Cerebral Palsy (CP) describes a heterogenous group of non-progressive disorders of posture or movement, causing activity limitation, due to a lesion in the developing brain. CP is an umbrella term for a heterogenous condition and is, therefore, descriptive rather than a diagnosis. Each case requires detailed consideration of etiology. Our understanding of the underlying cause of CP has developed significantly, with areas such as inflammation, epigenetics and genetic susceptibility to subsequent insults providing new insights. Alongside this, there has been increasing recognition of the multi-organ dysfunction (MOD) associated with CP, in particular in children with higher levels of motor impairment. Therefore, CP should not be seen as an unchanging disorder caused by a solitary insult but rather, as a condition which evolves over time. Assessment of multi-organ function may help to prevent complications in later childhood or adulthood. It may also contribute to an improved understanding of the etiology and thus may have an implication in prevention, interventional methods and therapies. MOD in CP has not yet been quantified and a scoring system may prove useful in allowing advanced clinical planning and follow-up of children with CP. Additionally, several biomarkers hold promise in assisting with long-term monitoring. Clinicians should be aware of the multi-system complications that are associated with CP and which may present significant diagnostic challenges given that many children with CP communicate non-verbally. A step-wise, logical, multi-system approach is required to ensure that the best care is provided to these children. This review summarizes multi-organ dysfunction in children with CP whilst highlighting emerging research and gaps in our knowledge. We identify some potential organ-specific biomarkers which may prove useful in developing guidelines for follow-up and management of these children throughout their lifespan. Cerebral palsy (CP) describes a heterogenous group of non-progressive disorders of posture or movement, causing activity limitation, due to a lesion in the developing brain . The worThere are many recognized risk factors for cerebral palsy, including preterm birth, multiple gestation, congenital malformation, genetic and metabolic abnormalities, intra-uterine exposure to infection or inflammation, birth asphyxia, perinatal stroke and thrombophilia . CP has Life-expectancy is reduced in children with CP, based on retrospective data collected between 1983 and 2010 in California , 8. RespWhile CP is heterogenous condition with a wide range of etiologies and subtypes it is acknowledged that functional level is a strong predictor of morbidity and mortality. Greater degrees of motor impairment are associated with a larger proportion of accompanying impairments , 10. MorWe aimed to summarize multi-organ dysfunction in children with CP whilst highlighting emerging research and gaps in our knowledge. We identify some potential organ-specific biomarkers which may prove useful for research purposes or for developing guidelines for follow-up and management of these children throughout their lifespan .Cerebral palsy, by definition, is attributable to a lesion in the developing brain . PerivenCerebral Palsy is the most common cause of motor disability in children . StudiesThe overall prevalence of epilepsy in children with cerebral palsy was found to be 38%, although this varies significantly depending on CP subtypes, etiology and cognitive function . PrevaleHypertonia is a significant issue for many children with CP, leading to impaired motor function, pain and difficulties with daily care. Hypertonia may manifest primarily as spasticity, dystonia or less commonly rigidity, alone or in combination . SpasticThe incidence of hearing impairment in children with CP is reported to be between 7 to 37.5%  with theChildren with cerebral palsy can be diagnosed with visual impairments that are ocular or cerebral in origin or combination of both . CorticaDisorders of the respiratory system are a significant cause of morbidity  and are Reasons for the high rate of respiratory morbidity are complex, multifactorial and several factors, such as seizures, oromotor dysfunction, gastro-esophageal reflux and scoliosis, may coexist within the same individual , 81. ImpSwallowing is inextricably linked with respiratory dysfunction. It is a complex process involving the brainstem, multiple overlapping cortical areas, sensory input from the oropharynx and a high level of coordination between the central and enteric nervous systems . Chewingn = 53, 90% with GMFCS ≥3) ventilated in the pediatric intensive care unit for 4 or more days carried abnormal bacteria flora, with Pseudomonas and Klebsiella being the most frequent. In children without CP (n = 257) the carriage rates of abnormal bacteria were 55% with 10% resistant bacteria. Almost half of these were resistant bacteria and the mortality rate was significantly higher amongst the group with CP compared those without CP (17 vs. 10%) (n = 30), 93% had bronchiectasis (Lower respiratory tract infections (LRTI) in general are more common in children with CP and they have more severe disease requiring admission to the intensive care unit . Thorburvs. 10%) . Bronchivs. 10%) . Similariectasis .n = 46) vs. without NI (n = 42) showed a reduction in the proportion of children with NI who had more than 4 respiratory infections per year from 33% pre-operatively to 8, 18, and 10% at 1, 2, and 3 year postoperative, respectively  recommends the use of mucolytics, such as nebulised saline, to assist clearance of “tenacious secretions” in children with neuromuscular weakness . PhysicaThe prevalence of sleep disorders among children with CP is up to 36%, although this varies within subgroups, according to CP phenotype  , 106 andn = 505, 216 had CP) which used parental questionnaires to evaluate sleep problems, 25% of children with CP had difficulties relaxing at night  , 115, PeCLOCK) genes are rhythmically expressed in the pineal gland which secretes melatonin and is crucial for regulation of the sleep-wake cycle  showed benefits in reducing symptoms of OSA as well as improvements in behavioral, quality of life and polysomnographic measures (p = 0.002) following tonsillectomy, leading the authors to conclude that adenotonsillectomy remained the mainstay of treatment for OSA in these children.Sleep-disordered breathing is more common in children with CP than in their typically-developing peers , 23, 131measures . SurgerySleep disorders can be difficult to diagnose in this population but can have a significant effect on the lives of children with CP and their families. It is important to be mindful of sleep issues and consideration should be given to regular screening for these disorders in children with CP.A cohort study which included 958 adults with CP reported that they had a 3-fold increase in disorders of the circulatory system . In a lin = 100), demonstrated increased CIMT when compared to controls (n = 35), suggesting that children with CP are at increased risk of atherosclerosis and coronary artery disease  reflects autonomic control of the sinus node. Significant reductions in HRV have been found between children with CP and controls. Within children with CP, HRV significantly decreases with poorer motor function as measured by GMFCS –145. Thin = 79) when combined with poor repertoire abnormal general movements (PR GMs) using Prechtl's assessment method  there were no differences between the subgroups to explain this subclinical dysfunction and suggest that there may be unknown factors involved. Krishnamoorthy et al. prospectively assessed myocardial dysfunction in patients with moderate to severe traumatic brain injury using speckle tracking echocardiography and compared them with age and sex-matched controls (n = 30)  . They ha(n = 30) .Although it is known that there is acute myocardial dysfunction at the time of the initial insult in some children who develop CP, the long term myocardial function of these patients is not known. Traditional markers of cardiac function such as ejection fraction/shortening fraction are too crude to recognize potential subtle signs of myocardial dysfunction and are unable to detect regional wall dysfunction. With the advancement of echocardiography, newer forms of assessing myocardial function are readily available such as deformation imaging using speckle tracking, tissue doppler, tricuspid annular plane systolic excursion, mitral annular plane systolic excursion and fractional area change. These more sophisticated echocardiography techniques may be able to detect early cardiac dysfunction helping to guide management of these complex patients.n = 54) showed that Troponin T is elevated in those with abnormal MRI findings and that Troponin T correlates with developmental outcomes at 2 years of age  have been shown to be useful markers of cardiac dysfunction in other populations, such as term neonates with perinatal asphyxia, children with chronic kidney disease and children with leukemia –159. A ps of age . Furthern = 27) in the following categories: spastic diplegia (n = 10), spastic quadriplegia (n = 7), spastic hemiplegia (n = 5), dystonic quadriplegia (n = 3), dystonic diplegia (n = 1), spastic monoplegia (n = 1) and intellectual disability (n = 15)  . The com(n = 15) . Disorde(n = 15) –169. Gre(n = 15) . GMFCS a(n = 15) , 171 alt(n = 15) . Reid et(n = 15) .n = 49, mean age = 31 years, 55% male, 98% GMFCS III-V), thus emphasizing the need for ongoing monitoring of people with CP and urinary tract symptoms  had a greater incidence rate of CKD than adults without neurodevelopmental disabilities (n = 6.5 million). This increased risk was maintained even when adjusted for demographics, diabetes, hypertension and cardiovascular disease. Adults with neurodevelopmental disabilities, throughout all subgroups, were also more likely to have advanced CKD. The incidence rate ratio of advanced CKD for those with CP compared to adults without NDDs was 1.83 (95% CI = 1.61–2.07)  . This hiOne of the most widely used methods of monitoring renal function is to measure serum creatinine but it does not rise until there is significant renal dysfunction. In addition, children with non-ambulatory CP have been shown to have lower serum creatinine concentrations at baseline . This liNovel biomarkers such as Neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, Interleukin-6 (IL-6) and Fibroblast Growth Factor (FGF-23) can improve the early diagnosis of AKI and CKD –197, preThere is a high prevalence of gastrointestinal disorders in children with cerebral palsy including dysphagia, gastroesophageal reflux disease (GORD) and chronic constipation . DysphagThe issue of drooling is inextricably linked with dysphagia and GORD and is defined as “the unintentional loss of saliva and contents from the mouth” . It occun = 9)  .A multidisciplinary approach to the management of drooling is advisable , 210. ThThe two main medical treatments are anti-cholinergic agents and intraglandular botulinum toxin injections to the submandibular and/or parotid glands. The anti-cholinergic drugs most commonly used are atropine, benztropine, glycopyrrolate bromide and scopolamine. Pharmacological interventions cannot selectively block stimulation of the salivary glands and as a result unwanted side effects can occur for example, constipation, blurred vision behavior disturbance, urinary retention and thickening of secretions .Botulinum Toxin Injections into the submandibular glands and/or parotid glands under ultrasound guidance is often used if there is an inadequate response to the anticholinergic drugs. The main drawback is that they are only effective for about 6 months, need to be repeated and responsiveness can diminish over time. Parents should be advised of the potential for adverse effects such as xerostomia and dysphagia . There iSurgery is usually reserved for children that have failed all the less invasive treatments discussed. Submandibular or parotid duct ligation as well as submandibular gland excision are not without significant complications, although rare. For example, salivary stones, scarring, facial and hypoglossal nerve damage , 213 cann = 58), of whom 90% were subsequently proven to have GORD by pH monitoring and endoscopic evidence of oesophagitis (n = 18), significantly prolonged gastric emptying and abnormal esophageal motility was demonstrated on manometry (p < 0.01), suggesting that GI motility dysfunction contributes to GOR and oesophagitis in this group  have published guidelines on the treatment of GORD, based on the available evidence . Lifestyn = 14) where children with CP and malnourishment completed a 6 month nutritional rehabilitation programme, 64% had an improvements in their “Gross Motor Function Measure” scores , 67.1% had acute pain and 31.4% had chronic pain with risk factors including dyskinesia, bilateral involvement and GMFCS IV-V (n = 22 and n = 42), gabapentinoids have been shown to reduce pain behaviors (Children with NI are at significant risk of acute and chronic pain with the abdomen accounting for a significant proportion (11–32%) of these symptoms , 37. In FCS IV-V  and, of FCS IV-V . AbdominFCS IV-V , 225. ThFCS IV-V . This meFCS IV-V . In two ehaviors , 228. PrGut and intestinal failure is increasingly being recognized in children with neurodisabling conditions . This isThere is evidence to suggest that cerebral infarction secondary to pre or perinatal cerebral occlusion occurs in 13-37% children with hemiplegic CP and the infarction may occur due to a thrombophilia , 41, 230The coagulation and inflammatory systems overlap and interact. Activated coagulation factors are proinflammatory and in turn inflammation can promote coagulation . Elevaten = 34) and found that children with CP have significantly more bleeding and that bleeding occurs earlier in the course of surgery (n = 25) and found reduced factor VII activity  and activated partial thromboplastin times (APTT) which are within the normal ranges but which are significantly longer than controls . They al surgery . Kannan activity . Childreactivity , 240, caactivity , and aziactivity . Therefoactivity .n = 108, age 8–29 years) with cerebral palsy, iron-deficiency was reported in 38% and anemia was found in 33.3% of participants. Both iron-deficiency and anemia were significantly increased in those who had liquid diets compared to normal diets  (n = 30) iron-deficiency anemia was found in 4 (13.3%) children with neuromotor disabilities  . In anotbilities . In compbilities , 249. Thbilities . In chilbilities . FurtherNE accounts for around 24% of all cases of CP in term infants . InfantsPerinatal inflammation is also associated with many neuropsychiatric and neuro-psychological disorders and it is suggested that inflammation has long term consequences on the brain during childhood . ChildreInfections are a significant contributor to childhood death, particularly in those with underlying conditions. CP was the most common underlying condition associated with death due to infection in the 1–4 year age category . Pneumonp = 0.13), operation-related infections , pneumonia , and urinary tract infection   found that 19.2% were overdue at least one vaccine   .n = 412) (n = 1143) were already vaccinated or their parents planned for vaccination against influenza  . This sunfluenza  and progn = 1,665) shows a higher risk of invasive pneumococcal disease amongst children with several chronic conditions. The adjusted risk ratio for children with a neurological disorder compared with children without such a disorder was 3.0   . There mRecent research has shown that inflammatory responses in children with CP are altered. Further research may help to clarify the role of inflammation as a tertiary cause of neurological injury with the potential to develop therapeutic targets. There may also be a significant impact on immune function and further work is needed to optimize vaccination programs for children with CP and improve infection-associated morbidity and mortality.Inborn errors of metabolism (IEM) can present with CP like symptoms. A systematic review by Leach et al. identified almost 70 IEMs belonging to 13 different biochemical categories, that closely mimic cerebral palsy (CP). While these only account for 0.1–0.2% of CP cases, early diagnosis is essential to prevent organ damage . MetabolIndividualized investigations for IEMs can be planned according to the individual clinical picture i.e., history, examination and any neuroimaging. These investigations may include plasma, urine or cerebrospinal amino acids, a plasma acylcarnitine profile and urine organic acids, mucopolysaccharides, and oligosaccharides , 266. TaMitochondrial disorders are neurometabolic diseases which can also present with CP like symptoms , 262. ThIt is important to be mindful of potential metabolic diagnoses when seeing children with CP as they can have significant implications, the most significant of which is to prevent deterioration and improve clinical outcomes.KCNC3, KANK1, AP4MI, GAD1, and ADD3 with different mutations linked to the development of different subtypes of CP . A genetic component to cerebral palsy may prompt the clinician to be particularly vigilant for specific multi-organ abnormalities. Several non-metabolic single gene disorders can present as CP. Many single gene mutations linked with CP have been identified using whole exome sequencing, including mutations in es of CP , 270–272es of CP  and hetesability . Each ofIt is clear there is no single “CP gene” but there is increasing recognition of a genetic element to CP in a large number of cases. Despite improvements in obstetric, prenatal and perinatal care, there has been little change in the incidence of CP in term neonates, which may be due to an underlying genetic pathophysiology , 273. InDe novo and inherited genetic variants may account for up to 30% of CP cases and have been postulated to, in some cases, directly cause CP, while in others merely contribute to CP susceptibility (n = 443) found that polymorphisms in Toll Like Receptor-4 (TLR-4) reduced the risk of developing CP, while polymorphisms in IL-6 and IL-8 may increase susceptibility to CP in the presence of viral exposure   . In the The vast genetic heterogeneity underlying CP emphasizes the complexity of the contribution of genetics to the etiology and development of CP and points toward a multifactorial etiology of CP with interaction between genetics and the environment , 282. WhAll children with disability are at risk for some form of endocrine dysfunction due to the disruption of endocrine feedback secondary to abnormalities in muscle, bone or brain mechanisms. Regular assessment from an endocrine perspective should be considered with the emphasis on growth, pubertal status and bone health. Knowing the underlying etiology of cerebral palsy can focus endocrine evaluation but is not essential.All children with cerebral palsy should have formal measurement of body proportions at least twice per year to guide nutrition and to identify growth anomalies. Assessing length or height in proportion to weight is important to ascertain whether short stature is due to nutritional deficiency or a hormone imbalance. Nutritional deficiency is more likely to result in delayed puberty. Exogenous obesity can drive growth in childhood but following puberty can result in obesity in an immobile child causing long term implications for respiratory function and sleep apnoea. Children with midline defects will have hypothalamic pituitary axis dysfunction which can result in growth hormone deficiency impacting on tone, mood and glycaemic control as well as stature. Studies have indicated that circulating GH secretion profiles are lower in children with cerebral palsy compared to controls , 283. HyCP is the most common childhood condition associated with osteoporosis, and children with CP frequently sustain fractures with minor trauma . Any chiPuberty also plays a role in the development of bone health. Clinical assessment of puberty with Tanner staging is therefore recommended . Mean agScoliosis and hip dislocation are common problems in children with CP. The overall incidence of scoliosis in CP of 20–25% , with a Hip dislocation develops in 15–20% of cases . There iBoth of the aforementioned orthopedic complications of CP may be linked. Hip dislocation or windswept deformity of the hip many cause pelvic obliquity and trigger scoliosis, while scoliosis itself can lead to pelvic obliquity and thus increase the risk of hip dislocation especially on the high side . Early in = 771). These contractures began at preschool age and the best predictor was high scores on the Manual Ability Classification System (The upper limb may also develop significant complications in CP. Upper limb contractures developed in 34% of a population-based sample of children with CP (n System . The levMulti-organ dysfunction in cerebral palsy to date has not been quantified. Better insight into multi organ dysfunction in children with CP may be gained by using novel biomarkers and new diagnostic tools. In this review, we focused on various long-term issues associated with each organ system and have identified parameters and novel biomarkers for monitoring MOD. In the future, with further study, biomarkers including serum and urinary NGAL, cystatin C and IL-6 show good ability to predict AKI and may be useful in long-term follow up. Cardiology assessment including measurement of serum troponin, pro-NT-BNP, echocardiography using tissue doppler and speckle-tracking may be used to monitor cardiovascular function in children with CP. The use of these biomarkers may initially prove most useful to the research community in providing new insights in to subtle organ dysfunction. However, this may lead to discovery of new therapeutic targets and improved outcomes. There is also the possibility that these biomarkers will become the norm in clinical care if there are clinically-relevant long-term consequences noted in those areas.Throughout this article, where possible, we have attempted to comment on the impact of dysfunction in each of the organ systems involved. For example, pain is one of the most significant consequences of dysfunction in the gastrointestinal system. It is also an example of the complex interactions between the neurological and non-neurological systems which may receive further attention by considering CP as a multi-system disorder with multi-organ dysfunction. However, in many cases, the answer to that question has not been adequately addressed in the literature. We hope that this article highlights some of those gaps and provokes further research into outcomes in the less well-studied organ systems of children with CP.An example of an area where further research and exploration of consequences is required is the immune system. Children with CP have altered immune function compared to age-matched controls. Understanding the immune response in these children with CP and exploring systemic inflammation holds promise for future development of immunomodulatory adjunctive therapies. Further research in this area can contribute to better prediction of outcome and improved prognosis.We believe that a MOD scoring system would prove useful, perhaps especially in the research context as a way to correlate with other health related outcomes. It may also prove useful in allowing advanced clinical planning, discussions around prognosis and follow-up of children with CP throughout the lifespan. CP registries are now in existence throughout the world. The information provided by these registries, as well as the expert collaboration that they promote, in conjunction with a MOD scoring system, might allow for the production of tailored guidelines for follow-up and management of MOD in children with CP. We suggest that follow up of multi-organ function is important to identify and pre-emptively manage potential long-term complications in CP.Another issue which may be raised, if one considers CP as a multi-system disorder, is the definition of CP. The definition developed by Rosenbaum et al.  which waThis review highlights the need for an awareness amongst healthcare professionals of the multi-systemic complications that are associated with CP, particularly in those with greater levels of impairment. That many of these children communicate non-verbally compounds the difficulties that the physician faces in understanding the source of many of their symptoms. The cause of symptoms such as pain, behavioral or sleep disturbance may be multi-factorial and present substantial diagnostic challenges. A step-wise, logical, multi-system approach, with support from a multi-disciplinary team, is required to ensure that the best care is provided to these children and their families.JA contributed to the conception and design, acquisition, analysis and interpretation of data, drafted the first and subsequent drafts of the work, revised it critically, and approved the final version of the manuscript. ZZ, SD, LW, and ZA contributed to the conception and design, acquisition, analysis and interpretation of data, drafting the work and revising it critically, and approved the final version of the manuscript. MS, OF, AG, AJ, TL, SQ, BE, JR, SP, PK, ER, CM, LB, OH, LG, and SK contributed to the analysis and interpretation of data, revising the work critically, and approved the final version of the manuscript. DM and EM contributed to the conception and design, analysis and interpretation of data, drafting the work and revising it critically, and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We aimed at characterization of the patients undergoing radical cystectomy (RC) using the prognostic model (a modified pentafecta). In the multicenter retrospective study, we enrolled 304 patients with bladder cancer (pTis-4N0-2M0) who underwent RC between 2015 and 2020 in experienced centers. The definition of the pentafecta was as follows: no Clavien–Dindo grade III–V complications at 90 days and no long-term complications related to urinary diversion <12 months, negative surgical margins, ≥10 lymph nodes (LNs) resected, and no recurrence ≤12 months. RC-pentafecta achievement rate was 22% (n = 67), varying from 47% to 88% attainment rate for different pentafecta components, and was the lowest for sufficient LN yield. Both 12-month recurrence-free survival (RFS) and cancer-specific mortality were compromised in pentafecta failers compared with achievers . The following were identified as crucial predictors of RC pentafecta achievement: modality of the surgery, type of urinary diversion, histological type of bladder cancer, advanced staging, and elevated preoperative serum creatinine. In conclusion, we found that the pentafecta achievement rate was low even in high-volume centers in patients undergoing cystectomy. The complexity of the procedure directly influenced the attainment rate, which in turn led to an increase in cancer-specific mortality rate among the pentafecta failers. The worldwide results of the treatment of muscle-invasive bladder cancer (MIBC) bring the image of suboptimal management of the disease with 50% of patients undergoing radical cystectomy (RC) not surviving 5 years . The majPredominantly, RC is performed in elderly patients with advanced cancer burden . AccordiThere were standardized outcome criteria proposed for reporting purposes, i.e., trifecta and/or pentafecta for partial nephrectomy and radical prostatectomy, which focused on both the quality of cancer management and the assessment of surgical complications , 19. It Here, we reintroduced the idea of the assessment model to be used for the quality analysis of RC. We aimed at characterization of the patients’ population undergoing RC, with particular emphasis on perioperative complications and the effectiveness of oncological treatment along with survival data, using the prognostic model that was constructed from clinical and histopathological variables (a modified pentafecta assessment). The tool was then used to evaluate the quality of RC treatment based on the attainment of the aforementioned pentafecta. Thus, the primary endpoint was to analyze the RC pentafecta in the present cohort, while the second was to determine the influence of attaining pentafecta on oncological outcomes and to define the risk factors compromising the pentafecta achievement.In the present retrospective study, five oncological centers with established experience meet the abovementioned criteria , including three high-volume centers (over 30 cystectomies yearly) . The anaThe following data were collected: gender, age, American Association of Anesthesiology (ASA) score, body mass index (BMI) score, smoking status, neoadjuvant systemic treatment, pre- and postoperative disease staging using the TNM scale based on imaging studies and pathological reports , duratioFirstly, Aziz et al. developed an RC-pentafecta idea based on expert opinions . Cacciam- no Clavien–Dindo grade III–V complications at 90 days and no long-term complications related to UD < 12 months- negative surgical margins  in post-cystectomy pathological report, ≥10 LN removal during the procedure, and no clinical relapse of bladder cancer ≤12 months after RC found in the follow-up CT. Based on other authors’ observations, we included the threshold of 10 LNs in further analyses –26.The following definitions were incorporated for the purpose of the present analyses: early complications, occurring within 90 days post cystectomy; late complications, occurring over 90 days but no more than 12 months after cystectomy; and LOH, all the periods of hospital stay . OverallAll patients signed an informed consent form, and the study was conducted under the ethics committee vote AKBE/133/2021 of the Medical University of Warsaw.All statistical analyses were performed in SAS software version 9.4. Results are presented in respective tables as the number of patients and percentage for categorical variables and medians, accompanied by the interquartile range (IQR) for continuous variables. Fisher’s test or chi-square test for categorized variables and Mann–Whitney U test for continuous variables were used to determine the differences between groups. The differences in the time to death were analyzed using the Kaplan–Meier method and log-rank test. In univariable analyses, logistic regression was utilized to identify factors associated with respective outcomes . Relevant factors from univariate analyses were used for further multivariable analysis. Odds ratio (OR) supplemented with 95% CI were derived from logistic regression. For all statistical analyses, we considered a two-sided p-value <0.05 as statistically significant.Three hundred four patients who underwent RC were included in the study. Standard neoadjuvant chemotherapy (NAC) was implemented in 76 cases (25%). The median age of the patients in the studied cohort was 68 years, and most patients were male (75%). Over 81% of patients were treated with cystectomy because of MIBC (cT2–T4), and in the vast majority of cases, the final pathological results proved the urothelial histology of cancer. Median postoperative follow-up was 18.5 months (IQR 11.6–33 months). Baseline characteristics of the cohort and subgroups stratified according to the RC-pentafecta achievement are presented in RC-pentafecta achievement rate was 22%. The following components included in the RC-pentafecta assessment were achieved in the lowest percentage: 12-month recurrence-free survival (RFS) of 64.8%, and ≥10 LNs in the RC specimen of 47% Table 2.Patients, who attained pentafecta, less frequently underwent open vs. laparoscopic surgery (54% vs. 94%) and more frequently received ileal conduit (64% vs. 38%) or orthotopic neobladder (9% vs. 0.8%), or UD, when compared with patients who did not attain pentafecta. In general, readmissions were more frequent in pentafecta failers (40.5% vs. 21%), but no significant difference was observed for early rehospitalizations 90 days) (25% vs. 18%). For details regarding the surgery and perioperative complications, please refer to In patients who did not attain RC-pentafecta, the pathological T staging of bladder cancer was more advanced (more often pT3–T4 tumors), the nodal staging was greater, and non-pure urothelial histological type of cancer was found more frequently. The preoperative staging regarding the LN assessment differed between groups of RC-pentafecta achievers and failures. Only 60% of pentafecta failures had cN0 compared with 85% of achievers (p < 0.0001) Table 1.Differences in survival between the abovementioned groups were demonstrated using the Kaplan–Meier curves Figure 1The following factors were identified as crucial predictors of RC pentafecta achievement: modality of the surgery, type of UD, pure urothelial histology of bladder cancer, advanced staging (pT3–T4), and elevated preoperative serum creatinine >1 mg/dl. For detailed univariate and multivariate analyses, please see In multivariate analysis, factors associated independently with cancer recurrence and major complications after RC were identified and shown in There is a growing need to develop and validate an adequate perioperative risk calculator for RC in terms of both survival and morbidity . Based oIn the current analysis of the quality of RC based on predefined factors, we found that only 22% of patients achieved the pentafecta, while some of its components, i.e., oncological and functional variables, were present in 47%–88.2% of cases. This reflects the heterogeneity of the aspects that determine the real value of the surgery and may play an important role in patients’ survival. The top influencers of the pentafecta, though, seem to be the number of resected LN and 12-month RFS, as the rest of the factors were attained in over 80% of cases. Similar findings were reported by Laymon et al.: only 33.6% of individuals who underwent open RC attained pentafecta, while the main reason for not achieving pentafecta was a low number of resected LNs  . AnotherStandardization may be the key to success that becomes approachable only after viewing the problem out of the box. Ladurner et al. bring back the opinion of the unification of the RC, the quality of which should be clearly defined, assessed, and supervised . On the The main reason for the promotion of pentafecta as a tool for surgical quality assessment is the hypothesis that it can act prognostic factor of oncological outcomes. In our cohort, CSS was greatly affected in the individuals who failed to attain the pentafecta. Laymon et al. reported the discrepancy between pentafecta failers and achievers in 5-year RFS reaching 20%  . Then, OTo determine the chance of pentafecta achievement, we focused on the search for its strong predictors, which were proved in multivariate analyses to be as follows: the surgical approach, the implemented method of UD, histological type of cancer, and advancement of the disease together with elevated serum creatinine level. The above factors might guide clinical decisions in preoperative workup to plan the most optimal surgery . Some authors formulated the hypothesis that surgeons favor ileal conduit, as they associate it with a low likelihood of UD-related complications and good quality of life of patients , 42. In We also found the predictors of cancer recurrence post cystectomy to be as follows: pT staging, presence of PSMs, blood transfusions, number of resected LNs, and presence of positive LNs. Other authors found that negative predictors of pentafecta in multivariate analysis were ASA ≥ 3, BMI ≥ 35, perioperative blood transfusion, and type of UD  . A recenFinally, Baron et al. hypothesized about incorporation into the existing models’ other factors, e.g., LOH, readmission rates, or use of NAC . Their uWe are aware of the inherent limitations of the retrospective nature of our study. The majority of the patients underwent open surgery. We incorporated different centers with surgeons of undetermined experience, using various techniques (including lymphadenectomy), so the impact of hospital volume remains hard to assess. The extent of LN dissection and a way of its submission  for pathology assessment was left at the discretion of the surgeon. Pathological assessment of LNs and its number reporting might have differed between centers and pathologists. The median follow-up was 18.5, which is similar to that reported by other authors , 21 due In conclusion, we found that the pentafecta achievement rate was low in the cohort of muscle-invasive and high-risk non-MIBC patients undergoing RC even in high-volume centers. The complexity of the procedure seems to directly influence the attainment rate, which in turn leads to a great increase in cancer-specific mortality rate among the pentafecta failers. As for the strongest predictors of the pentafecta achievement, we found the surgical approach, type of urinary diversion, histological type of bladder cancer, advanced staging, and increased preoperative serum creatinine to be significant. Further incorporation of the centers into the project might help in the establishment of the direct comparison between different tools, i.e., tri- or pentafecta, or enrich the existing ones with other clinical values.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics committee vote AKBE/133/2021 of the Medical University of Warsaw. The patients/participants provided their written informed consent to participate in this study.Conceptualization: ŁZ and AŚ. Methodology: ŁZ and AŚ. Software: AŚ. Validation: ŁZ, AŚ, and PZ. Formal analysis: ŁZ and AŚ. Investigation: ŁZ, BK, PK, ML, PL, JM, MN, KP, MPo, MPr, TS, and RW. Resources: ŁZ, BK, PK, ML, PL, JM, MN, KP, MPo, MPr, TS, and RW. Data curation: ŁZ and AŚ. Writing: ŁZ and AŚ. Writing and re-editing: ŁZ, AŚ, and PZ. Visualization: ŁZ. Supervision: TD, MR, WR, AW, and PR. Project administration: ŁZ. Funding acquisition: ŁZ. All authors have read and agreed to the published version of the manuscript.This work was supported by the Medical University of Warsaw (Publication Found).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The RPE scores , physiological index  , and percentage of maximal oxygen uptake (%VO2max)  demonstrated consistency without being significantly different between the normal weight (NW) and OW/OB groups. The RPE scores varied by age  = 0.677 ***, OW = 0.585 **), as well as by indoor temperature , body mass index  = 0.516 **, OW = 0.580 **), and test time . We conclude that RPE is appropriate for the following OW and OB people: (1) those who are older than 21.5 (the lowest age in the group of ≥18) years old and younger than 58.6 (the highest age in the group of ≥18) years old, without any other diseases, and (2) those who engage in low-intensity exercise while maintaining a standard indoor temperature. Future studies may address alternative techniques for increasing the reliability of longitudinal comparisons and gender comparisons, as well as investigate other possible confounding factors.The number of overweight (OW) and obese (OB) children, adolescents, and adults has increased globally. Exercise intensity, both actual and perceived, is a significant factor in a variety of health-related investigations and rehabilitation trainings. Despite this, literature on the connection between actual exercise intensity and the rating of perceived exertion (RPE) in overweight and obese populations is lacking. A systematic review, meta-analysis, combined analysis of variance (Brown–Forsythe ANOVA), and Spearman correlation were performed to fill this gap. After preliminary assessments, ten studies were classified as having a low risk of bias and a degree of heterogeneity (I There are many consequences of being overweight or obese, including health, social, and economic impacts ,2. The WMultiple studies have found that moderate- to high-intensity physical exercise is critical for several additional therapeutic benefits ,8, inclu2), maximum heart rate (HRmax), and maximal oxygen uptake (VO2max)) [Exercise intensity plays a vital role in the factors mentioned above. It has subsequently led to an increase in relevant studies of exercise intensity . TraditiVO2max)) ,27. HoweVO2max)) . One corVO2max)) ,30,31 anVO2max)) ,33. The VO2max)) . ExercisVO2max)) . FitnessVO2max)) . In the Journal of Motor Learning and Development recently ran a special edition consisting of five studies that attempted to answer whether AEI correlates with RPE [Due to the increased attention to RPE and exercise intensity, numerous studies have been conducted to determine the relationship between an individual’s AEI and RPE, because it has been verified that RPE could have a more accurate assessment of the real intensity of exercise in health individuals, thus increasing the validity and reliability of studies ,35,36. Fwith RPE ,39,40,41with RPE ,43,44,45In addition, when forming conclusions based on research findings, it is important to consider variables . For instance, the strength of the connection between AEI and RPE may be influenced by individuals’ intrapersonal variables, because RPE is a developing phenomenon that improves through developmental time in lockstep with overall cognitive growth . Second,Obesity is now a worldwide concern with health issues that urgently need to be addressed. RPE has been extensively utilized in scientific studies  and rehabilitation training assessment  ,49. HoweAs a result of the abovementioned factors, it remains unknown (a) how OW and OB individuals’ objectively assessed AEI values correlate with their RPE values and (b) whether this connection may diverge according to intrapersonal variables , RPE measuring, exercise modalities, or protocol for exercise. Thus, the objectives of this review were (1) to conduct a comprehensive examination and synthesis of scientific data on the association between AEI and RPE in OW and OB individuals and (2) to investigate various a priori identified possible mediators of the connection between AEI and RPE . Based on the explanations mentioned above, it was predicted that (1) research that utilizes perception measures that correspond to real exercise intensity assessment have greater correlations, (2) the strength of these relationships grows as individuals become older, (3) these associations may vary with BMI, and (4) associations may be stronger in different exercise types and protocols.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021270819.The current systematic review was conducted following the preferred reporting items for systematic review and meta-analysis (PRISMA) statement . It was Between March and May 2021, a systematic literature search for primary studies was conducted on EBSCOhost using the databases of MEDLINE, SPORTDiscus, Academic Search Ultimate, Health Source: Nursing/Academic Edition, and MasterFILE Premier. An advanced search was utilized; the search engine included Boolean/-phrase expanders applied to comparable topics and negative exclusion for papers that were not peer-reviewed or in English language. The subjects were overweight and obese. Selection criteria were (1) no age, gender, or year of publishing limitations (2) and a fit for our chosen topic. “and” and “or” were among the major Boolean operators used. The words “overweight” or “obese” or “obesity” or “fat” or “unhealthy weight” or “high BMI” or “high body mass index” were used in conjunction (and) with the terms “RPE” or “rating of perceived exertion” or “perceived exertion” or “Borg scale” or “OMNI”.Starting with the first stage, we removed duplicates and unnecessary titles, and we omitted non-full-text articles. In the second phase, two separate researchers (Y.H.L. and X.C.) scanned abstracts for possibly important information and then used the population, intervention, comparison, outcomes and study design (PICOS) process . The PICThe study sample included the overweight and/or obese population without other diseases and had no age or sex limitations.The study included an assessment of AEI. There were no restrictions on exercise protocol, type or interval time, or intensity.The study included an assessment of RPE. There were no restrictions on the scale , OMNI scale, and Borg scale (6–20)).The study analysis reported on the assessment of the relationship between AEI and RPE.The study had to include randomized controlled trials of NW and OW or OB individuals.To ensure the quality of the included articles, the impact factor of the articles had to be no less than 2.The full-text screening was conducted following the criteria below:-1 in mean and SD) and VO2 (mL/kg/min in mean and SD)), statistical methods, and results.Data were extracted from the chosen articles. The extracted data included authors, year of publication, the country in which the study was conducted, study population ), sex , BMI (mean and SD)), perceived exertion scores ), exercise , and protocol), temperature, physical signs  risk of bias tool to test for the presence of bias and the methodological quality of included studies. The COSMIN risk of bias tool provides criteria for determining if a study’s results can be trusted. To evaluate study quality, each standard must be evaluated. The worst-score-count approach must be used to estimate the risk of bias  . The phrWe performed a meta-analysis and variance analysis (Brown–Forsythe ANOVA) and included a Spearman correlation analysis. The Brown–Forsythe ANOVA was used to determine the differences in RPE scores and physiological indexes  between the NW and OW or OB groups. Spearman correlation analysis was used to study the correlation between intrapersonal factors (such as age and BIM), exercise type, exercise protocol, and RPE scores in all NW and OW or OB group studies. The final mean values for each group were examined together with their standard deviations for each outcome. Weights for the research were determined using the inverse variance technique. Depending on the sample size, the effect size was identified as Hedges’ g. The deviation correction factor was precisely calculated and the effect size using the Hedges and Olkin correcting standard errors.2 statistics, defined as I2 = 100% (Q-DF)/Q, where Q is Cochran’s heterogeneity index and DF denotes degrees of freedom [2 was less than 50%, a fixed-effects model was used; if I2 was more than 50%, a random-effects model was employed [The Cochran test was used to determine statistical heterogeneity among publications, and inconsistency was assessed using I freedom . A value freedom . For anaemployed . A funneA total of 1340 articles were found, 611 of which were from MEDLINE, 306 were from SPORTDiscus, 364 were from Academic Search Ultimate, 49 were from Health Source: Nursing/Academic Edition, and 10 were from MasterFILE Premier. After eliminating duplicates, irrelevant titles, and papers that were not accessible in full form, 378 potentially relevant studies remained. Following the reading of the abstracts, 41 potentially relevant publications were read in full, and 11 studies were selected for review. The search process shown in 2  [2  [Each study was a randomized controlled trial (RCT) . The years of publication ranged from 2002 to 2019. These studies included between 21 and 300 individuals; of the 741 subjects in 11 studies, 636 (85.8%) were female, and 105 (14.2%) were male. In this study, participants’ ages ranged from younger than or equal to 18  to over 18 , while their weights ranged from normal  to overweight  to obese n = 427; 57.6%). Additionally, six papers  utilized a continuous progressive exercise regimen .6%. Addi,61,62,63; 61.7%) ,61,62, s; 70.4%) ,59,60,62; 70.4%) .The intraclass correlation coefficient (ICC) was calculated to be more than 0.85 among reviewers. Decisions were made based on consensus for dissenting pieces. Ten studies were characterized as having a low risk of bias in all areas, except for that of Hassan et al. . The bia2 of 34% and a p-value of 0.05   was seen in the age group of <18  assessed RPE scores  . Because of 0.05 . Subgrou = 0.55) , but a lp of <18 .max) and percentage of maximal oxygen uptake (ml/kg/minute) (%VO2max) were used as reference criteria. In three studies [2 was not measured. max, and %VO2max as determined by the Brown–Forsythe ANOVA): diverse BMI samples did not significantly vary in %HRmax , RPE scores , and %VO2max , suggesting that different BMI samples demonstrated consistency in RPE scores, %HRmax, and %VO2max   scores) were >0.05, suggesting that there was no connection with RPE (NW) scores , BMI (NW), and test time (test RPE time), were found to be significant, and their correlation coefficients were all higher than 0, indicating a positive connection between age (NW), BMI (NW), test time, and RPE (NW) scores. Exercise type, intensity, gap-time , and control temperature (indoor temperature) were shown to have no statistically significant relationship with RPE (NW) scores. The correlation values were close to 0, and all the ) scores .p-values were more than 0.05, suggesting that no correlation existed between exercise type, intensity, gap time, test time, and RPE (OW/OB) scores , BMI (OW/OB), and temperature, were found to be significant, and their correlation coefficients were all higher than 0, indicating that there was a positive association between age (OW/OB), BMI (OW/OB), control temperature, and RPE (OW/OB) scores. No significant connection was seen between exercise type, intensity, gap-time, test time, and RPE (OW/OB) scores. Connection coefficients were near 0, and all ) scores .t-test was employed, necessitating the exclusion of the study by Michael et al. [p = 0.02; I2 = 0%; p = 0.71) (p = 0.80).Sensitivity analysis was performed to ascertain the possibility of outliers and/or influencing studies. Significant differences were discovered when the independent sample l et al. , the soll et al. , and stul et al. , which r = 0.71) . The fun = 0.71) , there wp = 0.859). The heterogeneity was modest . Subgroup analysis revealed no heterogeneity within the age group of ≥18 , but a low degree of heterogeneity  was seen in the age group of <18. Sensitivity analysis revealed that just one piece of research [This systematic review and meta-analysis were aimed to characterize the strength of the relationship between AEI and RPE in OW and OB individuals. It is the first review and meta-analysis intended to better comprehend and scrutinize the connection between the two concepts. The authors of this study also investigated the impact of moderator factors  on RPE. Overall, the primary hypothesis regarding a positive link between AEI and RPE in OW and OB individuals was validated. The RPE scores of OW and OB individuals were found to be greater than normal weight individuals, resulting in an overestimation of exercise intensity. However, there was no significant difference in RPE scores between NW and OW/OB  and %VO2max  during exercise revealed no significant differences between the NW group and the OW or OB groups. Indoor temperature, BMI, and age were all linked with RPE scores (OW/OB) and sequentially increased.With the exception of that of Hassan et al. , 10 stud2 being the most often used. As a result, %HRmax and %VO2max were used as actual reference indexes in this paper. Still, some studies only measured HR or VO2, and a few studies simultaneously measured multiple physiological indexes  VE and (minute ventilation) VT). One study did not use any physiological indicators as a reference [2 [We predicted that there would be significant correlations between all components of the AEI and RPE in either the OW or OB groups. The review and meta-analysis verified this hypothesis. The RPE scores of OW and OB were found to be greater than those of normal weight individuals, resulting in an overestimation of exercise intensity. However, there was no significant difference in RPE scores between NW and OW/OB. The validity and reliability of RPE in OW and OB people was also fully affirmed. To further verify the conclusion, in this research, ANOVA was used to compare physiological indexes and perceptual ratings between the NW and OW/OB groups throughout the study. As previously stated, using physiological indicators as reference values can allow for the correct assessment of actual exercise intensity during exercise. Based on the available data, no significant variations in either physiological or perceptual outcomes were identified between the two groups, suggesting that the real intensity of motion and perceived values were uniform. However, throughout the systematic review process, we discovered that 10 studies utilized distinct physiological indicators, with HR and VOeference . Inconsieference , and BMIrence [2 ,68. Thus2 = 30%; p = 0.13) was seen in the age group of <18. In other words, the correlation coefficient analysis provided findings that were consistent with this finding, and the correlation value of age was the greatest. Adults in the OW/OB groups had greater validity for RPE than children, as evidenced by Goodway et al. [We anticipated that a variety of variables influenced the RPE scores. We found that indoor temperature, BMI, and age were all linked with RPE scores (OW/OB) and sequentially increased. Firstly, developmental theory  and Stody et al.  and Noory et al. , who fouy et al. ,72. Consy et al.  was highThe correlation analysis shows that BMI was correlated with RPE scores, which was consistent with the meta-analysis results. Nonetheless, OW and OB participants had higher RPE scores than those of normal weight, resulting in an overestimation of the intensity of their exercise. However, the RPE scores showed no significant differences between normal weight and overweight/obese individuals. The validity and reliability of RPE were verified in OW and OB people. The BMI of a person who is either normal or overweight varies with age and sex, increasing with age . In ordeThe NW and OW/OB groups showed inconsistent correlations in test time and control temperature for the exercise protocol. Test time was associated with RPE scores in the NW group. The interval between RPE tests and exercise can cause recall bias , and theWhile the current systematic review and meta-analysis findings are noteworthy, it is recommended that their conclusions be interpreted with caution due to the risk of bias reported in eleven of the included studies. Except for that of Hassan et al. , the resWe have outlined the causes of heterogeneity based on the results of the bias assessment and hypothesis verification procedures. Firstly, heterogeneity mainly appeared in the children’s group. In the low age category (younger than 18), the mean age was 8 years. According to cognitive theory, the cognitive capacity of this cohort has not yet been developed to a high degree ,82. SecoOverall, while the objective of a systematic review and/or meta-analysis is to present a clearer picture of research in a particular field of study, this review highlights the lack of clarity in some aspects of AEI and RPE in people who are overweight and obese. Many possible moderating variables contribute to the intrinsic complexity of the connection between AEI and RPE. Clearly, a systematic approach to research in this field is necessary to uncover the underlying elements inherent in how individuals perceive their own exercise intensity. Among various self-concept aspects, RPE has been found to be the most effective predictor of exercise intensity among normal weight individuals . As a reFuture researchers interested in this topic may wish to investigate alternative strategies for increasing the reliability of longitudinal comparisons on the moderating role of age and gender in the relationship between AEI and RPE. Additionally, in order to accurately analyze the influence of moderate and vigorous intensity exercise, research with different exercise intensities in the same population is required. Finally, we suggest seeking to determine whether there are additional confounding variables that could affect the relationship between AEI and RPE, such as the method by which AEI is assessed in real-world settings rather than in the laboratory  and cross-cultural effects .This systematic review and meta-analysis were comprehensive. We found the reasons for the heterogeneity of the controversial research results and addressed multiple potential modifiers of the link between AEI and RPE in people with OW or OB. Additionally, we increased the reliability and validity of RPE in OW and OB populations. The authors performed searches without specifying a year or an age range. Though this article was not written in any of the author’s original languages, in order to ensure the accuracy and logic of the language used in the study, we sent it to colleagues whose native tongues corresponded to the written language of the study (as noted in the Acknowledgements section) and applied for the language improvement service of a professional agency. Therefore, we are sure that the search provides an accurate picture of the literature. Multiple variables were found to potentially affect the connection between AEI and RPE using a thorough investigation that considered the impact of possible confounding factors. The limited number of studies in the collegiate and senior age groups is a limitation of the study. We cannot establish gender impacts on OW and OB individuals due to an all-male research paucity. In the literature, only a small number of studies utilized moderate and vigorous intensity exercise. Thus, we could not conclude regarding the impact of moderate and vigorous intensity exercise on RPE, and there was an absence of relevant research after February 2019. Our focus on English likely resulted in the marginalization of relevant and significant literature in other languages. Finally, although the meta-analyses included various important moderators, it was not feasible to include every conceivable moderator in the analysis.According to the findings of this in-depth systematic review and meta-analysis, an association between AEI and RPE in OW and OB people was found in RPE scores, which were higher than in the NW group. Still, there was no statistically significant difference between the two groups based on the currently implemented methodologies of AEI and RPE. The associations of these constructions are usually distinguished by age, temperature (only in the OW group), BMI, and test time (only in the NW group). As a result, we conclude that RPE is appropriate for the following OW and OB people: (1) those who are older than 21.5 (the lowest age in the group of 18) years old, younger than 58.6 (the highest age in the group of 18) years old, and without any other diseases, and (2) those who engage in low intensity exercise while maintaining a standard indoor temperature.


Reynoutria japonica is one of the most harmful invasive species in the world, dramatically reducing the diversity of resident vegetation. To mitigate the impact of R. japonica on ecosystems and properly manage affected areas, understanding the mechanisms behind this plant’s invasive success is imperative. This study aimed to comprehensively analyse plant communities invaded by R. japonica, taking into account species traits, habitat conditions and seasonal variability, and to determine the ecological profile of species that withstand the invader’s pressure. The study was performed in fallow and riparian areas in southern Poland. Pairs of adjacent plots were established at 25 sites with no obvious signs of recent human disturbance. One plot contained R. japonica, and the other contained only resident vegetation. For each plot, botanical data were collected and soil physicochemical properties were determined. Twelve sites were surveyed four times, in two springs and two summers, to capture seasonal variability. The presence of R. japonica was strongly associated with reduced resident plant species diversity and/or abundance. In addition to the ability to quickly grow and form a dense canopy that shades the ground, the success of the invader likely resulted from the production of large amounts of hard-to-decompose litter. The indirect impact of R. japonica by controlling the availability of nutrients in the soil might also play a role. A few species coexisted with R. japonica. They can be classified into three groups: (i) spring ephemerals – geophytic forbs with a mixed life history strategy, (ii) lianas with a competitive strategy and (iii) hemicryptophytic forbs with a competitive strategy. Species from the first two groups likely avoided competition for light by temporal or spatial niche separation (they grew earlier than or above the invasive plant), whereas the high competitive abilities of species from the third group likely enabled them to survive in R. japonica patches. Reynoutria japonica, native to East Asia, is a highly invasive plant beyond its range. It easily outcompetes and displaces most species from plant communities it invades. However, there are some plant species that, due to their functional traits, can coexist with R. japonica and even benefit from its invasion. In our study, we found such species among spring ephemerals (they undergo a full vegetation cycle before the development of R. japonica canopy), lianas (they treat shoots of R. japonica as support for climbing and overgrow them) and highly competitive native plants. Reynoutria japonica) is one of the world’s most problematic invasive species , and to the economy  withstand its pressure and persist for a long time  in its dense stands  and reliability in delivering ecosystem services . The funR. japonica, with soil physicochemical properties, taking into account seasonal variability.Identifying and quantifying the importance of between-species relationships determining the success of alien or resident species is difficult because environmental factors interact with species characteristics (R. japonica patches and adjacent (unaffected) vegetation patches, (ii) link the occurrence of resident plants with soil properties and the season (early spring vs. late summer) and (iii) identify functional traits that enable resident plants to coexist with R. japonica.The aims of our study were to: (i) characterize differences in the resident plant community structure (species richness and composition) resulting from the invasion by comparing Reynoutria japonica is a perennial geophyte, which reproduces mainly vegetatively through the growth and regeneration of rhizomes and shoots. In early spring , the rapid growth of annual shoots begins and continues until early summer. The growth rate is very high, from 3 cm/day in the initial growth period to 5–8 cm/day in the second half of May  between the towns of Dąbrowa Górnicza, Wadowice, Katowice and Kraków. This area lies in the transitional climate zone between a temperate oceanic climate in the west and a temperate continental climate in the east. The average annual air temperature fluctuates between 7.1 and 8.1 °C, and the average annual rainfall fluctuates between 700 and 873 mm. Precipitation is the highest in June, July and August, and the lowest in February and March. Southwesterly winds are most frequent, followed by northeasterly winds. The growing season lasts 205 to 215 days .R. japonica formed large and compact patches [see]. The sizes of these patches were estimated using aerial photographs. Each study site consisted of two paired plots, 4 m2 each – one located in a patch with R. japonica (90–100 % cover) and one in adjacent resident vegetation – giving a total of 50 plots. The plots in a pair (invaded plot and uninvaded plot) were placed a few metres from each other (approx. 4–6 m between the edges of the plots) in patches with a similar disturbance history to obtain the highest possible habitat similarity and at the same time to minimize the impact of R. japonica on the uninvaded plot, and vice versa, the impact of resident plant community on the invaded plot.Twenty-five study sites were established in riparian zones of the Skawa, Soła and Vistula rivers, and in fallows, in places where Petasition hybrydi Sillinger 1933 alliance  – treeless vegetation, largely formed by flooding. It occurred in sites that were located in humid riparian zones, both natural and secondary habitats (e.g. wet meadows and arable fields abandoned ca. three decades ago); there were 20 such sites. The species with the highest frequency and coverage were Phalaris arundinacea, Rubus caesius, Aegopodium podagraria, Petasites hybridus, Urtica dioica, Chaerophyllum aromaticum and Anthriscus sylvestris. The community was also characterized by the presence of Calystegia sepium, Allium ursinum, Ficaria verna, Humulus lupulus and Symphytum tuberosum.Resident plant communities were identified according to Convolvulo arvensis-Elytrigion repentis Görs 1966 alliance . It occurred in drier habitats (compared with riparian sites) – fallows (N = 5). Among the species with high frequency and coverage were Calamagrostis epigejos, Agrostis stolonifera and Elymus repens. Apart from that, Cirsium arvense, Convolvulus arvensis and Artemisia vulgaris were usually present in this community.Another type of community was the R. japonica were included in the group of resident plants. This was also the case with Echinocystis lobata, a plant invasive in Poland. This means that the term ‘resident plants’ cannot be regarded as strict, but for convenience, it is used throughout this paper.Within each plot, vascular plant species were recorded using the 12-point cover-abundance scale . The plots were visited several times during the 2017–2018 growing seasons to obtain a complete list of species. The species nomenclature followed R. japonica was disturbed by shoot-cutting.Of the 25 study sites, 12 were selected to observe the between-season variability in the plant species occurrence. The plots  within these sites were surveyed four times: summer 2017 (August 28 to September 1), spring 2018 (April 23 to 24), summer 2018 (August 22 to 24) and spring 2019 (April 23 to 24). In the case of one site, we managed to sample only twice, in summer 2017 and spring 2018, because the patch of Reynoutria japonica was excluded from all the above calculations, since it was hypothesized to be the cause of (not part of) the studied patterns.The total number of vascular plant species (species richness), the total coverage and the number of species representing each plant trait were calculated. Before the calculations, the data from the four surveys (12 sites) were combined within the season; of the two cover-abundance values recorded for a given species, the higher was selected. The following traits were taken into account in this study: C-S-R life strategy , life foR. japonica plots, the thickness of the organic (O) horizon was determined; in the resident vegetation plots, the O horizon was almost absent, therefore it was not measured.In August/September 2017, three subsamples (approx. 20 × 20 × 20 cm) of the organo-mineral soil horizon (A horizon) were taken from each plot and bulked to obtain one composite sample per plot. In the 4, N-NO3, P-PO4 as well as the C/N and C/P ratios [see].Soil samples were analysed for a number of physicochemical properties; the methods of analysis and the obtained data (descriptive statistics for invaded and uninvaded plots) were published elsewhere  were excluded from the analysis due to the impossibility to calculate Bray–Curtis distances (species data) and HDFI and HDSI indices (vegetation parameters) for them. For the species data, in addition to PERMANOVA, similarity percentage (SIMPER) analysis . PERMANOVA models included in addition to the fixed effect (plot type) a random effect (site identifier). In the case of soil variables and vegetation parameters, PERMANOVA was performed based on Euclidean distances, while in the analysis of species data, Bray–Curtis distances were used. Sites with empty plots  separately for invaded plots and uninvaded plots.R. japonica patches and habitat conditions was determined with distance-based linear models (DistLM)  was used.To visualize the differences between the two types of plots, a principal coordinates analysis (PCoA) ordination was generated, wherein plots were symbol-coded according to plot type. The differences between the two seasons were visualized in the same way. PCoA was performed after each PERMANOVA on exactly the same data as the corresponding PERMANOVA. To visualize the relationship between habitat conditions and the species composition of resident plants in the R. japonica plots; due to the small number of species in these plots, no species were excluded.As a rule, species with a low frequency, i.e. occurring on <10 % of plots, were excluded from multivariate analyses. An exception was made for species data from All multivariate analyses were carried out using PRIMER 7 with the PERMANOVA+ package (R. japonica (invaded) plots did not differ from the resident vegetation (uninvaded) plots in terms of soil physicochemical properties . This lack of differences was also confirmed by univariate tests  vascular plants were found in the studied plots (N = 50), of which one—Allium ursinum—is protected by Polish law. There were 28 species shared by both types of plots, 51 species unique to the uninvaded plots and only 4 species unique to the invaded plots. Among the latter, Echinocystis lobata was the most common; it occurred in four plots with abundance from 1 to 7. The number of species (species richness) ranged from 0 to 9, averaging 4, in the invaded plots, while it ranged from 4 to 24, averaging 11, in the uninvaded plots. Based on the lists of species and the results presented below, vegetation of R. japonica plots was classified as Reynoutrietum japonicae Görs et Müller in the Görs 1975 association .A total of 83 species of resident . In the PCoA diagram, it is manifested by a clear shift of points representing the invaded plots to the right  in relation to those representing the uninvaded plots , the other included plants associated with uninvaded plots, primarily Phalaris arundinacea and Rubus caesius . The results of the analyses also showed that two species, Aegopodium podagraria and Urtica dioica, were relatively constant components of the plant communities of both types of plots; they contributed to the within-plot type similarity . This result was well visualized by the PCoA diagram  were associated with the uninvaded plots , which means that they did not distinguish any type of plot.When the vegetation parameters  were sub diagram ; points ed plots . Three vF = 1.8, P = 0.067). For the uninvaded plots, this difference was statistically significant but weak .According to PERMANOVA, the difference between spring and summer in the species composition of resident plants in invaded plots was at the verge of statistical significance  was less pronounced and other variables contributed to it. The points representing the summer surveys , and the top of the diagram by nitrophilous species with high competitive abilities, i.e. Urtica dioica, Chaerophyllum aromaticum and, partially, Aegopodium podagraria. Variables related to the dbRDA2 axis suggest that the availability of potentially limiting nutrients, N and P, might determine the occurrence of these species in invaded plots.DistLM analysis selected eight habitat variables to explain the species composition of resident plants in invaded plots; they were shown in the dbRDA diagram . Among thickness . Only liR. japonica with soil physicochemical properties, which, combined with extensive sampling taking into account seasonal variability, allowed for strong inferences. As expected, the invasion of R. japonica caused profound changes in resident plant communities. It not only dramatically reduced their species diversity, leading to a significant homogenization of the plant cover, but also strongly influenced community structure .Our study is the first to link the diversity and species composition of resident vegetation affected by invasive R. japonica and its strong ability to spread and form near-monoculture stands, which results in limitations of light availability to other plants  were associated with a thick O horizon, the hardly decomposing organic matter produced by R. japonica should be considered as a kind of environmental stress, which, together with the reduced availability of light, has a strong impact on resident vegetation. Our results are in line with the findings of other studies where large amounts of R. japonica organic matter were harmful to the establishment of most vascular plants and the performance of microbial populations , in the R. japonica plots is possible not only because of their ability to use a short period of high light availability but also because of their adaptation to growth under thick litter mat conditions .It is well known that litter affects plant community structure and dynamics . In respR. japonica might affect resident plants through indirect allelopathy, the negative effects of which are mediated by the soil microbiome .Many field and laboratory studies indicated that crobiome . In contR. japonica. Indeed, our recent study showed that the content of phenolics in the R. japonica tissues, especially in the rhizomes and leaves, was very high  for fast growth in spring when they do not yet face competition for nutrients and light . This suggests that they survive in the R. japonica patches, occupying niches associated with periodic nutrient deficiencies possibly created by the invader.Altering resource availability, e.g. by releasing both nutrients and secondary metabolites into the soil, is another strategy to facilitate invasion  are another group of species that do well under the R. japonica invasion. Their strategy, however, is different from that of spring ephemerals. They start to grow in spring, use withered [see] and then live shoots of R. japonica to climb, then overgrow the supporting plant [see], and finally, in late summer, produce seeds, thus closing the growing cycle. Interestingly, one of the recorded liana species was Echinocystis lobata—an invasive plant. Apparently, it used the invasion of R. japonica to spread itself. This species was observed in four R. japonica plots, where it achieved relatively high coverages (up to 7). It should be emphasized, that its frequency and abundance is underestimated, because, when establishing the study sites, we tried to select places unaffected by other invasive plants than R. japonica.Lianas , the latter use their climbing abilities to lift the foliage above the invader canopy . In the case of resident species occupying a similar niche as the invasive species, those with a high potential to compete for resources have a chance of survival , Phragmites australis  and Pteridium aquilinum  can also dramatically reduce the diversity and change the structure of resident vegetation . If their formation was initiated by any factor, then this factor acted rather locally, in the middle of the present patches, from where the invasive plant then spread by its own forces. Since we established the plots in pairs close to each other , the R. japonica plots were closer to the edge than to the middles of patches, i.e. outside the hypothetical place of disturbance. The absence of any differences in soil physicochemical properties supports this scenario.When interpreting the results of field studies, their limitations should be taken into account. These studies assume that the pre-invasive state of invaded and non-invaded plots is the same. This is not necessarily true. The invasion at a given location could be induced or facilitated by, for example, local soil disturbances or a slightly different structure of the community , which could also affect, apart from the invader itself, resident vegetation . We cannR. japonica has a strong negative effect on resident vegetation by either completely displacing or drastically reducing the abundance of many plant species. The great success in outcompeting other plants results from the multifaceted influence of the invader. This includes quickly occupying new space, limiting access to light and producing a thick layer of hard-to-decompose litter (O horizon). It seems that direct and indirect (e.g. via soil microorganisms) allelopathic effects and the control of nutrient availability may also play a role. Not all species are displaced by R. japonica. There are some that perform well in invaded patches and even take advantage of invasion. It seems to be determined by a combination of plant traits: Grimes’s strategy, Raunkiaer’s life form and belonging to one of the functional groups. Species that are able to coexist with R. japonica can be classified into three groups:Our study showed that •R. japonica.geophytic forbs with a mixed life strategy that take advantage of the periodic (spring) release from competition (mainly for light) from •R. japonica, using it as a support, and thus avoiding competition for light; they seem to tolerate the thick O horizon formed by the invader litter.lianas with a competitive strategy—plants that rise above •R. japonica, have an outstanding ability to dominate the community and create almost mono-species stands; thanks to this trait, they are able to utilize resources and, although they do not win against the invader (in terms of abundance), they cannot be completely eliminated.hemicryptophytic forbs with a competitive strategy—plants that, like The following additional information is available in the online version of this article—Reynoutria japonica patch (right) and resident vegetation (left). (B) An invaded plot in summer, with a fully developed, compact R. japonica canopy, and a floor almost devoid of other species. (C) Dense R. japonica canopy overgrown by a liana—Humulus lupulus. (D) An invaded plot in early spring, with withered and new, fast-growing annual shoots of R. japonica and a flowering geophyte—Symphytum officinale. (E) H. lupulus in early spring climbing up the old shoots of R. japonica. Phot. M. Woch.R. japonica) and 25 uninvaded plots. Soil samples were taken from horizon A to a depth of 20 cm. According to paired t-tests, none of the variables differed statistically significantly (P > 0.05) between the two plot types.R. japonica) and 25 uninvaded plots, and selected functional traits .plab035_suppl_Supplementary_MaterialsClick here for additional data file.


Objective: Switching between second-generation antipsychotics (SGAs) is a common clinical practice in the treatment of schizophrenia and schizoaffective disorders due to differences in the drugs’ tolerability and safety profiles as well as the challenge of obtaining an ideal response. However, the factors associated with SGA switching remain uncertain and related real-world data are scarce. The main objective was to identify the factors associated with the switching of SGAs in patients with schizophrenia or schizoaffective disorder.Methods: We conducted a retrospective cohort study of outpatients with schizophrenia or schizoaffective disorder, who were aged ≥18 years and received a SGA  from a Brazilian pharmaceutical assistance program for at least 3 months. We identified SGA users from 2008 to 2017 by using a national administrative database (Ambulatory Information System-SIA/SUS). The factors associated with the switches were evaluated by Cox proportional hazards regression and adjusted for sex and age; the confidence interval was set at 95% (95% CI).Results: In total, 563,765 patients were included. Female sex, advanced age of ≥70 years, residence in the Brazilian northeast region, and the type of antipsychotic used were associated with an increased risk of switching (p < 0.001). The incidence of switching ranged from 37.6/100 person-years for clozapine users to 58.2/100 person-years for risperidone users. Compared to the adjusted hazard ratio, for clozapine users, the corresponding ratios for risperidone, ziprasidone, quetiapine and olanzapine were 1.59 , 1.41 , 1.25  and 1.11  respectively.Conclusion: The groups most susceptible to SGA switching in real-life setting were older individuals, women, and those living in the Brazilian northeast region. Risperidone was associated with the highest risk of switching and as expected, clozapine was associated with the lowest risk of switching than that associated with the other SGAs. Switching of antipsychotics in the treatment of schizophrenia or related psychotic disorders is a common clinical practice and has been recommended to ensure a more appropriate treatment option in the face of issues including efficacy, safety, or tolerability . TherapeThe decision to switch from one antipsychotic to another should be made considering the possible risks associated with the switching process, such as relapses, exacerbation of some symptoms, new adverse effects, withdrawal syndromes, rebound, and serious drug interactions . PatientAntipsychotics switching could be influenced by various factors: in particular, factors related to the patient, illness, environment, antipsychotics availability, acceptability of treatment, and especially related to the medication  need to be evaluated . First-gIn case of an abrupt switch from an antipsychotic with high cholinergic affinity, such as olanzapine or clozapine, to that with a low affinity, cholinergic rebound syndrome is likely . SwitchiSGAs are considered high-cost medicines and are dispensed and funded by the Brazilian National Health System (SUS) after an analysis of compliance with the National Clinical Guidelines . The cosHowever, despite the burden and risks, few studies have explored the factors associated with switching antipsychotics in the treatment of schizophrenia and other psychotic disorders . TherefoThis study followed the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) Statement which reporting items specific to observational studies using routinely collected health data .This was a retrospective cohort study conducted in all patients who were on SGAs for schizophrenia or schizoaffective disorder treatment and received these medicines through a pharmaceutical assistance program from the SUS, from January 2008 to December 2017.The cohort was conducted using register-based data from a nationwide administrative database , where in information regarding all outpatient care procedures is collected, and processed and which is used for providing high-cost medicines or procedures for specific diseases according to Brazilian guidelines. This database represents over 200 million procedures/month . These iThe public health system in Brazil, SUS, is universal and free for everyone, and assists approximately 75.6% of the population . The priThe patients get access to these medicines via SUS only after an analysis of compliance with Brazilian guidelines for the treatment of schizophrenia and schizoaffective disorders. So, patients with schizophrenia or schizoaffective disorder who seek to obtain these medicines fully funded by SUS should schedule a doctor’s appointment (from the public or private sector), which will make a proper diagnosis and then will fill out a form to request these medications. This form together with supporting documents are analyzed by the manager of pharmaceutical services and if everything is in accordance with the current Brazilian clinical protocol, the medicine is provided. This process guarantees the supply of medicines up to three months (90 days). After 90 days, if there is a need to continue treatment, the whole process is repeated. For this reason, we adopted the 90-days cut-off. All of this information such as sex, age, race, state of residence, diagnosis, prescribed SGA, dose, quantity dispensed by pharmacy, and date of dispensation are available for consultation and analysis at SIA/SUS database.Currently, the following SGAs are available through the SUS: oral clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Aripiprazole or injectable SGAs are not available through the SUS.Brazilian guidelines for schizophrenia or schizoaffective disorders treatment recommend SGA monotherapy . There iThe study included all patients aged ≥18 years, who were identified from SIA/SUS database, received SGAs  for more than 90 days, during January 2008 to December 2017, and diagnosed with one of the following diseases according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10): Paranoid schizophrenia (F20.0), Hebephrenic schizophrenia (F20.1), Catatonic schizophrenia (F20.2), Undifferentiated schizophrenia (F20.3), Post-schizophrenic depression (F20.4), Residual schizophrenia (F20.5), Simple schizophrenia (F20.6), Other schizophrenia (F20.8), Schizoaffective disorder, manic type (F25.0), Schizoaffective disorder, depressive type (F25.1), Schizoaffective disorder, depressive type (F25.2).All data were extracted from a single database, SIA/SUS, which contained the data related to the demographics and clinical variables. The drugs were identified in the database using the code belonging to the SIA/SUS.Exposure groups were considered according to the SGA used at the cohort entry: clozapine, olanzapine, risperidone, quetiapine and ziprasidone.The following baseline demographic variables were considered: sex, age at cohort entry, race (reported by the physician), geographic region of residence at study entry, and year of cohort entry . The baseline clinical variables considered were: SGA used at cohort entry, diagnosis according to ICD-10 at cohort entry and mean treatment duration (entire study period) in months.The data on all the patients identified were gathered from the registers of the nationwide database SIA/SUS. The files that make up the database are fragmented by state, year, and month. The records were linked by the National Health Card number for follow-up using deterministic linkage. There was no linkage with another database.The first date of SGA provision identified in the SIA/SUS database during the period from January 1, 2008, to December 31, 2017, was considered as the cohort entry date. Some patients might already have received SGAs when they entered the cohort.During the 10-year study period, all patients were followed up until the last patient record in the SIA/SUS or death. Our analysis did not exclude or censor any patient during the period of study.The primary outcome was defined as the switch between SGAs. The switch was considered when a patient switched from an oral one SGA to another oral SGA. The following were considered as possible factors associated with SGA switching and that were available in the SIA/SUS: 1) sex, ii) age, iii) year of cohort entry (2008–2017), iv) geographic region of residence; v) diagnosis according to ICD-10 codes, and vi) SGA used at study entry .Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables as percentages only for descriptive statistics. Pearson’s Chi squared test was performed to analyze correlations between switches and categorical variables. Incidence rates of switches were calculated as cumulative incidence (events/100 patient-years) and compared using the hazard ratio. Absence of switches was estimated using the Kaplan-Meier method. Log rank test was used to assess the significance of differences between absence of switches curves. Cox regression analysis was performed to analyze the association of age, sex, year of cohort entry, geographic region of residence, diagnosis and SGA used at cohort entry. A multivariable Cox proportional-hazards regression model adjusted by all variables was used to examine the hazard ratios of the included factors.The same procedure was repeated in the sensitivity analysis with patients who entered at cohort in 2009 to exclude eventual cases of patients who were using SGA before 2008. To assess the consistency of the multivariate model, the proportional-hazards assumption on the basis of Schoenfeld residuals was tested. If the model was not proportional, a comparison was made between the investigated factors using the restricted mean survival time.p <  0.05 were used. All statistical analyses were performed using Stata 14.2.All tests were two-tailed. Confidence intervals of 95% and a significance level of We identified 759,654 patients with schizophrenia or schizoaffective disorder who were on SGA provided by the SUS from 2008 to 2017. From among these patients, 25.8%  did not met the inclusion criteria due to their age or time of use of SGA. A total of 563,765 patients met the inclusion criteria and were included in the cohort, Most of the patients were women (51.6%), the mean patient age at study entry was 46.4 (±18.6) years, lived in the south of Brazil (60.3%) and the most commonly diagnosed disorder was paranoid schizophrenia (78.2%). The most commonly used SGA at study entry was olanzapine (31.8%), followed by risperidone (29.2%), quetiapine (28.4%), ziprasidone (5.3%), and clozapine (5.2%). The mean follow-up duration was 27 months (IQR: 12.6–57.8), There were sex, age, residence region, and treatment length related differences in the frequency of the SGA used. Clozapine, olanzapine, and risperidone were the most often prescribed SGA among men in the entry of the study. The proportion of quetiapine and ziprasidone use among women was higher than that in men.Quetiapine was more frequently used by elderly individuals aged higher than 60 years, and the frequency of use increased progressively with advancing age .The frequency of SGA use differed among the various regions of Brazil. In the southeast region, quetiapine (32.4%) and risperidone (29.8%) were the most used, while in the northeast region, the most commonly used SGAs were olanzapine and risperidone. The median treatment duration varied from approximately 23 (IQR: 11.6–45.3) months for quetiapine to 36 (17.3–81.2) months for clozapine.p < 0.001 for each variable, Almost all (99.9%) switched the SGA at least once during follow-up. Female sex, advanced age (>70 years old), residence in the northeast region, study entry from 2009, and a diagnosis of schizoaffective disorders were associated with an increased risk of switching . When repeating the analysis using the restricted mean survival time, the factors associated with switch of SGA were the same.Increased risk of SGA switching was associated with female sex, advanced age, a diagnosis of schizoaffective disorder, and type of SGA used at study entry. Risperidone users were more likely to switch to another SGA, while clozapine users were less likely to switch than other users.Switching antipsychotics is a common clinical practice in schizophrenia management . Our finWomen were more likely to switch SGAs than were men. This finding is consistent with that in other studies  and coulAdvanced age was another factor associated with switching, which conflicts with other findings, whose age group of switchers was between 42 and 55 years . This diResidents of the northeast region of Brazil were more likely to switch SGAs, which may reflect of socioeconomic factors. The northeast region is one of the poorest regions in Brazil, with high rates of unemployment, illiteracy, and poor basic sanitation. It succeeds the southeastern part in the number of schizophrenia cases in Brazil and is considered a vulnerable region in terms of the development of this disease, and treatment gaps and non-adherence . AlthougThe subtypes of schizophrenia are generally not studied separately and studies involving patients with schizophrenia also include patients with schizoaffective disorder . AlthougThe use of risperidone was associated with a higher risk to switching in our cohort. Despite widespread use, low price, and no clear differences in effectiveness compared to those of other SGAs risperidone produces more movement disorders and prolactin increase than do other SGAs . In a stPatients using clozapine switched less than did patients using other SGAs. Meta-analyses have shown that clozapine is more effective than other SGAs, being superior for positive symptoms in the short and long term . RegardiHowever, clozapine is used less frequently and later in treatment. Studies have shown that there are long delays in starting treatment with clozapine in resistant patients . GuideliThis is the first national cohort study that assessed the factors associated with switching of SGAs dispensed by the Brazilian public sector over 10 years. The use of a nationwide pharmaceutical database allowed us to investigate a large quantity of data on the use of antipsychotics in real-life and to obtain a representative and very large patient population with schizophrenia. Our clear and comprehensive methodology led to robust findings to the public health which could direct future researches.There are some limitations of this study. First, despite the reliability of the data, the diagnoses were not validated. Second, SIA/SUS is an administrative database that does not consider dispensation from private pharmacies, which could lead to an underestimation of the use of these antipsychotics. Nevertheless, APAC/SIA covers more than 70% of the Brazilian population (more than 148 million inhabitants). Third, as an administrative database, it is not intended for research purposes and may have system data feed errors. However, we carefully checked data inconsistencies to avoid this type of bias and excluded patients who received antipsychotics only once or for less than 90 days. Fourth, detailed clinical data, comorbities, use of concomitant drugs, as well as the reasons that determined the switches are unavailable because the original purpose of this database is to register the consumption, the charge, and the payment of dispensing high-cost medicines.This nationwide cohort study elucidated the factors associated with SGAs switching in a real-world setting. The choice of the prescribed antipsychotic can determine the trend for switching and affect the long and short-term outcomes for patients with life-long disorders. The findings of our study have implications for future research.