.  LP is considered a benign lesion with the potential for malignant transformation, which reinforces the need for its early diagnosis and the constant monitoring of patients with LP. Papilloma is the most common benign tumor affecting the larynx, which may present as a single event or as recurring and/or affecting more than one topography, as occurs in laryngeal papillomatosis (LP) . LP is dALP is considered to be the most important clinical manifestation of human papillomavirus (HPV) larynx infection and is correlated mainly with low-risk HPV's of malignancy types 6 and 11 . The disMalignant transformation of LP is rare, having been described in about 1–4% of cases [A search for English language articles was carried out in the PubMed, Scopus, and Web of Science databases using the following keywords: malignancies in ALP and epidermoid carcinoma/squamous cell carcinoma from ALP. The search period extended from 1988 to the present, and only the reports in which the onset of the disease occurred in the adult phase were considered; cases in which malignancy occurred in patients of juvenile onset LP were discarded.A 47-year-old male patient noticed a change in his voice (hoarseness) 4 months previously. During the anamnesis, he did not report any addictions or habits, but systemic hypertension had been diagnosed and controlled. During intraoral physical examination, a pediculated exophytic lesion with a rough surface and coloration similar to adjacent mucosa was observed in the right tonsil. Examination by laryngoscopy revealed an exophytic lesion in the right paralyzed vocal fold, occupying its anterior two-thirds, in which the mucosa was covered by fibrinopurulent exudate. An incisional biopsy was performed on the vocal cord and excisional on the palatine tonsil. Microscopically, the vocal cord biopsy revealed a squamous epithelium exhibiting architectural disorganization, covered by a fibrinopurulent membrane. This epithelium exhibited projections towards the connective tissue and was infiltrated into the connective tissue, forming islands and strands of malignant epithelial cells .The squamous layer showed clear epithelial cells with a vacuolized nuclei, and some cells similar to koilocytes were present in the upper layers of the epithelium. The epithelium was found with digitiform projections and fibrovascular connective tissue centers containing mononuclear inflammatory infiltrate . A transOn the other hand, the histological sections of the right palatine tonsil region revealed a squamous papilloma demonstrated by proliferation of the stratified squamous epithelium, predominantly nonkeratinized, presenting exocytosis and basal layer hyperplasia with typical mitoses.The following procedures were carried out from the biopsy block: dewaxing, peroxidase blockade, and enzymatic digestion, followed by a pretreatment with a 95% EDTA bath for 15 min, followed by several rinses with distilled water and dehydration. After drying, the probe was added onto the material, the slices were covered by a coverslip, and sealing was performed. The material was denatured for 5 min at 75°C, and hybridization was performed at 37°C for 60 min for high-risk HPV. The ZytoFast Plus CISH Implementation Kit-HRP-DAB  was used. In the next step, the coverslip was removed, and the slides were washed in TBS buffer at 55°C for 5 min, and then, the primary antibody was incubated at 37°C for 30 min in a humid chamber. For tagging, chromogen diaminobenzidine  was used for 10 min, and Mayer's Hematoxylin was used for the counterstaining. Reactions were performed with negative and positive controls.Surgery was performed, including tracheostomy, with the final diagnosis of SCC originating from LP, staging T3N0M0. One month after the surgical procedure, the patient returned without complaints. In the other nasofibroscopy and bronchoscopy examinations, no changes were observed. Follow-up by a speech therapist was fundamental for significant voice improvement. The patient has been undergoing maintenance for 36 months and has no complaints and no signs of relapse.Fifteen articles were found, totaling 27 cases of malignant transformation of LP with onset in adult patients. The mean age of the patients was 57.03 years (SD = 13.76). Of these, including the present case, 25 (89.28%) were male patients , and in In adults, the exact mode of infection is controversial; transmission during sexual contact and reactivation of a slow-progressing latent infection acquired in childhood has been suggested . The aggGastroesophageal reflux and immunosuppression may also be aggravating factors for patients with papillomatosis , 16. In Pou et al.  reportedThe incidence of high-grade dysplasia for LP is between 10% and 17.6% –26. The Pulmonary imaging (RX or CT or PET scan) is recommended, in addition to careful histopathological examination, which should be repeated every time a surgery is performed to remove papillomatosis. There should be routine following-up of patients with LP, since there are reports of pulmonary dissemination, which develops into malignancy in a short period of time and which, if detected early, guarantees a greater survival time for the patient . Within Although LP is a benign lesion, it can present a severe course with malignant transformation, especially when high-risk HPV is detected. Therefore, the follow-up of these patients is highly recommended.


Patients with schizophrenia are often described as impaired in several cognitive domains. Specifically, patients with schizophrenia often exhibit problems in solving tasks requiring theory of mind (ToM), i.e., the ability to ascribe mental states to oneself and others, communicative-pragmatic ability, i.e., the ability to use language and non-verbal expressive means to convey meaning in a given context, and executive functions (EF). This study aims to investigate the role of cognitive functions, such as general intelligence, selective attention, processing speed, and especially EF , and ToM in explaining the performance of individual with schizophrenia in comprehending and producing communicative acts expressed with different communicative intentions , and realized through linguistic and extralinguistic/non-verbal expressive means. Thirty-two patients with schizophrenia and an equal number of healthy controls performed tasks aiming to investigate their capacity to comprehend and produce sincere, deceitful, and ironic communicative acts in addition to a series of cognitive tasks evaluating EF and ToM. The results indicated that individuals with schizophrenia performed worse than the controls in the comprehension and production of all pragmatic phenomena investigated, as well as in all the cognitive functions examined. The patients with schizophrenia also exhibited an increasing trend of difficulty in comprehending and producing sincere, deceitful, and ironic communicative acts expressed through either linguistic or extralinguistic means. Furthermore, a multiple regression analysis of the patients’ performance on the pragmatic tasks revealed that overall, the role of attention, general intelligence, and processing speed did not appear to significantly explain the patients’ communicative-pragmatic performance. The inclusion of EF into the analysis did not contribute to increase the explained variance of the patients’ ability to comprehend and produce the various pragmatic phenomena investigated. Only the addition of ToM could significantly increase the explained variance, but only in the comprehension and production of deceit expressed by language and the production of sincere communicative acts, also limited to linguistic production. We conclude that neither EF nor ToM are able to explain the decreasing trend detected in the patients’ pragmatic performance. Since shifting to switch attention among multiple tasks; updating to manipulate information in working memory (WM); and inhibition to suppress pre-potent responses  should be considered the core cognitive impairment of the disease and that such deficits are primary . EF refeesponses . This seesponses . These aesponses . Previouesponses . Pickup Impairment in communicative-pragmatic ability is another well-documented impairment associated with schizophrenia . SeveralTypically, the studies in the literature have focused on the ability of patients with schizophrenia to use language e.g., , while nFew empirical studies in the literature have systematically explored the relationship between ToM and pragmatic ability in schizophrenia; among these studies, Very few studies have investigated the role played by EF and ToM in the pragmatic performance of patients with schizophrenia to disentangle the specific effects of each specific function. Given the importance of analyzing both the comprehension and production ability and with the aim of extending the investigation to the extralinguistic expressive modality, Overall, the state of the evidence concerning the relationships between cognitive functions and ToM and comprehension and production of specific communicative acts in schizophrenia is not completely clear. ToM appears to be the factor more closely related to pragmatic difficulties of patients with schizophrenia. However, the role of ToM has varied greatly across different studies depending on the communicative phenomena investigated . In addiThe present study aims to investigate the role of cognitive functions, i.e., general intelligence, selective attention, processing speed, EF and ToM in explaining the ability of patients with schizophrenia to comprehend and produce specific types of pragmatic phenomena, i.e., sincere/literal, deceitful, and ironic communicative acts, expressed through linguistic and non-verbal/extralinguistic means. To the best of our knowledge, this study is the first to investigate the specific role that such cognitive functions play in explaining patients with schizophrenia ability to comprehend and produce communicative acts having different intentions  while simultaneously considering both linguistic and extralinguistic/non-verbal expressive means. Consistent with SD = 2.46] and 32 healthy controls  participated in the study. The experimental and control groups were matched by age, education, and gender.A group of 32 individuals with schizophrenia [7 women, 25 men; mean age = 40.17 years, standard deviation (SD) = 10.19; mean education = 10.59 years, All patients fulfilled the DSM-IV criteria for the diagnosis of schizophrenia . The indThe inclusion criteria for participation in the study were as follows: (1) native Italian speakers; (2) absence of severe cognitive or linguistic deficits as assessed by not exceeding the cut-off scores on the following neuropsychological tests: Mini-Mental State Examination MMSE; .The exclusion criteria for both the experimental and control groups were as follows: (1) evidence of current or prior neurological disorders ; (2) substance or alcohol use disorder; (3) anamnesis of major neurological or neuropsychological disease; (4) hearing or vision problems; and (5) history of head injury.We employed the linguistic and extralinguistic scales of the Assessment Battery for Communication ABaCo, , 2015.linguistic comprehension, linguistic production, extralinguistic comprehension, and extralinguistic production) includes the following experimental tasks: four sincere communicative acts, four deceitful communicative acts, and four ironic communicative acts.Each scale of the battery evaluates the comprehension and production of different communicative acts: sincere communicative acts (direct and indirect), deceit and irony. In each task, the examiner showed the participants a video-recorded scene in which two semi-professional actors engage in a communicative exchange. In the linguistic scale, the actors in the video communicated using language, and the participants were required to reply verbally to the examiner. In the extralinguistic scale, the actors in the video communicated using performative gestures without any language support, and the participants were required to reply using only communicative gestures. The scale was organized into two subscales, i.e., comprehension and production subscales, which evaluated the comprehension and production of communicative acts, respectively. In the comprehension subscale, after the video was presented, the participants were required to interpret the final statement uttered by one actor in the video. In the production subscale, after the video was presented, the participants were required to produce a communicative act in response to the final statement uttered by one actor in the scene. Each subscale (The utterances that were spoken in each scene of the battery have been controlled for the number of words (7 ± 2) to maintain constant memory and attention requirements. The battery was administered individually to each participant and video-recorded, and after administration, it was scored off-line by two independent raters who were blinded to the aims of the study. The psychometric validity of the battery in terms of construct and content validity, as also reliability, has been measured and tested with good results confirming both the validity than the reliability of the tool. For additional details, please see Regarding external validity, the battery has been designed such that the items are as ecological as possible in adults. The participants either deals with videorecorded communicative interactions set in everyday contexts or interact with the examiner in short exchanges/conversations. Even if we are unable to provide direct experimental evidence supporting the external validity of the instruments, a recent studies  support The individuals with schizophrenia and healthy controls were administered a battery of cognitive and ToM tasks to assess the cognitive functions most important for the communicative-pragmatic ability. The following cognitive functions were investigated:Basic cognitive functions:1.Attention: Attentive Matrices  with pragmatic phenomena  as the within-subject factor and group (two levels: patients vs. controls) as the between-subjects factor.t-tests for each cognitive task examined, i.e., general intelligence, selective attention, processing speed, WM, inhibitory control, planning, cognitive flexibility and ToM.To investigate the significant differences between the cognitive performances of the patients and controls, we performed a series of independent-samples To analyze the role of the cognitive factors and ToM in the pragmatic performance of the individuals with schizophrenia, we performed a hierarchical regression analysis. The relevant predictors were included in the model in three consecutive steps based on their increasing importance in determining pragmatic performance. In particular, in the first stage, we entered basic cognitive factors  considered necessary to solve any task. In the second step, EF  were entered as relevant predictors. In the third and final step, we entered ToM. We conducted regression analyses separately for each of the four subscales of the ABaCo .t-tests showed no significant differences between the experimental and control groups in age (t(62) = 0.042, p = 0.967) and education (t(62) = 0.152, p = 0.879).The independent-samples The descriptive statistics of the performance of the patients and controls in the tasks assessing the different pragmatic phenomena, i.e., sincere communicative acts, deceit and irony, evaluated by the ABaCo linguistic and extralinguistic scales are reported in F = 18.824; p < 0.001;  = 0.233), indicating that the group of individuals with schizophrenia performed significantly worse than the group of healthy controls on the linguistic comprehension subscale. The main effect of the pragmatic phenomena was also significant  = 5.131; p = 0.007; F = 7.450; p = 0.008; post hoc pairwise comparisons revealed that there were no differences between the patients and controls in the comprehension of the linguistic sincere communicative acts (p = 0.32), while significant differences were observed in the comprehension of the deceitful (p < 0.001) and ironic communicative acts (p = 0.004). See On the linguistic comprehension subscale, the ANOVA revealed a significant main effect of group  = 27.747; p < 0.001; F = 31.261; p < 0.001; F = 42.818; p < 0.001; post hoc pairwise comparisons revealed that there were differences between the patients and controls in the production of linguistic sincere (p = 0.048), deceitful (p < 0.001) and ironic (p < 0.001) communicative acts. See On the linguistic production subscale, the ANOVA showed a main effect of group  = 37.739; p < 0.001;  = 0.378). The individuals with schizophrenia obtained significantly lower scores than the healthy controls on the extralinguistic comprehension subscale. We found a main effect of the pragmatic phenomenon  = 21.714; p < 0.001; F = 37.252; p < 0.001; post hoc pairwise comparisons revealed that there were no differences between the patients and controls in the comprehension of extralinguistic sincere communicative acts (p = 0.08), while significant differences were observed in the comprehension of the extralinguistic deceitful (p < 0.001) and ironic (p < 0.001) communicative acts. See On the extralinguistic comprehension subscale, the ANOVA revealed a main effect of group  = 22.253; p < 0.001; F = 17.997; p < 0.001; F = 29.763; p < 0.001; post hoc pairwise comparisons showed that there were differences between the patients and controls in the production of extralinguistic sincere (p < 0.001), deceitful (p = 0.026), and ironic (p = 0.002) communicative acts. See On the extralinguistic production subscale, the analysis revealed a main effect of group (rony see . The post-tests: 2.142 < t(62) < 7.17;.0001 < p < 0.036).The performances of the individuals with schizophrenia and healthy controls in the different cognitive functions and ToM tasks are reported in F = 4.967; p = 0.034), for the linguistic production of sincere communicative acts  = 8.044; p = 0.008), and for the linguistic production of deceit  = 4.801; p = 0.037) , in the analysis did not significantly increase the level of the explained variance of the comprehension and production of any of the pragmatic phenomena. The inclusion of Model 3, i.e., theory of mind, significantly increased the explained variance only for the linguistic comprehension of deceit (037) see .The aim of the present research was to investigate the role that cognitive functions, such as general intelligence, selective attention, processing speed, and especially EF  and ToM, have in explaining the ability of individuals with schizophrenia to comprehend and produce communicative acts expressed with different communicative intentions  and realized through both linguistic and extralinguistic expressive means.First, we found that in all investigated tasks, the individuals with schizophrenia performed worse than the controls, except for the comprehension of linguistic and extralinguistic sincere communicative acts, which were the easiest tasks analyzed. This pattern of results in line with the relevant literature, confirming that communicative-pragmatic difficulty is a core contributor to the deficits exhibited by most patients with schizophrenia .More specifically, in line with The novelty of the present investigation was to explore the role that different cognitive components have in explaining the ability of patients with schizophrenia to comprehend and produce different types of pragmatic tasks, i.e., sincere, deceitful, and ironic communicative acts. Thus, we examined the performance of patients with schizophrenia and controls in different cognitive domains, i.e., general intelligence, selective attention, processing speed, EF  and ToM. In line with the relevant literature , we founThen, we performed a multiple regression analysis to investigate the predictive role of the cognitive factors in explaining the patients’ pragmatic performance on each specific pragmatic phenomenon, i.e., sincere, deceitful, and ironic, on each of the four subscales of the ABaCo (i) linguistic comprehension, (ii) production, (iii) extralinguistic comprehension, and (iv) production. Specifically, we first analyzed the role of basic cognitive factors  considered necessary to solve any type of pragmatic tasks. Overall, the role of attention, general intelligence and processing speed in explaining patients’ pragmatic performance was modest and did not appear to significantly explain the patients’ communicative-pragmatic performance. Then, we evaluated the role of EF  as a relevant predictor. EF can be considered a set of top–down cognitive processes that enable people to control, regulate, and monitor goal-directed behavior and other brain processes necessary to effectively adapt to the environment and achieve goals . We enteThe results showing the role of ToM in explaining the ability to deal with deceit is in line with Notably, such processes might also involve ToM abilities. This issue deserves further empirical investigation in order to be clarified.In summary, the novelty of the present study is the investigation of the specific role played by specific cognitive functions in explaining the ability of patients with schizophrenia to comprehend and produce communicative acts with different underlying intentions  while simultaneously considering both linguistic and extralinguistic/non-verbal expressive means. Our most original result is that the linear increasing trend of difficulty detected in the comprehension and production of sincere, deceitful, and ironic communicative acts expressed through both language and extralinguistic  expressive means seems to not be explained by the increasing role of a specific set of cognitive components . In line with previous investigations , we suggOur results seem to support a recent study showing that impairments in pragmatics is a core and specific deficit of patients with schizophrenia . SpecifiIn summary, the results of our study suggest that in addition to the domain usually considered in the clinical assessment of the cognitive impairment of patients with schizophrenia, the role of pragmatic and specifically the role of the (increasing) inferential processes involved in a specific pragmatic phenomenon should be considered to better comprehend the communicative difficulty that characterizes such pathology.Finally, despite the limitations, the present study has relevant implications for the assessment of cognitive abilities in patients with schizophrenia, highlighting the importance of considering patients’ pragmatic symptoms as a distinct domain of assessment with respect to other cognitive domains, such as EF and ToM. This study may also provide useful suggestions for the development of rehabilitative strategies aiming to help patients recover and enhance their communicative performance since recent studies have revealed a correlation between pragmatic ability and communicative effectiveness in daily life  and the This study was carried out in accordance with the recommendations of ‘A.S.L. To2 ethics committee’ with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the ‘A.S.L. To2 ethics committee.’FB experimental design and paper writing. LB contact with patients. AP statistical analyses and administration of experimental material.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BB declared a shared affiliation, with no collaboration, with several of the authors, FB and AP, to the handling Editor at the time of review.


To determine whether there are changes in sexuality after breast cancer, to better understand the sexual function of women with breast cancer, and to investigate the potential relationship between sexual dysfunction and socio-demographic and clinical variables.A cross-sectional study. This study included 514 women with breast cancer between 21- and 66-years-old. The cases were gathered between June 2016 and January 2017. The instruments used were the questionnaire on Women’s Sexual Function and a questionnaire to collect socio-demographic and clinical data.The average age  of participants was 46.34 ± 8.28 years. Their average age at date of diagnosis was 42.26 ± 8.56 years, and the average time suffering from cancer was 4.05 ± 5.23 years. There were significant differences (p = 0.002) in the presence of sexual dysfunction before (32.1%) and after (91.2%) cancer. The primary sexual dysfunctions were due to penetration pain (50.6%), lubrication (50.6%), dysfunctional desire (44.6%), and dysfunctional excitement (44.6%). Two-thirds of participants were satisfied with their sexual relations. The women who presented most sexual dysfunction were those that had a bilateral mastectomy (p = 0.009) and those who received chemotherapy, radiotherapy and hormonal-therapy (p < 0.001).Sexual function was changed in women with breast cancer. The main problems included penetration pain, desire, lubrication, and dysfunctional excitement. It is important that Health professionals recognize which circumstances influence the sexual function of women with breast cancer and to make interventions that facilitate sexual adjustment. Breast cancer is the second most common cancer worldwide. In 2012, the estimated number of new cases was 1.67 million . In Western Europe, there are 96 per 100,000 women with breast cancer [According to the Spanish Society for Medical Oncology , the canThe Spanish healthcare system is public with universal access. This system includes programs for the prevention, screening, and treatment of breast cancer . FurtherBreast cancer treatment affects women’s sexual function. These treatments, which include hormonal therapy, chemotherapy, and surgical treatment, can produce vaginal dryness, vasomotor symptoms, and loss of sexual satisfaction, loss of desire, and changes in self-image ,6,7. StuIn Spain, no recent studies have addressed sexual dysfunction in women with breast cancer. Sexual function depends on several biological, psychological, and sociocultural factors. Here we investigate sexuality in women with breast cancer in Spain.The aims of this study were: to determine if there are changes in the sexuality of women after breast cancer; to understand the sexual function of women with breast cancer in Spain; and to describe the relationship between socio-demographic and clinical variables with sexual dysfunction.This is a cross-sectional study carried out from June 2016 to January 2017. The population of the study consisted of 514 women with breast cancer who belonged to FECMA. Inclusion criteria: women with breast cancer, 18-years-old or older, and completed chemotherapy, radiotherapy or surgical intervention at least 3 months before the present study. Exclusion criteria: women with other cancers, metastases, and terminal conditions.The sample size was determined using Granmo software . This was calculated using a population estimate based on the study carried out by Panjari et al. (2011) , in whicQuestionnaire on Women's Sexual Function (WSF) of Sánchez et al. (2004) [An online questionnaire was used to collect the different socio-demographic and clinical variables. This online questionnaire also included the . (2004) . This sc. (2004) .To determine whether the women had any sexual problem before cancer, the online survey had two questions: 1) “Before suffering cancer, have you had any sexual problem?”; 2) If your answer is “YES”, could you specify what type of sexual problem you have had?”Age (quantitative), level of education , profession , civil status , type of surgical intervention , breast reconstruction , adjuvant treatment , sexual dysfunction before breast cancer , age of women at date of diagnosis (quantitative), and time elapsed after diagnosis (quantitative).Desire, excitation or arousal, lubrication, orgasm, penetration pain, anticipatory anxiety, sexual initiative, communication and sexual satisfaction .Before the study, the FECMA directors were contacted and invited to participate in the study. They sent to their members an email with information about the study. The email included a direct access link to fulfill the online questionnaire available on Google Forms. When clicking on the link, the participants had to read the information sheet and provide informed consent to proceed with the questionnaire. The application respected the participant’s anonymity.th of December, on the Protection of Personal Data. The study was approved by FECMA. The participants were provided with an information sheet and gave informed consent. We respected the participants’ anonymity at all times. The Ethical Committee authorized this study (CEITO N° Exp 138).This study conformed to the main principles of the Helsinki Declaration, the Universal Declaration of the UNESCO, and the Spanish Organic Law 15/1999, 13The statistics program IBM SPSS  was used for statistical analysis. A descriptive analysis of the variables was performed by counting of recounts (n) and proportions (%) of the qualitative variables and by the average (m) and the standard deviation (SD) of quantitative variables.Also, a proportional comparison of categorical variables through chi-square tests for contingency tables was provided. The variables, which were significates with sexual dysfunction in the contingency tables, were included in the regression model. A multiple logistic regression was performed to identify possible factors related to sexual dysfunction after suffering from breast cancer. We used the Wald statistic, such that the variables for which p ≥ 0.15 were eliminated one-by-one from the model. The odds ratios (OR) was calculated with their confidence intervals. All hypotheses were bilateral, and the level of confidence was 95% (p < 0.05).Five-hundred-twenty-seven women responded to the questionnaire, 13 of these completed the test incorrectly or incompletely. Finally, 514 women with breast cancer composed the size. The study participants were aged between 21- and 66-years-old (mean 46.34 ± 8.276 years), an average age at the date of diagnosis of 42.26 ± 8.563 years, and time suffering cancer of 4.05 ± 5.226 years. Regarding sexual activity , the majThe relationship between socio-demographic and clinical variables and the different types of sexual dysfunction in participants after cancer were studied . We founUsing the significant variables, we created a multiple logistic regression model to understand whether the variables affected every type of sexual dysfunction Tables  and 5. IAfter analyzing the data related to the type of sexual dysfunction , we obseSexual dysfunction related to desire is associated with the age of women at date of diagnosis, the type of surgical intervention , breast reconstruction (women who did not receive breast reconstruction had a 1.84-fold greater probability than those who did) and cohabitation (women with a partner but who are not living together had a 0.54-fold reduction in probability compared to women living with a partner).Sexual dysfunction related to excitation is associated with the age of women at date of diagnosis, the type of surgical intervention , cohabitation (women with a partner but who are not living together have a 0.45-fold reduction in probability compared to women living with a partner) and profession (women who work have a 0.48-fold reduction in probability than those who are retired).Sexual dysfunction related to lubrication is associated with the age of women at date of diagnosis, the time elapsed after cancer diagnosis, the type of surgical intervention , cohabitation (women with a partner but who are not living together have a 0.51-fold reduction in probability compared to women living with a partner), and hormonal therapy .Sexual dysfunction related to orgasm is associated with the age of women at date of diagnosis, the type of surgical intervention , breast reconstruction (women who have not received a breast reconstruction have a 2.57-fold greater probability than those who had), and cohabitation (women with a partner but who are not living together have a 1.79-fold increased probability compared to women living with a partner).Sexual dysfunction related to penetration is associated with the age of women at date of diagnosis, the time elapsed after cancer diagnosis, cohabitation (women with a partner but who are not living together have a 2.55-fold reduction in probability compared to women living with a partner), and hormonal therapy .Anticipatory sexual anxiety is associated with the time elapsed after cancer diagnosis, cohabitation (women with partner but who are not living together have a 2.01-fold reduction in probability compared to women living with a partner), occupation (women who work have a 2.10-fold increase in probability than those who have retired), and hormonal therapy .According to other studies , 11, 12,After cancer, the majority of women in this study (70.2%) confirmed that they continued to have sexual activity, with is consistent with the literature , 15, 16.The main sexuality problems are decreased sexual desire , 18, 19,Regarding the treatment and presence of sexual dysfunction, participants who had received chemotherapy presented more sexual problems that those who were not treated with chemotherapy , 21, 22.In our study, the majority of women were treated with hormonal therapy (75.7%) , which led to early menopause. As found in other studies, the use of these drugs is related to reduced vaginal lubrication, decreased sexual satisfaction, and loss of sexual desire , 24, 25.The type of surgical intervention is associated with the presence of sexual dysfunction. Women with lumpectomy present fewer dysfunctions that those who have a unilateral mastectomy or a bilateral mastectomy , 26, 27.Women who were old at the age of diagnosis reported that they had more sexual problems , 30. HowCivil status is associated with the presence of several sexual dysfunctions. Women without a partner do not have problems related to orgasm and penetration. Another finding is that women who have a steady partner but do not cohabitate have fewer problems related to desire, excitement, and lubrication compared to married women or couples living together. Although we found no study similar to ours, Morais et al.  reportedThe study has some limitations. First, a cross-sectional design was used, so it is not possible to establish causal relationships. Second, a convenience sample was used. Finally, the online questionnaire prevents women from asking about any doubts they might have, and the analyzed data are self-reported information. However, on the other hand, the online questionnaire has the strength that the women can provide detailed answers about their sexuality more freely and without shame, which is not always possible in a face-to-face interview.Furthermore, although the sample was recruited for convenience, it has a large size (more than 500 women). Also, we believe that the women can adequately respond to questions addressing their clinical situation. This is because, in Spain, the Health System is public and the physicians are obligated to give to their patients  a report that includes specific information about their type of cancer, type of surgery, and type of treatment.Our findings highlight the impact of breast cancer treatments on female sexuality and the impact in women with breast cancer.Based on our findings, it is necessary that health professionals recognize which variables influence sexual function in women with breast cancer. A multidisciplinary team should plan interventions to facilitate sexual adjustment.Furthermore, women with breast cancer are capable of choosing whether to be sexually active or not. It is the duty of health professionals to guarantee that women with breast cancer and their partners receive accurate information about sexuality, treatment, and emotional support .Sexual function changes after breast cancer. Ninety percent of cases suffer from some type of sexual dysfunction. The most frequent problems are dysfunction due to penetration pain, lubrication, desire, and excitation. The type of surgical intervention, hormonal therapy, age, and civil status are associated with the presence of sexual dysfunction.S1 File(SAV)Click here for additional data file.S2 File(DOCX)Click here for additional data file.