Transcutaneous electrical nerve stimulation (TENS) is the usage of a mild electrical current through electrodes that stimulate nerves. Patients with malignancies experience pain and chemotherapy-induced peripheral neuropathy. A systematic review was performed to find research evaluating the effect of TENS on these two common symptoms decreasing the quality of life in cancer patients. PubMed, the Cochrane Central Register of Controlled Trials and EMBASE were searched. Original studies, namely randomized controlled trials, quasi-randomized controlled trials and controlled clinical trials, published between April 2007 and May 2020, were considered. The quality of the selected studies was assessed. Seven papers were incorporated in a qualitative synthesis, with 260 patients in total. The studies varied in terms of design, populations, endpoints, quality, treatment duration, procedures and follow-up period. Based on the results, no strict recommendations concerning TENS usage in the cancer patient population could be issued. However, the existing evidence allows us to state that TENS is a safe procedure that may be self-administered by the patients with malignancy in an attempt to relieve different types of pain. There is a need for multi-center, randomized clinical trials with a good methodological design and adequate sample size. Around 70% of cancer patients experience pain. It significantly influences health-related quality of life (HRQoL), being a subject of interest with regard to numerous instruments used for HRQoL assessment . In halfTranscutaneous electrical nerve stimulation (TENS) is the usage of a mild electrical current through electrodes that stimulate the nerves. The battery-powered hand-held stimulating device passes an electrical current through the intact skin surface. The TENS device modulates the frequency, width, duration and intensity of the pulse ,13,14. JThe reasons for TENS application are various . In the Thus far, two systematic reviews (SR) have been performed on TENS usage for cancer-related pain, the last one ten years ago. Both studies were inconclusive due to the insufficient amount of randomized controlled trials (RCTs) that could be included in the review ,21. The A review regarding neuromuscular electrical stimulation (NMES) usage and safety in cancer patients was performed. Nevertheless, due to critical differences between the two techniques, the conclusions cannot be transferred .The aim of the current study was to assess whether TENS is effective for pain or chemotherapy-induced peripheral neuropathy management in comparison to sham TENS or no treatment or standard management in adult cancer patients.The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to perform a systematic literature search and review . The maiThe study question was defined using the ‘patient, intervention, comparison, outcome’ (PICO) strategy, as shown in The MeSH terms used for the MEDLINE/PubMed search and the strategy applied for EMBASE are provided in the A systematic search was performed independently by MP and KAT in April 2020, and repeated by MP, KAT, AGW and RPM in August 2021. All titles and abstracts were revised by all researchers in order to check against the eligibility criteria. Chosen papers underwent full-text review, with reference screening for eligible papers. Any disagreement was discussed between the reviewers and a supervisor, FE, until agreement was achieved. The selection criteria are presented in Additional quality assessment was performed with the usage of the validated five-point Oxford Quality Scale for included articles .Data extracted from selected articles included the name of the first author; year of publication; patients’ data ; type of intervention, type of comparator intervention, and type of study/trial design; outcome of intervention (baseline and end of study outcomes); type of scale used to measure pain/CIPN intensity; quality of life data; scale used for quality of life data assessment; adverse events (AEs); intake of analgesics. Availability of data for result analysis was checked.Primary—patient-reported pain/CIPN with the usage of commonly accepted and validated scales;Secondary—patients’ functioning; quality of life; intake of painkillers; adverse events (patients’ safety);Two authors, MA and KAT, judged the risk of the following biases in selected articles—selection bias; performance bias; detection bias; attrition bias; reporting bias. The Cochrane Collaboration’s risk of bias tool as described in the Cochrane Handbook for Systematic Review of Interventions was used. Any disagreement was resolved by a discussion between authors until a consensus was reached.Outcome measures were as follows:The PRISMA flow chart of the study selection process is provided in Seven studies published between 2007 and 2020 were included in this SR ,38,39,40The study by Robb et al., (2007) was a randomized, placebo-controlled, blinded, crossover study. Bennett et al., (2010) performed a randomized, placebo-controlled, blinded, crossover feasibility study. Papers by Ferreira et al., 2011 and Fiorelli et al., (2012) described randomized, placebo-controlled trials. Erden and Celic (2015) performed a randomized controlled study. Lee et al., (2019) was a randomized, double-blinded, placebo-controlled, crossover pilot trial. Finally, Siemens et al., (2020) designed a randomized, blinded, sham-controlled, pilot, crossover study.All studies allowed only adult patients and included 260 patients in total (range between 24 and 50 participants) aged 18 to 79 years.A description of the study populations is included in Details of pain managed by the intervention are collected in In all trials, the active arm involved conventional TENS (with high frequency of minimum 50 Hz and intensity causing paraesthesia without pain or motor contraction).Detailed characteristics of interventions are presented in 1. Primary outcome :In Bennett et al., (2010), NRS and a visual rating scale (VRS) were used to measure pain intensity. The points were baseline, +30 min, and +60 min. Additionally, the Short-Form McGill Pain Questionnaire (SF-MPQ) was applied before and after the procedure to measure pain quality. The primary endpoints were pain intensity at rest and on movement at +60 min. To measure pain sensation, Robb et al., (2007) used the Brief Pain Inventory (BPI) short form, completed at baseline and then every week and after the end of the treatment: +3 months, +6 months, and +12 months. Pain relief was also measured in patients’ daily diaries.Ferreira et al., (2011) used a visual analog scale (VAS) to measure pain intensity and severity at three time points: before the intervention, immediately after the intervention, and + 60 min. It was measured with patients at rest, with upper limb elevation, with a change in decubitus, and while coughing.Fiorelli and colleagues (2012) reported pain by VAS before thoracotomy and then at +6 h, +12 h, +24 h, +48 h, +72 h, +96 h, and +120 h. Erden and Celic (2015) assessed pain with the usage of VAS at rest and while coughing at +24 h, +48 h, +96 h, and +120 h after the operation. In the study by Lee et al., (2019), the SF-MPQ and VAS (resting and function) were applied to measure overall pain and pain intensity before the procedure and during three visits thereafter. Siemens et al., (2020) used BPI with NRS to measure the change in pain intensity during the preceding 24 h as the primary outcome. To measure the change in pain perception during TENS, a 7-point VRS was applied.2. Secondary outcomes :In Bennett et al., (2010), the authors used their own patient satisfaction questionnaire. AEs were assessed according to common terminology criteria for adverse events (CTCAE) v 3.0 at the end of TENS application and 48 h after completing each procedure .Robb et al., (2007) applied the Hospital Anxiety and Depression Scale (HADS), which was completed at baseline and then every week and after the end of the treatment: +3 months, +6 months, and +12 months. Patients’ functioning  was assessed at baseline and at the end of the intervention (each time). Patients reported the usage of painkillers in their diaries. Additionally, the authors devised a questionnaire that was used after completion of a 12-week study to measure patients’ satisfaction with each intervention. AEs were monitored.Fiorelli and colleagues (2012) reported respiratory function +72 h, +96 h, and +120 h after thoracotomy; additionally, the intake of narcotic medications received during the first 5 days after the operation was monitored.Erden and Celic (2015) assessed analgesics usage +24 h, +48 h, +96 h, and +120 h after thoracotomy. In the study by Lee et al., (2019), the functioning  and fatigue intensity (with the usage of VAS) were measured before the procedure and during three visits thereafter. To assess HRQoL, the European Organization for Research and Treatment of Cancer quality of life questionnaire C30 was used in the study by Siemens et al., (2020). The analgesics intake was also documented in this study.p = 0.04, which was considered significant), although there were no differences when the least and last recorded interference scores were compared. When assessing the brief questionnaire, TENS was recorded to be significantly more effective than during other arms of the study (Chi-squared p < 0.001). Overall, 63% of participants that finished the study decided to continue using the device; the group was the largest for TENS . Patients found the device easy to use and reported AEs to be minimal. The usage of painkillers was constant in 71% of patients .In the study by Robb et al., (2007), there were no statistically significant differences between groups in terms of worst pain, least pain, or average pain scores, as well as for pain relief scores from the patients’ pain diaries or BPI. Moreover, results for anxiety, depression, or the movement of the ipsilateral shoulder joint showed no differences between study arms. The authors reported that TENS ensured lower maximum pain interference scores  7.55 to 66.2%). No statistical significance was reached when using the NRS score for pain intensity and pain relief on movement.Overall, 37.5% of patients reported AEs (1.6 per patient); most of them were assessed as not related to TENS, with equal distribution in the active and placebo arms. Two withdrawals were connected to pain during the procedure (one during active TENS usage). Overall, the procedure was considered acceptable and safe.p = 0.038), and a trend was seen at +60 min with limb elevation (p = 0.05). The differences were not visible for coughing and changing decubitus. The paper by Ferreira et al., (2011) showed that pain severity was significantly lower at rest in the active group immediately after TENS application (p < 0.001) at different time points after the surgery: +6 h, +12 h, +24 h, +48 h, +96 h, and +120 h; moreover, pulmonary function was significantly better in the active arm. The morphine and non-opioid intake was lower in the TENS arm . One participant from the active arm refused to continue with the trial; in another three cases (one from the active and two from the placebo arms), other factors did not allow the authors to collect all measurements from the patients.In the work by Fiorelli et al., (2012), pain assessed on the VAS was significantly lower in TENS than in the control group (p < 0.05). Additionally, the analgesics consumption intake was lower in the test group: for opioid consumption, it was statistically significant at +48 h, +72 h, and +96 h; for non-opioids, it was significant at +24 h (p < 0.05).In the study by Erden and Celic (2015), the TENS group scored significantly better in terms of pain level. At rest, the TENS group performed better at the time point of +72 h; during coughing, the active group had a lower pain level at +48 h, +72 h, and +96 h . There were no differences in terms of changes in pain with function and oral function. TENS was also statistically more effective in the treatment of fatigue in comparison to the no-TENS arm (p = 0.03)Lee et al., 2019 showed that resting pain measured by the SF-MPQ and VAS decreased more after TENS than placebo/no TENS and the results were statistically significant , the change in pain intensity did not differ between groups. However, findings showed better responder rates for active TENS as a secondary outcome. One patient in each group found the procedure uncomfortable. The study showed TENS to be a safe and acceptable procedure, especially active in the case of women and people experiencing incidental pain. Risk of bias assessment with the usage of the Cochrane Collaboration’s risk of bias tool is presented in There is a very limited number of guidelines from international societies regarding cancer patients and TENS usage ,42. The In terms of safety, the work by Houghton and colleagues, which addresses the Guidelines of the Australian Physiotherapy Association and British Chartered Society of Physiotherapy, offers a chapter devoted to electrical stimulation and malignancy ,44. AccoAll trials selected for this SR revealed that TENS may show some effectiveness in certain areas of pain/CIPN treatment. However, due to the small sample sizes, it is difficult to draw any far-reaching conclusions, and there is a significant risk of producing incorrect estimates. The studies were not homogenous in terms of their design, population, comparison groups, outcomes, quality, treatment duration, procedure administration, or follow-up period. Additionally, studies lacked details allowing their replication.Pain is a complex symptom, and, in these RCTs, it was assessed by both one-dimensional scales (such as VAS or NRS) and validated questionnaires. The number of instruments used in the included studies, as well as the different timing of pain measurement, makes it difficult to compare the results between the studies. Moreover, it was rarely described how patients were instructed about rating their pain severity on a chosen instrument. Of great value would be a simple statement indicating whether a measurement was performed during TENS or after its ending, as there are suggestions for maximum pain relief with ongoing use . One mayUnlike in the study by Hurlow et al., (2012), the trial by Gadsby et al., (1997) was not included in this SR. The reason for this was the exclusion of studies using acupuncture-like TENS as a study intervention in this SR. There are data suggesting that some conditions, especially common in the cancer patient population , influence these two types of TENS  in a different manner. This statement makes reporting in trials on TENS conditions used as an intervention even more important.There were very few AEs described in the studies, with no serious AEs, although only three of the trials reported them ,37,39.One study incorporated HRQoL as a secondary objective with the usage of a validated tool, and, therefore, it was impossible to report on this secondary outcome in this SR .There was consistency with the results of other systematic reviews. Similarly to our study, the vast majority of SRs concerning the usage of TENS in various settings are inconclusive, e.g., concerning phantom pain, neuropathic pain, fibromyalgia, cancer-related pain, or chronic pain in adults ,45,46,47Economic analysis of TENS was not an aim of this study; however, an assessment of the cost-effectiveness of this procedure is being applied in planned RCTs . CurrenThis study has certain limitations. As TENS is commonly connected to acupuncture techniques, there are probably a number of studies performed in Asian countries, so involving a search of local databases for trials conducted in Asian countries could offer some new data. On the other hand, it is quite probable that searching the references for the chosen RCTs and existing related SRs would reveal such studies if they were of good quality. The authors of this SR decided not to follow this SR with a meta-analysis due to the limitations of the selected papers and did not contact the authors of the included RCTs if data were missing, in order to obtain a clearer picture of these studies. As the inclusion criteria allowed not only RCTs but also quasi-RCTs and controlled clinical trials, the study by Erden and Celic (2015) was not excluded from the qualitative analysis, even though it received only one point on the Jadad scale. The risk of missing articles in the literature search phase is a possible bias. We attempted to minimize this using a variety of adjusted key terms and repeating the process.Following the results obtained in this research, we propose the following recommendations.TENS cannot be implemented as a standard procedure for pain or CIPN treatment in the cancer patient population;TENS can be used in patients with cancer and pain or CIPN, but this decision should be individualized and performed in a multidisciplinary team setting;TENS is a safe procedure with a small number of AEs;Staff should be trained in terms of what TENS is and where the cancer patients with pain or CIPN not reacting to standard treatment can access this treatment option.Recommendations for clinicians:Patients should be informed about the possibility of using TENS in the case of different types of pain or CIPN not responding to standard treatment;Patients should be trained in terms of TENS device usage if they wish to use it;Patients should not resign from the standard pain treatment in order to implement TENS;If TENS application leads to the lowering of the dose of analgesics, it can be allowed;TENS can be applied as a safe and easy-to-use procedure.Recommendations for patients:Validated scales  should be implemented and patients should be trained in terms of using them;Minimal sample size should be counted according to existing suggestions/power calculations should be applied;Pain characteristics should be precisely described ;Efforts should be applied to blind a procedure, patients, and staff;Short- and long-term AEs should be followed up;Follow-up period should be planned;TENS settings should be described ;Planned trials should be multicenter;Separate trials regarding the treatment of CIPN should be planned in a cancer patient population.Recommendations for researchers planning future trials:Currently, the data do not support the recommendation of TENS as a standard procedure for the treatment of different types of pain or CIPN in the cancer patient population. However, the existing evidence allows us to state that TENS is an easy-to-use and safe procedure that may be self-administered by patients with malignancy in an attempt to relieve different types of pain after individual consultation with healthcare specialists. To give clear instructions about the type of pain or/and specific cancer patient populations where TENS could be especially effective, future, well-designed trials with a longer follow-up period are needed. The existing data suggest pain relief on movement and acute postoperative pain as promising fields of study. Additionally, the sample size has been calculated and suggested for future trials ,53.


In respect to the ophthalmologic chart evaluation for PD patients, the most frequent disturbances were identified in the Ishihara color perception testing (33%). The regression analysis showed significant results for the Ishihara testing in relation to the cpRNFL thinning in the temporal retinal sectors for both eyes. cpRNFL thinning was predominantly contralateral to the parkinsonism (p = 0.001). The temporal and global values of the cpRNFL were significantly lower in all PD patients < 70 years old, compared to the age-matched healthy controls. (4) Conclusions: Specific patterns of cpRNFL thinning were found in the PD subjects younger than 70 years. A multidisciplinary approach is essential for a complete evaluation of PD patients.(1) Background: The purpose of this paper is to report the data of the first study in a Clinical Research Hospital, in the Transylvania region, focusing on the Spectral Domain Optical Coherence Tomography (SD-OCT) measurements in the early stages of Parkinson’s disease (PD), and to compare the results with age-matched healthy controls. (2) Methods: This study assessed the circumpapillary retinal nerve fiber layer (cpRNFL) SD-OCT measurements  of two study groups: patients suffering from PD (Hoehn−Yahr stages 1–3) and healthy controls. Secondary objectives were to investigate the reported visual symptoms by evaluating the color vision, contrast sensitivity, and the central visual defects for macular disease using standardized charts. Subjects with prior history of ophthalmologic diseases, advanced stages of PD (Hoehn−Yahr stages 4–5), or with psychiatric conditions were not included in this study. The same team of neurologists and ophthalmologists evaluated all individuals in order to have comparable data and to eliminate inter-examiner differences. All subjects were recruited from the same Clinical Research Hospital in the Transylvania region, Romania. (3) Results: 72% of the PD patients ( HighlightsMore than two thirds of the PD patients reported at least one visual symptom33% of the PD patients had color vision disturbancesp = 0.001)cpRNFL thinning was predominantly contralateral to the parkinsonism More than 200 years have passed since James Parkinson first described in detail “the shaking palsy”, known today as idiopathic Parkinson’s disease (PD). Researchers and clinical practitioners continuously discover and study this complex neurodegenerative pathology. PD has gone through many epochs of both diagnosis and management, being, nowadays, mostly clinically diagnosed and unsatisfactorily treated with dopamine substitutes. We know today that PD is characterized by a combination of both, the well-known motor and the non-motor symptoms, including visual function changes ,2,3.Optical coherence tomography (OCT) is a non-invasive, easy-to-perform technique, which uses the infrared light to scan the retinal structure. Some authors compare OCT  with ultrasonography , because of the similar principles involved in the scanning process. The value of OCT is well established in ophthalmology, but it has recently grown to provide neurologists with important information regarding the retinal changes in different neurological diseases . Because the retina is part of the central nervous system, it is important to have a tool that can analyze it in vivo, non-invasively ,7,8,9.It is known that the retinal dopaminergic cells send axonal projections to the inner and outer plexiform layers, synapsing with the horizontal cells. If these cells are affected in PD, then thinning of the inner retinal layers could be found by OCT examination. ,10,11,12Regarding the lateralization of cpRNFL thinning and the predominantly affected body side in PD, other authors have found that retinal thinning is contralateral to the parkinsonism ,19,20. AMost of the patients included in our study come from Cluj County, which is one of the most populated areas in Transylvania ,23. In 2The purpose of our research is to investigate and compare the circumpapillary retinal nerve fiber layer (cpRNFL) measurements in PD patients with age-matched healthy controls. By doing so, we intend to evaluate the SD-OCT measurements in the early stages of PD. Secondary outcomes are to investigate PD-related visual symptoms and to characterize the study population.n = 6) in the individual age groups, and the comparison between the two study samples (PD and controls). We also studied the lateralization of the cpRNFL in respect to the parkinsonism and evaluated the relation between cpRNFL values and disease severity. To our knowledge, this is the first study of this kind that has been done in a Clinical Research Hospital, in the Transylvania region, Romania. By studying the OCT measurements in this region, we can compare the data of our research to previous studies and point out the similarities or differences.A distinctive feature of our research is the analysis of each retinal sector (n = 17 PD patients) with Parkinson’s disease in the early stages of evolution, and 23 eyes of age-matched healthy controls , all of which were Caucasian individuals. For each PD patient in this study, we enrolled an age-matched healthy control (HC). In addition, age stratification was done for both study groups, in order to control this potential confounder. The PD patients were recruited from the Neurology Clinic I of the Emergency County Hospital Cluj-Napoca, while the HC were recruited from the Ophthalmology Clinic of the same hospital. Healthy individuals were considered those who did not suffer from any chronic neurologic or ophthalmologic disease.This observational, prospective study evaluated six retinal sectors in 30-patient eyes  adheres to the Declaration of Helsinki, and was approved by the review boards of the University of Medicine and Pharmacy “Iuliu Haţieganu” Cluj-Napoca, Romania, and the Emergency County Hospital Cluj-Napoca, Romania. All necessary precautions were taken to preserve the confidentiality of the patients’ data.The inclusion criteria were as follows: patients > 18 years, suffering from PD (Hoehn−Yahr stages 1–3), who agreed to participate in the study. Patients with a medical history of a severe ocular disease , which could influence the results, and those with advanced stages of PD and related complications, were excluded. All patients were receiving optimal dopaminergic medication at the time of study enrollment. Examination took place in the “on-therapy” period in order to avoid examination difficulties. All subjects had normal intraocular pressure values measured by aplanotonometry.All enrolled individuals (PD patients and HC) underwent a complete neurologic and ophthalmologic examination, including visual acuity testing, visual field exam, ophthalmoscopic examination, biomicroscopy, and measurement of the intraocular pressure. The color vision testing was done, using the Ishihara charts, for both eyes separately. The central visual defects for macular disease were tested with the Amsler grid . The contrast sensitivity was tested with the Pelli-Robson letter chart. A questionnaire was used for reporting the visual symptoms.n = 4 PD and n = 11 HC) from the OCT analysis due to various causes . The Spectralis SD-OCT device  was used to examine all subjects in order to have comparative data. The SD-OCT device had the Eyetracking module enabled, in order to prevent motion artefacts due to tremor or eye movements. The cpRNFL thickness was measured in six retinal sectors: temporal, temporal-superior (TS), nasal-superior (NS), nasal (N), nasal-inferior (NI), temporal-inferior (TI), and a global value was automatically provided by the machine’s software  and CDC Epi Info version 7.2.4.0 software. For the data analysis, we used tables and graphs of the most significant results, and descriptive analyses were represented as mean ± standard deviation (SD). ANOVA and Student’s The preliminary results of this ongoing study included 30-patient eyes with PD in the early stages of evolution and 23 age-matched healthy control eyes.The mean age of the PD patients was 68 ± 8.92 years, while that of the controls was 57.12 ± 10.95 years. Most PD subjects were in the 60–69 year (44%) and 70–79 year (39%) age groups. The gender distribution of the PD subjects showed an asymmetry, favoring men (78%) versus women (22%).Most PD patients come from urban areas of Transylvania, Romania (94%), and are retired from their professional activity, according to the legal age (89%). Furthermore, 61% of the PD subjects report no professional toxic exposure in the past, while 89% are non-smokers.The most frequently encountered PD subtype was the tremor predominant type (66.5%), versus the akinetic-rigid predominant type (27.5%) and the equivalent type (6%) see .Moreover, 44% of PD patients had a disease evolution of ≤ 5 years (mean 3.17 ± 1.03 years), while the longer disease evolution categories had a similar distribution (17–22%). The analysis of the PD subjects according to the MMSE scores revealed a distribution in favor of the MMSE scores of 25–29 points (50%) and 30 points (38.8%). The Hoehn−Yahr grading scale showed an approximate similar distribution between stages 2–3.r = 0.121 in the PD sample.  with ple. see The ophthalmologic chart evaluations showed the highest percentage of disturbances in the PD sample for the color perception tests (33%), compared to the Amsler grid distortions (11%) and the modified contrast sensitivity (22%).p = 0.001).In the PD sample, the most motor-affected body side was the right side (65%), while the most predominant retinal thinning was observed in the left eye (71%). The analysis of the lateralization of the parkinsonism in relation to cpRNFL thinning revealed that the predominant retinal thinning measured by OCT was contralateral to the parkinsonism .Lateralization was analyzed for each PD individual separately see . Moreovet-test for independent samples were used to compare the mean cpRNFL thickness of PD patients with age-matched controls, and revealed statistically significant results in the temporal, nasal-inferior (NI), and global value of all age groups < 70 years old. Each age group displayed specific patterns for thinning. In the 40–49 year old age group, the temporal, nasal-superior (NS), nasal-inferior (NI), and global value were significantly thinner in both tests (ANOVA and t-test). In the 50–59 year old age group, the temporal, temporal-superior (TS), NI, and global value were significantly thinner, while in the 60–69 year old age group, the temporal, TS, NI, temporal-inferior (TI), and global value were thinner.In p = 0.001), but also for the TI value in the 60–69 year old age group (ANOVA p = 0.0002).Highly significant results stood out for the global value in the 50–59 year old age group  of the temporal, TI quadrants, and global values in the PD sample (blue) and controls (green), according to each age group, is visualized in p values for the Ishihara testing in relation to the cpRNFL thinning in the right eyes for the temporal quadrant (p = 0.014) and global value (p = 0.004), and in the left eyes for the temporal quadrant (p = 0.047). In addition, the presence of the non-motor symptoms showed significant results for the right eye global value (p = 0.040) and the left eye temporal quadrant (p = 0.011) and global value  of PD is between the ages of 45 and 70 years old, but many authors believe that the pathological process begins as early as 10 years before the first clinically evident signs and symptoms. This observation might be an important milestone in trying to find a specific and sensitive biomarker to diagnose PD reliably in earlier stages of evolution ,25,26.In the category of non-motor features, visual function changes were found to be present in 78% of the parkinsonian patients, according to Sauerbier and colleagues in 2013 . DespiteIn 2000, Pieri and colleagues revealed that PD patients often complained of blurry vision, which they thought to be influenced by disturbances in color discrimination and contrast sensitivity. It is believed that the perifoveal dopaminergic cells are reduced in PD. Some authors have stated that the visual function may be influenced by medication (Levodopa), although Pieri and colleagues did not find any correlation in their study . In our All these visual disturbances have complex pathogenetic mechanisms and many have insufficient explanations. Some authors believe that dopamine has an important role in retinal function. D1 and D2 receptors have been found in the retina. These dopamine receptors are implicated in the transition from nocturnal to diurnal vision, but also in pre-processing images, increasing the contrast sensitivity, color discrimination, and others .The main dopaminergic neurons in the retina are considered to be the amacrine and interplexiform cells. These neurons send axonal projections into the internal and external plexiform layers of the retina towards the horizontal cells. Thus, dopaminergic cell loss in the retina would generate a thinning of the inner retinal layers see , which ct-test). In the 50–59 year old age group, the temporal, TS, NI, and global values were significantly thinner, while in the 60–69 year old age group, the temporal, TS, NI, TI, and global value were thinner.In our study, the cpRNFL was thinner, with statistically significant results in the temporal, NI, and global value of all age groups < 70 years old. Each age group displayed specific patterns for thinning. In the 40–49 year old age group, the temporal, NS, NI, and global values were significantly thinner in both tests (ANOVA and p = 0.001), but also for the TI value in the 60–69 year old age group (ANOVA p = 0.0002).Moreover, highly significant results stood out for the global value in the 50–59 year old age group .In 2004, Inzelberg and colleagues studied the thickness of the peripapillary retinal nerve fiber layer in PD by using an OCT device, and demonstrated that the temporal-inferior (TI) sector was thinner in PD compared to the healthy controls . They alIn 2014, a meta-analysis conducted by Ji-guo Yu and colleagues on 13 studies comparing the RNFL thickness by OCT in PD with healthy controls, revealed a significant thinning mostly in the temporal retinal quadrant in PD patients. They argued that the temporal fibers, involving the papillomacular bundle, are more susceptible to neuro-degenerative disease processes. It is, however, relevant to specify that these studies were based on different OCT devices . Visser In 2014, Schneider and colleagues presented the results of their study on parkinsonian monkeys, who were evaluated with OCT in vivo. They demonstrated the thinning of the RNFL in the nasal-inferior (NI) quadrants of the retina in the predominant akinetic-rigid forms of parkinsonian monkeys. The macular volume and foveal thickness were also reduced .The NI quadrants were found to be thinner in the akinetic-rigid type of PD compared to the tremor dominant type, according to Rohani et al., based on his study of 27 PD patients .Another study conducted by Jeeyun Ahn et al. in 2018 showed, by examining PD patients with OCT and PET scans, that the retinal thinning in the TI quadrants revealed by OCT was correlated well with the dopaminergic loss in the nigral substance revealed by the PET scans. They emphasized the importance of the OCT in evaluating PD patients in the early stages of the disease .In 2015, Slotnick et al. studied the foveal thickness by OCT in 72 PD patients and concluded that the superior-inferior foveal slope was mostly thinned in these patients .r = 0.121 in the PD sample.In 2014, Jimenez and colleagues studied the cpRNFL of 52 PD patients compared to healthy controls, and came up with a potential valuable formula that could predict disease severity. This was possible because of their observation that the cpRNFL gradually diminishes with the disease evolution. They also believed that OCT measurements could be useful tools in differentiating PD see  from othp = 0.001). Previous studies examined randomly only one eye, but this method fails to take into consideration the possibility of lateralization of the parkinsonism regarding retinal thinning [Our study reveals an important link to lateralization of the cpRNFL with parkinsonism, showing that the predominant retinal thinning measured by OCT was contralateral to the parkinsonism  is reduced in the eye that is contralateral to the tremor and parkinsonism, both in PD and essential tremor patients. This reveals the asymmetry of these diseases .p = 0.001) in our PD sample. Despite this, more data are still needed to confirm this supposition and to establish screening programs for visual function changes in PD patients.On the other hand, from a clinical  point of view, considering screening larger populations of PD patients for visual function changes could raise problems regarding evaluation times. Each thorough ophthalmologic examination (including OCT) of each patient takes time. This generates delays in examining large PD populations and reduces the chance for timely and optimal therapeutic management. This in turn decreases the QoL for our patients. A time-saving solution could represent scanning only one eye (the left retina) in the screening process, as we showed that the left retina was predominantly affected . With regard to this, for future studies, it would be beneficial to have a large sample size in order to eliminate such errors.Some authors have found thinning of the inner retinal layers in the macular region. The fovea is considered to be important in color vision and contrast sensitivity because of the richness in photoreceptors. Therefore, foveal thinning should explain the reduced color discrimination and contrast sensitivity in PD patients. Garcia-Martin et al. found a negative correlation between the thickness of the nerve fiber layer (representing the axons of the ganglion cells of the retina) and the Hoehn−Yahr staging, explaining the possibility that foveal thickness may predict the severity of PD. Other authors have not found any correlations regarding this issue ,20. Our Despite the fact that 30 to 60% of PD patients develop visual hallucinations (VH) in the evolution of the disease, Kopal and colleagues believe that these symptoms have no link to the retinal changes, because they did not find any retinal thickness differences between 15 PD patients with VH compared to 15 PD patients without VH [In 2018, in an editorial, Onofrj and Gilbert estimated the prevalence of the VH related to PD to be 22–38%. The VH seemed to be correlated with increased mortality and cognitive decline. They cited Firbank et al., who, with the help of Magnetic resonance spectroscopy, demonstrated that in PD with complex VH there were reduced concentrations of GABA in the visual cortex, thereby exonerating the retina for being implicated in the appearance of the complex VH .In 2019, Leyland and associates studied the retinal volume in PD patients with dementia, and concluded that the thinning of the ganglion cell layer and the inner plexiform layer was correlated with the risk of PD dementia . In thisp = 0.42) in 1227 Caucasian individuals [The gender distribution of the PD subjects in our study showed an asymmetry, favoring men (78%) versus women (22%). Despite this, according to Mauschitz et al. (2019), there were no significant differences between cpRNFL SD-OCT measurements between men and women . The practical outcome of the study is represented by the need of continuous ophthalmological monitoring of PD patients in order to identify further changes along the evolution of this condition over time.


Considering the limited data, we aimed to identify the greatest immune activation irradiated site of common metastases and response to immune checkpoint inhibitors simultaneously in non-small cell lung cancer (NSCLC).A total of 136 patients with advanced NSCLC who had received radiation to a primary or metastatic solid tumor were enrolled. We recorded blood cell counts in three time periods, before, during, and after radiotherapy (RT), and derived some blood index ratios including monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The delta-IBs were calculated as medio-IBs ÷ pre-IBs − 1. We analyzed the changes before and during RT using Spearman rank correlation test, Kruskal–Wallis rank sum test, and logistic regression analyzing their correlation with efficacy.The medians of delta-MLR and delta-PLR were both the lowest while the median of delta-L was the highest in brain. Therapeutic effect evaluation showed that the objective response rate (ORR) of 48.65% (18/37) in the brain irradiation group was the highest, compared with 17.07% (7/41) in bone and 41.94% (13/31) in lung.In this study, results suggested that irradiation to brain has the best immune activation effect and patient outcome compared with other organs in NSCLC, and when the earlier-line ICIs were combined with RT, a better patient outcome was reached. Prospective studies are also necessary to provide more convincing evidence and standards for clinical irradiation metastases selection. Advanced NSCLC is the most common pathological type in lung cancer with a 5-year survival rate of less than 5% . After tRT mainly activates immune system by enhancing antigen presentation, as well as increasing the infiltration of inflammatory cells . StudiesIn terms of lung cancer, common distant metastatic sites include brain, bone, liver, adrenal gland, contralateral lung, and draining lymph node, which indicate a poor outcome frequently . HoweverThis retrospective study intended to find out the strongest irradiated sites in immune activation effect and treatment response with immunotherapy in advanced NSCLC. A total of 136 patients were included in the analysis, who had received radiation to any organ for a primary or metastatic solid tumor during immune monotherapy or combined with chemotherapy or vascular endothelial growth factor receptor (VEGFR) therapy in Shandong Cancer Hospital from July 2018 to February 2021. The inclusion criteria included age, gender, height, weight, smoking, drinking, Karnofsky performance status (KPS), TNM staging, pathological pattern, treatment stage, medication of immunotherapy, and the modality of RT. The exclusion criteria included SCLC patients, age under 18 years old, KPS score under 70, III or earlier-stage NSCLC, and radiotherapy before or after immunotherapy. The patients were all staged according to the American Joint Committee of Cancer eighth edition TNM classification and staging system . The datAll patients were treated with ICIs intravenously every 3 weeks regardless of the expression of PD-1 or PD-L1. Some of them were subjected to combination chemotherapy and the regimens included pemetrexed, docetaxel, and gemcitabine, with or without platinum. VEGFR was added to some patients, and several patients were treated with the combination of the above three therapeutic regimen. As for the VEGFR, the representations are mainly Bevacizumab and Anlotinib. During the immunotherapy, patients underwent 10 to 30 fractions of CFRT at 1.7–4.5 Gy per fraction, or 5 to 10 fractions of SBRT at 5.0–10.0 Gy per fraction for cancer of any histologic type and site  simultaneously. These sites were irradiated according to patients’ symptoms or clinical relevance preferentially, once daily, five fractions per week. Radiation plans were normalized in that 95% of the plan tumor volume received 100% of the prescribed dose. Besides, doses of organs at risk (OARs) were limited within the safe range.Blood cell counts were recorded for all patients in three time periods. The first stage was about 1 month before RT, during which the blood indicators were called pre-inflammatory biomarkers (pre-IBs). The other two stages were during and after radiotherapy, called medio-inflammatory biomarkers (medio-IBs) and post-inflammatory biomarkers (post-IBs), respectively. Pre-IBs were specifically defined as from the first day of immunotherapy to the beginning of radiotherapy. Medio-IBs simply referred to the blood indicators between the first and last day of radiotherapy. While considering the memory effect of immunotherapy, post-IBs were defined as the period from the end of radiotherapy to 2 months after the end of immunotherapy, before the next line treatment. We recorded blood cell counts more than once in each period and then averaged or derived them, including neutrophils, lymphocytes, monocytes, platelets, MLR, NLR, PLR, and SII. The delta-IBs were calculated as follows:The evaluation of the RT to different sites during immunotherapy was based on immune response criteria in solid tumor (iRECIST) . The enhα, whose significance was assumed at less than 0.0083 (0.05/6). Univariate logistic regression analysis was performed to evaluate the effect of independent variables on short-term efficacy. We also conducted the factors whose p-value were lower than 0.05 into multivariate analysis in case of missing indicators that might have clinical significance. IBM SPSS Statistics software, version 25.0 , was used for statistical analysis.We converted the continuous variables in the study into binary variables by using receiver operating characteristic (ROC). Spearman rank correlation test was used to compare the correlation between blood indexes and different irradiated groups and short-term efficacy. If the correlation coefficient is greater than 0.2, it is considered to have statistical correlation. Kruskal–Wallis rank sum test was used to determine which indicators have differences within groups and then to compare pairwise with a corrected Clinical baseline characteristics of the 136 patients enrolled are summarized in r = 0.339, 0.383, and 0.271, p < 0.001) and delta-L was negative . After Kruskal–Wallis rank sum test, it was found that three of these four indicators have inter-group differences, namely, delta-MLR, delta-PLR, and delta-L . Then, we performed pairwise comparison among groups based on the three indicators, and significance was assumed at p less than 0.05 (p = 0.000 and 0.002). The median was lowest in the brain group, but highest in adrenal gland . Similarly, in delta-PLR, there was statistical difference between the brain group compared with the bone, lung, and adrenal gland group , and the medians of the four groups increased in turn . However, it was the highest in brain in terms of delta-L , which statistically differed from bone, lung, and adrenal radiotherapy groups as well . Besides, there were subtle differences between lung and bone in meaningful indicators , 72 patients were SD , and 15 patients were PD , yielding an ORR of 32.03% (41/128) and a CBR of 88.28% (113/128).p = 0.021] and treatment stage  .In the univariate analysis of Binary logistic regression, we found that two factors were significantly associated with short-term efficacy, which were groups  Table 3.The therapeutic evaluation of each group showed that the ORR of 48.65% (18/37) in the brain irradiation group was the highest, compared with 17.07% (7/41) in the bone group and 41.94% (13/31) in the lung group Figure 2The combination of radiotherapy and immunotherapy seems to be a major treatment in NSCLC in the future. However, compared with more regulated immunotherapy, the irradiated site and modality of radiotherapy are still inconclusive to date . In clinThe results of this analysis that enrolled 136 patients showed that the medians of delta-MLR and delta-PLR were the lowest and that of delta-L was the highest in the brain radiation group during immunotherapy. Considering the significance of blood indicators in the immune system , we hypoStudies have revealed that primary metastases had various levels of genomic heterogeneity to distinct tumor migration patterns . RelatedIn recent years, RT especially SBRT for oligometastases (OMs) made a big progress in NSCLC. The concept of OMs was firstly proposed in 1995 by Hellman and Weichselbaum, of which the consensus was established by the ESTRO and ASTRO committee in 2020 referring to 1–5 metastatic lesions, with a controlled primary tumor being optional and all metastatic sites being safely treatable , 41. ManAnother concept of “Dissociated Response” (DR) was defined as the coexistence of responding and non-responding lesions within the same patient in the evaluation of cancer systemic therapies . The incBy means of this clinical retrospective study, we can further explore the mechanism of this phenomenon performed as an immune activation effect of different irradiated sites during ICIs. Understanding the differences of related molecular pathways, inflammatory cell infiltration, and protein expression plays a guiding role in discovering irradiated organs’ heterogeneity, which could maximize the benefit of radioimmunotherapy. In future prospective research, attention should be focused on the following points: firstly, the choice of time point, the best choice of patients treated firstly in order to reduce interference with the results; secondly, the screening of clinical indicators and laboratory molecular phenotypes; and finally, the proper statistical analysis of results.To date, this is the first study in advanced NSCLC to evaluate the differences between immune system activation and short-term efficacy of radiotherapy for primary lesion or distant metastases during immunotherapy. However, there are several limitations in this study. As it is a retrospective analysis, the characteristics of clinical cases were complex. For example, earlier multi-line treatments and local radiotherapy were involved, which might have delayed the effect on immunotherapy subsequently. Also, there are various kinds of ICIs and regimens, which may influence the efficacy of immunotherapy. Prospective clinical trials are warranted to provide more convincing evidence and specific standards for combination therapy with RT and immunotherapy in advanced NSCLC.We have seen the differences in systemic immune activation after RT to the brain, bone, lung, liver, adrenal gland, and soft tissue during immunotherapy synchronously. The lowest medians of delta-MLR and delta-PLR, the highest median of delta-L, and the greatest ORR suggested that irradiation to brain may have the strongest activation effect and best short-term efficacy compared to other organs, which could provide clinical guidance for patients with oligometastases undergoing SBRT and patients with DR. Moreover, we discovered that when the earlier-line ICIs were combined with RT, a better patient outcome was reached. Surely, we could not exclude the fact that the dose, volume, and modes for irradiated sites influenced the observed results. What we hypothesized was that RT to brain compared to other organs may be more immunomodulatory with simultaneous systemic immunotherapy. However, considering the limitations of this study, future prospective studies and lines of evidence are essential for standardizing the specific irradiated metastases, which could maximize the benefits of radioimmunotherapy in advanced NSCLC patients.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.MW, JL, SW, JRL, HW, JY, and XM contributed to the study. XM and JY designed the project and approved the final manuscript. JL made critical appraisals. JRL, HW, and SW are responsible for modifying and editing this article. MW collected the clinical patients information and drafted the article. All authors contributed to the article and approved the submitted version.This work was supported by the following grants: National Key Research and Development Projects of China (2018YFC1312201), the Foundation of National Natural Science Foundation of China , National Natural Science Foundation of China (81972864), the Academic Promotion Program of Shandong First Medical University (2019RC002), the Science and Technology Support Plan for Youth Innovation Teams of Universities in Shandong Province (2019KJL001), and the Medical Science and Technology Project of Henan Province (SB201901112).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 aim of this study was to assess the influence of a patient’s general status on perioperative morbidity and mortality after radical cystectomy, and to assess which of the used scales is best for the prediction of major complications. The data of 331 patients with muscle-invasive bladder cancer, who underwent radical cystectomy, were analyzed. The general status was assessed according to the American Society of Anesthesiologists (ASA), Charlson Comorbidity Index (CCI), Eastern Cooperative Oncology Group (ECOG), and Geriatric-8 (G-8) scales. Complications were classified according to the Clavien–Dindo classification system. In a group of patients with the highest complication rate according to the Clavien–Dindo scale, (i) statistically more patients rated high according to the ASA and ECOG scales, (ii) patients had significantly higher CCI scores (minor complications (I-II), and (iii) there were significantly more patients rated as frail with G8—predominantly those with 11 points or fewer in the scale. A patient’s general status should be assessed before the start of therapy because patients with a high risk of death or serious complications  should be offered conservative treatment. None of the scales can describe the risk of cystectomy, because the percentage of patients with major complications among those who achieved worse score results on any scale was not significantly different from the percentage of patients with major complications in the general group. Bladder cancer is the fourth most common cancer in men and the twelfth most common cancer in women . At presUntil recently, only age and standard clinical assessment were used to guide treatment decisions, but several scoring systems have been developed to recognize patients’ general status before RC. From those, Geriatric-8 (G8), the Eastern Cooperative Oncology Group (ECOG) scale, and the Charlson Comorbidity Index (CCI) are commonly used. To assess the risk of anesthesia prior to surgery, the American Association of Anesthesiology (ASA) scale is usually applied ,7,8,9.Platinum-based chemotherapy, which is commonly used in bladder cancer patients, is effective, but its use is limited by its severe, dose-limiting side effects . TherefoThe personalized approach also depends on the histopathological result of tissue taken during transurethral resection of the tumor before radical treatment. The majority of bladder cancers are classified as pure urothelial carcinoma, and the rest are assessed as other histological variants , includiBesides histology, a personalized approach should also include assessment of general and nutritional status, because low albumin levels can have a negative impact on the risk of perioperative morbidity, and hypoalbuminemia is a recognized risk factor of postoperative complications  and infection . HoweverThe patient’s general status should be assessed before surgery, using specially designed scales to adjust the type of treatment to the patient’s fragility status. The most common is the ECOG scale. Another scale is the CCI, which is an independent risk factor for postoperative mortality . It consThe G8 is a simple eight-item screening scale, which considers seven factors from the Mini Nutritional Assessment tool . It was This study aimed to explore the influence of the patient’s general status, measured by four designed scales , on perioperative morbidity and mortality related to RC. We also assessed which of the four scales is best in terms of prediction of major complications after RC. This retrospective study included data from 331 consecutive patients from three institutions who underwent RC between 2013 and 2021. Of these, 80 underwent operations by ORC, 61 by LRC, and 190 by RARC. The choice of surgical technique depended on availability in the department and the surgeon’s decision. Indications for RC were in accordance with the guideline of the European Association of Urology (EAU) [Surgery was performed by four different surgeons, but most laparoscopic and all robot-assisted surgeries were performed by the same operator. All consecutive patients that qualified for surgery in one center were operated by the same method, irrespective of any clinical variables .All patients underwent a preoperative examination, including routine laboratory tests, a chest radiogram, an abdominal ultrasonography scan, a computed tomography (CT) scan, and/or magnetic resonance imaging (MRI). Oncological variables and results were noted, and neoplasm staging was performed according to the TNM classification system .Anesthesia risk was assessed and scored according to the ASA physical status classification system. General status was assessed according to the CCI, ECOG, and G8 scales. Complications were classified according to the Clavien–Dindo classification system. Major complications were defined as a Clavien–Dindo score of grades 3–4, and minor as grades 1–2 . Groups Because this study was a retrospective chart review, informed consent was not required. All procedures were performed in accordance with the ethical standards of the Ethics Committee of the Nicolaus Copernicus University (number 439/2013) and with the Declaration of Helsinki (1964) and its later amendments or comparable ethical standards.p < 0.05 for all tests.The normality of the data was checked by the Shapiro–Wilk test. The chi-square test was used to identify associations between dichotomous and categorical data. The Kruskal–Wallis test was used to compare the patients’ results among the categories followed by the post hoc Dunn multiple comparisons test. Statistical significance was considered at Women accounted for 20.8% of the study population. The median age was 68.5 (range 17–91) years (Q1–Q3: 62.0–74.0), the mean age 67.82 (SD 9.32).Patients from the study group were scored according to the ASA, ECOG, and G8 scales. The details are presented in It was observed that according to the CCI, 106 patients (32%) had no chance of 10-year survival. In the rest of the group, the chance of 10-year survival was between 2% and 98% .In the whole group, the most frequent were Clavien–Dindo grades 1 and 2 (82% of patients), and the grades were dependent on the type of urinary diversion; when more complex urinary derivation is applied, a significantly higher percentage of patients suffer higher grades of complications .The percentage of minor complications was highest in patients with ASA 1 and lowest in those with ASA 4. Death (Clavien–Dindo grade 5) was only noted in patients assessed as ASA 4 and ASA 3 .p = 0.021)  .p > 0.05).At the same time, there were no significant differences in subgroups according to the type of urinary diversion (p < 0.01 vs. minor complications (1–2)—p < 0.01 and vs. major complications (3–4) p < 0.05) .Patients with the highest complication rate according to the Clavien–Dindo scale had significantly higher CCI scores  . In relap < 0.01; comparison vs. minor and vs. major p < 0.001) . In the group with Clavien–Dindo grade 5, there were significantly more patients rated as frail with the G8 scale, predominantly those with 11 points or fewer in the scale, whereas in the group of patients with minor and major complications, there were predominantly those with a cut-off level above 14  . When dip = 0.233, p = 0.404, and p = 0.165)). The same applies to the subgroups according to the urinary derivation .The study group was evaluated according to the nourishing status  therapy, while others with similar pathological grading are BCG refractory. Some tumors respond well to chemotherapy, and some are not chemosensitive. This suggests that urothelial carcinoma cannot be distinguished only on the basis of pathological examination, and outcomes of treatment cannot be predicted with the traditional classification system. The currently used pathological parameters of the tumor cannot fully reflect the true biological characteristics of bladder cancer. Therefore, a personalized approach to treatment according to the new findings of cancer biology and genetics is necessary to improve the outcomes of therapy and to distinguish those patients who require aggressive treatment. Current findings, based on transcriptional analysis, assign bladder cancer to one of two main molecular types: luminal and basal. With gene expression profiling, six subtypes were distinguished: luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous, and neuroendocrine-like .Luminal cancers arise in the superficial layer of the urothelium, and they show up-regulation of PARγ target genes with enrichment of FGFR3, ELF3, CDKN1A, and TSC1 mutations. However, basal tumors arise in deeper parts of the urothelium and show up-regulation of p63 target genes with enrichment of TP53 and RB1 mutations. It is also interesting that both types exhibit similarities to the basal and luminal subtypes identified in breast cancers. The recognition of those variants with an estimation of expression of only two markers, GATA3  and KRT5/6 , is important because both types show different clinical outcomes and lead to different therapeutic approaches. Both types show different responses to frontline chemotherapy, with the basal subtype exhibiting more aggressive behavior with shorter survival than luminal cancers, but with much better response to platinum-based chemotherapy .Proteins, which are synthesized from mutated genes and are overexpressed in luminal and basal subtypes of molecular subtypes of bladder cancer, may represent attractive therapeutic targets. They include E-Cadherin, HER2/3, Rab-25, and Src in luminal tumors and CD49, Cyclin B1, and FGFR in basal ones. Studies are ongoing on the use of specific agents personalized to the type of mutation present in the tumor cell. FGFRs are a family of receptor tyrosine kinases that are involved in tumor cell differentiation, proliferation, and angiogenesis. They can be upregulated in various tumor cell types, including bladder cancer. Erdafitinib, an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was approved for second-line treatment of patients who progressed following platinum-based chemotherapy. Its use is currently under investigation, and future implementation in bladder cancer treatment will be significant.Another way to personalize treatment would be to incorporate modern immunotherapy into the clinical setting, possibly combining it with cisplatin chemotherapy. These include atezolizumab (blocking anti-PDL1 antibody)  and atezNew discoveries in the field of molecular bladder cancer subtypes can improve treatment pathways of bladder cancer patients, not only in the advanced urothelial disease, but also in non-muscle invasive disease initially treated with transurethral resections and BCG installations. In the near future, various anti-tumor agents will be added to the treatment  ,28,29.Clinical use of molecular subtyping is under investigation, so the decision about the type of treatment in patients with advanced urothelial carcinoma is currently based on clinical data only. For this purpose, it is necessary to divide patients into risk groups, using the most reliable and safe method possible. For clinical assessment, designated scales have been developed, which divide patients into those with moderate, high, and very high risk of post-operative complications.Older adults generally have a worse prognosis and a higher postoperative complication rate. Therefore, radical treatment was proposed only to a small group of patients, and for the rest, only palliative treatment was used . CurrentIn the current study, we aimed to establish whether the personalized approach based on assessing risk with designed scales can be used, and whether the risk of complications can be determined before surgery. We also aimed to assess which of the four scales is best in terms of predicting major complications after radical cystectomy. It is interesting that the highest number of patients (58%) were screened as ECOG 0–1 and 35.2% as ASA 1–2. Self-reported results of the ECOG scale tended to present patients in better condition than the real situation, as seen by anesthesiologists . The G-8 is a short report scale, which should be used as a screening tool to identify patients in need of further assessment and appropriate geriatric assessment, with a threshold value of 14. Patients with a total score of 14 or lower are considered frail, and their radical treatment should be reconsidered. Indeed, in the group of patients with major complications, and in those who died, there were significantly more patients rated as frail . On the In our study, the complication rate depended on the type of urinary derivation, which concurs with reports from other authors. In contrast, the presence of diabetes, renal insufficiency class III or more, and lower levels of albumins did not have a negative prognostic value in terms of the complication rate (in relation to urinary derivation). This proves the importance of good nutritional preparation before surgery as well as controlled diabetes. In our previous studies, we have shown that the type of approach had an impact on complication rates, with a shift towards more frequent, higher-grade complications in the open approach than the minimally invasive ones (laparoscopic and robot assisted) . It was 2 retention and hypoventilation with decreased venous return can result in metabolic acidosis. Additionally, the Trendelenburg position with peritoneal gas insufflations increases the intraabdominal pressure and can cause increased intracranial pressure during lower abdominal procedures. Therefore, laparoscopy in elderly adults was contraindicated because of pneumoperitoneum in cardiac and pulmonary physiology. With improved anesthetic and operating techniques, these contraindications are not valid in most cases. Moreover, several studies have confirmed the benefits of laparoscopy in elderly adults, including reduced hospital stays, lower rates of pulmonary complications, and fewer wound-healing problems compared to traditional operative approaches [Modern minimally invasive methods of approach (LRC or RARC) reduce the number of minor and hemorrhagic complications . Howeverproaches ,38.The use of LRC and RARC also decreases complication rates in terms of surgical site infections . To conclude, evaluation of the patient’s frailty level and personalized geriatric assessment can lower the risk of complications.It is possible to safely modify the treatment of patients with advanced neoplasmatic disease even when the 10-year survival rate is very low. In our study group, even in older and frail patients, the risk of fatal complications was low, probably due to the use of a minimally invasive surgical approach with short operation time and low blood loss. The patient’s general status should be assessed before the start of therapy because patients with a high risk of death or serious complications  should be offered conservative treatment.In a clinical setting, it seems that none of the scales can ascertain the risk of cystectomy because the percentage of patients with major complications among those who achieved worse score results on any scale is not different from the percentage of patients with major complications in the general group . When more complex urinary derivation is applied, a significantly higher percentage of patients suffer higher grades of complications, so the patient’s general status should be assessed to personalize the type of urinary derivation. Precise pre-operative preparation of patients results in a significant reduction of complications; well-prepared patients in our study group did not show any differences in complication rates in relation to hypoalbuminemia, uncontrolled diabetes, or renal insufficiency.


Background and Aims: COVID-19 has been proven to harm adolescents' mental health, and several psychological influence factors have been proposed. However, the importance of these factors in the development of mood disorders in adolescents during the pandemic still eludes researchers, and practical strategies for mental health education are limited.Methods: We constructed a sample of 1,771 adolescents from three junior high middle schools, three senior high middle schools, and three independent universities in Shandong province, China. The sample stratification was set as 5:4:3 for adolescent aged from 12 – 15, 15 – 18, 18 – 19. We examined the subjects' anxiety, depression, psychological resilience, perceived social support, coping strategies, subjective social/school status, screen time, and sleep quality with suitable psychological scales. We chose four widely used classification models-k-nearest neighbors, logistic regression, gradient-boosted decision tree (GBDT), and a combination of the GBDT and LR (GBDT + LR)-to construct machine learning models, and we utilized the Shapley additive explanations value (SHAP) to measure how the features affected the dependent variables. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was used to evaluate the performance of the models.Results: The current rates of occurrence of symptoms of anxiety and depression were 28.3 and 30.8% among the participants. The descriptive and univariate analyses showed that all of the factors included were statistically related to mood disorders. Among the four machine learning algorithms, the GBDT+LR algorithm achieved the best performance for anxiety and depression with average AUC values of 0.819 and 0.857. We found that the poor sleep quality was the most significant risk factor for mood disorders among Chinese adolescents. In addition, according to the feature importance (SHAP) of the psychological factors, we proposed a five-step mental health education strategy to be used during the COVID-19 pandemic .Conclusion: In this study, we performed a cross-sectional investigation to examine the psychological impact of COVID-19 on adolescents. We applied machine learning algorithms to quantify the importance of each factor. In addition, we proposed a five-step mental health education strategy for school psychologists. Since it was first reported by the World Health Organization (WHO) on December 31, 2019, the coronavirus disease 2019 (COVID-19) has cumulatively infected more than 130 million people, and it caused nearly 3 million deaths worldwide as of April 14, 2021 , naturalAdolescents are members of society that are vulnerable to the psychological impacts of COVID-19. Many countries have closed schools to prevent the spread of the disease, resulting in multiple consequences for adolescents' daily lives: increased screen time, worry for their families and countries, social distancing, and home confinement. Given that adolescence is a critical neurobiological period in the development of higher-order cognition, stressful experiences, such as lockdowns and social isolation, can lead to the early development of multiple psychiatric disorders . Hawke eCOVID-19 cases recently rose for a seventh consecutive week with a rate of over 4.5 million new cases per week . ProlongTo this end, we performed a cross-sectional investigation based on 1,771 adolescents from six independent middle schools and three independent universities in Shandong province to examine the psychological impacts of COVID-19 on adolescents. We focused on psychological resilience, perceived social support, coping strategies, subjective social/school status, screen time, and sleep quality, constructed machine learning models for these factors, and applied the SHAP  to quantify the impact of each factor. In addition, we proposed a five-step mental health education strategy for school psychologists.The Ethics Committee of Shandong University approved this human-involved survey (ECSBMSSDU2021-1-067). Throughout the whole study, we strictly followed the Declaration of Helsinki, did not collect or involve any subject-identifying information, and electronically obtained informed consent from all of the participants.www.wenjuan.com). According to a statement from the WHO, individuals aged 10 – 19 years were defined as adolescents  and grade . We investigated the impact of COVID-19 on the participants' families, including having relatives or friends who had been infected (yes/no) and having relatives or friends who had been quarantined (yes/no).We also investigated two aspects of personal living styles: physical activity and screen time. Physical activity was assessed according to the average time spent participating in moderate to vigorous physical activity over the last week. The amount of physical activity was categorized into four levels: <= 30, 30 – 60, 60 – 120, and more than 120 min. According to the WHO, physical activity includes play, games, sports, transportation, chores, recreation, physical education, or planned exercise in the context of family, school, and community activities for children and young people . Screen We utilized the General Anxiety Disorder-7  to assess the symptoms of anxiety experienced in the previous 2 weeks. The GAD-7 is a self-reported and simple anxiety measurement with high reliability and validity , and itsWe utilized the Patient Health Questionnaire-9  to assess the depressive symptoms experienced in the previous 2 weeks. The PHQ-9 is a self-reported depression measurement with high reliability and validity , and itsWe utilized the Self-Rating Scale of Sleep (SRSS) to assess sleep quality. The SRSS is a self-reported sleep quality measurement tailored for Chinese people . Its relWe utilized the Subjective Social Status-Adolescent  scale, which was derived from the MacArthur Subjective Social Status scale , 32. TheWe utilized the Connor–Davidson Resilience Scale-10  to assess the participants' psychological resilience over the last month. The CD-RISC-10 is a self-reported psychological resilience measurement that includes ten five-point Likert scales that range from “not true at all” (0 points) to “true nearly all the time” (four points) . The higWe utilized a recently developed eight-item coping strategy measurement derived from the original Ways of Coping , 37. andWe utilized the Multidimensional Scale of Perceived Social Support  to investigate the social support of each participant; this is a self-reported and highly effective social support measurement . The relU test to determine whether the average value of each feature was different between two labels. According to the results of the univariate analysis, we preprocessed the dataset to improve the models' performance.First of all, it is necessary to use univariate analysis methods in order to explore the basic relations between features and labels. To be specific, we applied the Chi-square test for the binary and polytomous unordered features. In particular, for features that had cells with a count of, <5, we used Fisher's exact test to assess the accuracy. For polytomous ordered features, we calculated Somer's d coefficients in order to measure the consistency . On the other hand, in terms of consistent features, we applied the Mann-Whitney k-nearest neighbors (KNN), logistic regression (LR), gradient-boosted decision tree (GBDT), and a combination of the GBDT and LR (GBDT+LR).It should be noted that this is a typical binary classification problem. Therefore, we chose four widely used classification models: KNN: KNN is a widely utilized machine learning algorithm in the field of classification and regression prediction due to its simple implementation and outstanding performance . The KNNGBDT: GBDT is a new algorithm that combines decision trees and holistic learning techniques. Its basic idea is to combine a series of weak base classifiers into a strong base classifier , 44. In LR: LR is a supervised machine learning algorithm for learning classification and regression problems. It is one of the most widely used methods in health sciences research, especially in epidemiology . Many prGBDT+LR: GBDT+LR is a very novel machine learning algorithm for classification and regression problems. The performance of LR model depends strictly on feature extraction since LR can only find a linear relationship. Under this circumstance, using GBDT to firstly process the variables by finding their locations in trees' leaf nodes and encoding them into new features contribute to solving this problem. It helps to combine the information of the features automatically and improve the performance of the following LR model .To determine the optimal parameters, we used the sklearnGridSearchCV module to perform a grid search, the details of which are listed in the following. Firstly, we set up the optional ranges of all parameters. Secondly, we used five-fold cross-validation to test the AUC (area under the curve) on the validation dataset with the parameters in every possible combination. The combination that had the highest AUC value was considered the best. Five-fold cross-validation involved randomly dividing all of the datasets into five equal subsets and using four of them as the training dataset to fit the model. The effect of the model was measured with the AUC value, which we obtained by applying the model on the one subset that was left as a validation dataset.The AUC of the receiver operating characteristic (ROC) curves, sensitivity, and specificity (sensitivity = TP/ (TP + FN), specificity = TN/ (TN + FP), where TP represents true positive assignments, TN represents true negative assignments, FP represents false positive assignments, and FN represents false negative assignments) were used to evaluate the machine learning models.S of the AUC value, sensitivity, and specificity of these models for the test set. The formulas listed below estimate the mean and the asymptotic 95% confidence intervals (95% CI) of these indices.To evaluate the effects of the machine learning models, we randomly split the dataset more than 100 times, with 85% as the training set and 15% as the test set. After splitting the dataset, we applied the four models mentioned above to fit the training set. By repeating the random splitting of the dataset, we countered the randomicity of the results. Then, we calculated the sample mean P-value of < 0.05 was considered statistically significant.Our datasets were collected and descriptively analyzed using Excel 2016. Univariate analysis was performed using IBM SPSS Statistics 25. The machine learning models were constructed using the scikit-learn 0.24.2 package. A The GAD-7 and PHQ-9 were utilized to evaluate the anxiety and depression among 1,771 participants. The rate of occurrence of anxiety symptoms was 28.3% . A total of 21.7%  of the participants showed mild anxiety symptoms, 4.5%  of the participants showed moderate anxiety symptoms, and 2.1%  of the participants showed severe anxiety symptoms. The rate of occurrence of depression symptoms was 30.8% . A total of 21.2%  of the participants showed mild depression symptoms, 5.6%  of the participants showed moderate depression symptoms, 2.7%  of the participants showed moderate to severe depression symptoms, and 1.3%  showed severe depression symptoms. In addition, 20.1%  of the participants showed both anxiety and depression symptoms. Then, we divided the 1,771 participants into two groups according to whether they were anxious or depressed for further factor analysis.P < 0.05). As for personal living styles, more physical activity and less screen time could prevent adolescents from experiencing anxiety/depression (P < 0.05). Among the included psychological factors, sleep quality, resilience, subjective social/school status, perceived social support (from family/friends/significant others), and adaptive coping strategies were protective factors, and maladaptive coping strategies were a risk factor (P < 0.05). The results of the descriptive analysis showed that all of the factors were statistically associated with mood disorders in the adolescents, which was rational and consistent with previous research. However, as we previously speculated, simple descriptive statistical methods cannot quantify the impact of each factor on anxiety/depression in adolescents, which limited the clinical significance of these factors. Therefore, we introduced machine learning methods in order to further analyze the importance of each factor.The results of the descriptive analysis of the 1,771 participants are presented in th, 8th, 10th, and 11th grades, as well as those in the first year in college, had similar psychological statuses. The psychological conditions of adolescents in the 9th and 12th grades were significantly worse than those of other adolescents. It was not hard to find the reason: In China, 9th and 12th grade students are faced with the stress of gaining admission to higher education, i.e., senior high schools or colleges, thus causing relatively worse psychological statuses. Therefore, we converted the grade variable into the graduation grade variable. Adolescents who were in grades nine and 12 received a “Yes”, and those who were not received a “No”. For the two ordered variables, physical activity and screen time, and the other continuous variables, we found that the psychological conditions of students had approximately monotonic trends as these variables increased. Thus, no extra processes were performed for these features. In addition, the value of the total social variable was actually the sum of the values of the three variables above, which apparently indicated the existence of collinearity. Thus, we deleted this variable  and did not take its influence into account.As shown in As shown in Conventionally, logistic regression models have been used in psychological and other medical areas to measure the influence of every feature more precisely by calculating the odds ratio (OR). Because the LR model also performed well on our datasets, here, we present the results from the LR model .In this cross-sectional study, we investigated the current mental status of Chinese adolescents. The rates of occurrence of anxiety and depression symptoms were 28.3 and 30.8%. Compared with the rates at the beginning of the outbreak , adolescSleep quality had the closest relation with mood disorders among Chinese adolescents. Traditionally, psychiatrists/psychologists have treated insomnia and other sleep disorders as secondary symptoms that are mainly caused by psychiatric disorders, which account for >50% of insomnia cases. However, studies in adolescents indicate that sleep problems could directly contribute to subjective sleepiness , cognitiThe WHO reported that 50% of all psychological problems start by the age of fourteen, but most cases are undetected and untreated , and theWe also found that some demographic characteristics and personal living styles were relevant to mood disorders. Adolescents who were female, were in graduation grades, and had relatives or friends who had been infected by COVID-19 or quarantined were more likely to develop mood disorders. In addition, adolescents who held relatively low subjective social and school status were susceptible to mood disorders. School psychologists should pay more attention to the mental health of students with these specific characteristics. Furthermore, schools can never discriminate against students due to their academic performance, family socioeconomic status, or gender, and they must propose a comprehensive and robust anti-bullying policy in order to protect students from bullying at school. Every adolescent should be free from discrimination or degrading treatment in school. As for personal living styles, we found that more physical activity and shorter screen time were related to healthier mental status. A wide range of investigations have shown that physical activity is beneficial for mental health in adolescents. Biddle et al. proved that there is a causal association between physical activity and cognitive functioning and depression . CurrentThis study has some strengths. First, the machine learning algorithms were reliable and appropriate. The AUCs were 0.819 for anxiety and 0.857 for depression, indicating that the factors that we screened had a close relationship with mood disorders in adolescents. Second, we collected the subjects without selection bias. The participants were from three independent junior high schools, three independent senior high schools, and three independent colleges .This study still has some limitations. Firstly, we did not explore the causal relationship between anxiety/depression and the screened factors because our statistical results are based on cross-sectional data, but not cohort data. A prospective cohort study is still needed. Secondly, our study was performed in Shandong province, China. The clinical value of our conclusions may be limited in other areas. Thirdly, this investigation was performed during Apr.20–Apr.30, 2021, when the COVID-19 in China had been well-controlled. Therefore, the results may have bias. Fourthly, due to ethic requirements, children (aged under 12) and adolescents who have recently suffered severe negative life events or were diagnosed with severe psychological disorders were not invited, which may also lead to selection bias. Finally, we did not perform a pre-survey to select included features. There might exist other significant psychological factors influencing adolescents' mental health. Besides, all the psychological scales included in this study were self-reported. This may lead to systematic measurement errors that either inflate or deflate the observed relationships between constructs, generating both Type I and Type II errors.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by The Ethics Committee of Shandong University. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.ZR and ZW Data collection was performed. YX Statistical analyses were performed. ZR and YX The manuscript was written. DL, YX, ZR, and ZW The study was designed and Contributed equally to this research. DL, RH, and CH The manuscript was revised. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts 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.


Conclusions: For PD patients, the serum OPN level was correlated with cfPWV and could play an important role in the process of AS.Background: Osteopontin (OPN) is regarded as a proinflammatory and proatherogenic molecule related to atherosclerosis. We aimed to evaluate the relationship between serum OPN and aortic stiffness (AS) of peritoneal dialysis (PD) patients. Methods: OPN and carotid-femoral pulse wave velocity (cfPWV) were measured by a commercial enzyme-linked immunosorbent assay kit and a validated tonometry system, respectively. Patients with cfPWV > 10 m/s were designated into the AS group. Results: Twenty-two patients (31.4%) were segregated into the AS group. Multivariate linear and logistic regression analysis showed that OPN was significantly related to cfPWV and was an independent predictor of AS. The receiver operating characteristic curve analysis showed that OPN was correlated with AS with an area under the curve of 0.903 (95% CI 0.809–0.961,  Cardiovascular diseases (CVD), which may be caused by traditional risk factors, such as diabetes mellitus (DM) and hypertension (HTN), as well as other specific risk factors, have been reported to be related with the worse prognosis of patients with chronic kidney disease (CKD) . Aortic Osteopontin (OPN) was initially found to be a calcium-binding glycophosphoprotein that is involved in bone remodeling, and was later known to have multiple roles in promoting the inflammatory process, such as cell recruitment to inflammatory sites, cell attachment, and wound healing. It was reported to be a mediator in regulating the pathogenesis of sepsis, and had a role in predicting the survival or recovery from renal replacement therapy in patients with acute kidney injury ,9,10. InAlthough OPN has been considered to have a role in a variety of diseases, its relationship with AS in patients on hemodialysis (HD) had been controversial . MoreoveFrom June 2015 to October 2016, with approval from the Protection of Human Subjects Institutional Review Board (IRB103-136-B), patients who underwent regular PD for more than three months at a medical center were included. Participants were excluded if they refused to sign informed consent or had an acute illness, such as infection, malignancy, stroke, heart failure, acute coronary syndrome, or amputation, at the time of blood sampling. All participants provided informed consent before participating in this study.Data on the adequacy of dialysis, which included the weekly fractional clearance index for urea (Kt/V), total clearance of creatinine, and peritoneal clearance of creatinine, were retrospectively reviewed and collected from the medical records. The morning systolic blood pressure (SBP) and diastolic BP (DBP) of all patients were measured three times at five-minute intervals by trained staff using standard mercury sphygmomanometers with appropriate cuff sizes and after having the patient rest for at least 10 min. HTN was defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg, or as a receipt of any antihypertensive medication in the past two weeks. DM was defined as fasting plasma glucose > 126 mg/dL or the use of oral hypoglycemic medications or insulin.A total of 70 patients on PD were enrolled in this study. Of these patients, 50 received continuous ambulatory PD , with three to five dialysate exchanges per day; the 20 remaining patients underwent four to five dialysate exchanges each night with an automated device ).Body mass index (BMI) was calculated as the body weight in kilograms divided by the square of the height in meters. It was measured individually to the nearest half centimeter and to the nearest half kilogram, with each patient wearing light clothing and no shoes.g for 10 min. Within 1 h of collection, the serum samples were stored at 4 °C and sent for biochemical analyses. Serum levels of blood urea nitrogen, creatinine, fasting glucose, albumin, total cholesterol, triglyceride, total calcium, phosphorus, and C-reactive protein (CRP) were measured using an autoanalyzer . The serum levels of the OPN  and intact parathyroid hormone (iPTH)  were quantified by commercially available enzyme-linked immunosorbent assays [In the morning before exchanging the dialysate, approximately 5 mL of blood sample was collected from each participant and was immediately centrifuged at 3000× The cfPWV was transcutaneously measured by recording the arterial pressure pulse waveform on applanation tonometry , as previously described . Measuret-test. Variables with non-normal distribution  were expressed as median and interquartile range (IQR), and were compared between the groups using the Mann–Whitney U-test. Categorical variables were expressed as number (percentage) and were analyzed by the χ2 test. The risk factors for developing AS were determined by multivariate logistic regression analysis. The associations of cfPWV with the variables were analyzed by simple and multivariate forward stepwise linear regression analysis. The receiver operating curve (ROC) was used to calculate the area under the curve (AUC) to identify the optimal cutoff value of OPN so as to predict a high AS in patients on PD. Data were analyzed using SPSS for Windows . A p value of <0.05 was considered statistically significant.Continuous variables were analyzed for normal distribution using the Kolmogorov–Smirnov test. Variables that had a non-normal distribution were logarithmically transformed for linear regression analysis. Normally distributed continuous variables were expressed as mean ± standard deviation (SD) and were compared between the groups using two-tailed independent Student’s p = 0.001), had longer PD vintage (p = 0.024), and had higher serum levels of CRP (p = 0.005) and OPN (p < 0.001), but had a similar proportion of men and women, PD model, BMI, frequency of coexisting DM and HTN, adequacy of dialysis, and medications used, including the usage of calcium carbonate, calcitriol, and Icodextrin.The clinical characteristics of the 70 patients included in this study are presented in p < 0.001) and PD vintage  (p < 0.001)  . For the< 0.001) .r = 0.394, p = 0.001), logarithmically transformed (log) CRP , and serum log-OPN level . After adjusting for these covariates by multivariable forward stepwise linear regression analysis, the log-CRP  and log-OPN levels  were found to be independently correlated with cfPWV (For the simple linear regression analysis, cfPWV was positively correlated with age (th cfPWV .This study showed that patients on PD and with high OPN levels had a high risk of developing AS. In addition, OPN levels could be a predictor of AS, independent of age, sex, comorbidities, and medications used.Aside from the traditional CV risk factors, including DM, hyperlipidemia, and elevated BMI, as well as mineral metabolism derangements that cause elastin fragmentation and medial layer calcification in CKD, aging might contribute to the structural and functional changes in vessels and have been shown to be related with the development of AS ,22,23. IOPN is a hyperphosphorylated extracellular matrix protein that has a variety of functions in the immune system, cell viability or proliferation, and wound healing. It is a key factor in atherosclerosis and is now being regarded as an important mediator of atherosclerotic plaque formation and arterial calcification ,15,29,30The limitation of this study was its cross-sectional design with a limited number of patients on PD. Therefore, the causal relationship of serum OPN with AS and the role of OPN in the development of AS in patients on PD should be confirmed by further longitudinal studies.In conclusion, along with old age, high CRP, and long duration on PD, the serum OPN level could be a novel biomarker for predicting the development of AS in patients on PD. OPN might modulate the process of AS, but the mechanism remains to be studied.