Alarms were sent to the clinicians in the presence of pre-established undesired clinical events and could be used to make treatment adjustments throughout the one-month study. Results. With the exception of anger, clinically significant changes  were greater in the app + alarm condition across outcomes . The clinicians were willing to use the app, especially the version with alarms. Conclusions. The use of apps may have some benefits in individual health care, especially when using alarms to tailor treatments.Background. The usefulness of mHealth in helping to target face-to-face interventions for chronic pain more effectively remains unclear. In the present study, we aim to test whether the Pain Monitor mobile phone application (app) is well accepted by clinicians, and can help improve existent medical treatments for patients with chronic musculoskeletal pain. Regarding this last goal, we compared three treatment conditions, namely usual treatment, usual treatment with an app without alarms and usual treatment with an app with alarms. All treatments lasted one month. The three treatments were compared for all outcomes, i.e., pain severity and interference, fatigue, depressed mood, anxiety and anger. Methods. In this randomized controlled trial, the usual monitoring method (i.e., onsite;  Chronic pain is a multidimensional, distressing experience that can occur with or without tissue damage and persists over extended periods of time (at least three months) . This diIn this scenario, various efforts have been made to improve chronic pain treatments in recent decades. However, existing reviews only provide modest support for the most popular chronic pain treatments, including medical interventions, physical therapy, psychological treatment—or a combination of these ,14,15. SDue to its chronic nature, management of chronic pain often requires prolonged and regular contact with the health care system . In thisThe aforementioned variability of symptoms in patients with chronic pain means that a single measure may not be representative of the entire experience. Furthermore, retrospective pain assessment leads to recall bias and reduces accuracy . This coAnother problem related to the current model of care in chronic pain refers to decision-making in the face of unwanted events. Specifically, the current approach to care requires patients to judge when an undesired event is problematic and what is the preferred action to take in the face of that event ,31,32. TTelemonitoring with episodic phone calls, which is becoming an increasingly common practice, also only partially solves the aforementioned problems. First, because undesired events  can occur at different treatment stages , which mTaking all the previous into account, it has been argued that our societies will not be able to sustain the current model of care for this condition ,21,35,36In fact, although it has been argued that mobile technology —especially the use of smartphone apps—facilitates this paradigm shift towards telemonitoring in chronic pain care, reviews on this topic have evidenced that randomized controlled trials (RCT) evaluating the usefulness of these tools are lacking in the chronic pain literature ,43,44,45This RCT had three conditions, i.e., usual treatment (TAU) with the usual assessment method , TAU with app-based assessment without clinical alarms and TAU with app-based assessment with clinical alarms. Eligible patients were adults with chronic musculoskeletal pain, the most common chronic pain condition, which included pain in the bones, muscles, nerves, ligaments or tendons . As recoThe study goal is to compare the response to one month of usual pain treatment for patients in the three monitoring conditions, namely usual episodic monitoring, monitoring with an app without clinical alarms and monitoring with an app with clinical alarms. All patients received the usual treatment for their pain, so differences in outcomes  across outcomes were expected to occur as a consequence of the assigned monitoring condition. Another goal was to investigate the opinions about the app of health professionals involved in the study .We expected that the use of the app with alarms that were sent to the healthcare professional in the presence of unwanted clinical events would allow a quick detection of patient suffering .This is a superiority RCT with three conditions: (1) treatment as usual (TAU); (2) TAU + daily assessment using the Pain Monitor app (TAU + app); or (3) TAU + daily assessment using the Pain Monitor app with alarms . Because we want to ensure that telemonitoring and not the daily response to pain-related items in the app is responsible for patient benefits, we allocated patients using the app into two conditions: telemonitoring  and daily app use without alarms. Patients were randomly assigned to the study condition before agreeing to participate. Randomization was performed by an independent researcher with an online randomization tool. There was no allocation ratio. The patients’ treating physicians performed the enrollment and assignment to previously randomized conditions. Patients were assigned to conditions based on a random allocation sequence. If they refused to participate because of the assigned condition, the TAU was offered, but they were excluded from the study.Patients and treating physicians were not blinded to allocation. In the case of patients, this was done for ethical and safety reasons, especially for those using the app without alarms, as they needed to know that the app would not report any adverse event to the physicians. Regarding the medical staff, blinding was not possible because the clinicians had to know that they would receive alarms from a subset of patients, and they had to check their electronic clinical records to decide whether a change in the treatment was required after receiving an alarm. Most assessments were completed by patients, who, as noted earlier, were not blind to their assigned condition for ethical and safety reasons. The only evaluation that was conducted by health professionals, i.e., the follow-up assessment in the TAU group, was as well not blinded. There are several reasons to explain why assessment was not blinded in this case either. For example, calling the patient required accessing to patient personal data, which is restricted to health professionals. Additionally, the TAU condition aimed at recreating the usual practice at the pain clinic, which implies that a health professional is in charge of patient episodic monitoring between appointments. All the physicians at the pain clinic participated in the study, so calls could not be performed by a clinical external to the study and blinded to the patients’ condition.The study was advertised by physicians at the pain unit of the Vall d’Hebron Hospital, a tertiary care hospital in Barcelona. The study was presented to all consecutive patients with chronic pain that met the inclusion criteria. Eligibility included being over 18 years of age, not presenting any psychological disorders or problems with language that would make participation difficult, having a mobile phone with Android operating system, accepting the assigned condition and signing the informed consent form. There were no exclusion criterion in terms of previous or existing treatment for pain at study onset or treatment changes during the study, so that the study was as naturalistic as possible, and the sample representative of patients treated at the clinic. In relation to the limitation to Android operating systems, note that by the time the study was conducted the app was only available for Android for economic reasons, as this is the operating system used by more than 90% of phones in Spain .Sample size was calculated a priori with the statistical software G*Power  considerAll patients received the same intervention (TAU). This consisted of the usual medical treatment for their pain at the pain unit according to the usual practice at the pain clinic and pain guidelines ,52. The The prescribed treatment (TAU) remained unchanged during the whole study duration (one month), except when an alarm was received by the clinicians . Only in this scenario, phone calls were made by the physicians to explore whether a treatment change was required. Alarms were notified to the clinicians on the following working day after their occurrence. These were expected to be responded to on the same day or the next two days, depending on the severity of the alarm.The duration of the study was set to one month since treatment onset because the clinicians considered that this is a critical period in which most problems with the treatment occur .Pain Monitor is a mobile phone app developed for Android, in which patients are asked to respond twice daily during 30 days . A reminder is sent to the participant at 10 am and 7 pm and again 90 min later if a response had not been provided. The app incorporates different algorithms which allow sending clinical alarms to professionals  completed the aforementioned measures  at baseline (the same day treatment was proposed) and the end of the study (30 days after). However, patients in the TAU + app and the TAU + app + alarm conditions also responded to the protocol twice daily. This was done to control for the effect of daily measuring (TAU + app) and to generate the alarms . The protocol was automatically prompted in the morning and in the evening to reduce the reliance on the patient’s memory.Patients in the TAU condition completed the protocol as usual, i.e., with paper and pencil at baseline and by phone at the end of study (30 days later). This second measurement was not done face-to-face because patients are usually scheduled no earlier than 4–5 months after the previous appointment. In the TAU follow-up assessment, one of the pain clinic physicians, AM, made the phone calls to the participants. If patients were unavailable, they were called daily for up to three consecutive days. If no response was obtained, this was considered a missing value. The other two groups  were assessed with the Pain Monitor app at all times. The comparability of the paper-and-pencil and app assessments was not conducted here because the validity of the current assessment protocol across measurement modalities was already performed in past research .The participating clinicians helped patients download the app during the initial appointment and provided support during this first use . Patients also received the contact information from the lead researcher, CSR, in case technical problems occurred with the app.n = 6) were invited to participate in this survey at the end of the study. All questionnaires were anonymized.In addition to patient measurement, we explored the professionals’ experience with the app. Consistent with the technology acceptance model , we evalFirst, a descriptive analysis of the sample , including the study flow chart, was conducted. This included an analysis of means and standard deviations for age and percentages for the remaining variables. Next, we investigated whether randomization resulted in comparable groups in terms of study outcomes .Originally, we planned to explore between and within changes in all study outcomes using a repeated measures MANOVA. However, during the review process it was noted that nonparametric statistics should be used due to the ordinal nature of the measures used  . TherefoAgain different from that which was planned, we added an analysis of clinically meaningful improvements at the individual level due to insufficient power and loss in sample size (see the results section). This analysis is recommended in guidelines for pain trials and a reduction in 30% of severity of symptoms is argued to be a useful benchmark, representing at least moderate clinically significant changes (CSC) for the individuals ,62. TherAs a final step, an analysis of variance (ANOVA) was computed to compare the number of side effects experienced by patients in the app + alarm and patients in the app without alarm conditions. This was followed by an analysis of frequencies of the types of alarms received and the clinicians’ opinion about the app. As planned, interim analyses were not conducted because no harm was expected from adding the app to TAU .Trial registration code in ClinicalTrials.gov is NCT03247725. The ethics committee of the Vall d’Hebron Hospital approved the present study and its procedures (code PR(ATR)381/2015).The study flowchart is shown in Overall, the response to the prompted daily questions in app was good  and comparable to past research . Note thPatients had a mean age of 52.1 years  and the majority were women (73.8%). Most of the participants were married or in a relationship (73.2%). One third of the patients were working at the time of assessment (34.4%). The rest of the participants were on temporary sick leave (20.6%), had compensation for permanent disability (19.1%) or were retired (11.5%), unemployed (7.6%) or homemakers (6.9%). Regarding educational level, 33.1% had only completed primary education, 32.3% had completed secondary studies, and 34.6% had completed tertiary education .Patients had musculoskeletal pain, most frequently pain in the low back or in the neck. Patients had been experiencing pain for between 6 months and 1 year (9.9%), 1–5 years (37.2%), 5–10 years (24.0%) or over 10 years (28.9%).p = 0.196), pain interference , fatigue , sadness , anxiety  and anger  were comparable across conditions. The same occurred with sociodemographic characteristics, namely age , gender , marital status , educational level , job status  and pain duration .A MANOVA was conducted to investigate whether the randomization had effectively resulted in comparable patient profiles at baseline. The results supported the success of randomization. Specifically, baseline pain severity . The Kruskal–Wallis test revealed that none of the change scores differed across conditions .As explained in the data analysis section and the beginning of the results section, two analytical approaches were followed due to sample size and reduced power. The first was the planned analysis of differences at the group level . As indicated in In addition to changes at the group level, we also investigated changes at the individual level by means of an analysis of CSC . The results are reported on p = 0.226) in the group without alarms  compared to the group with alarms .As noted earlier, the daily frequency of undesired and unusual physical symptoms was evaluated with the app only, so these were not assessed in the TAU condition for reasons of feasibility and fidelity to usual practice. The ANOVA results indicated that the average daily number of unwanted symptoms was slightly, but not significantly higher , gait instability (n = 10), interference of pain on sleep (n = 5), urine retention (n = 4), very severe pain levels that do not improve with treatment (n = 3) and sleepiness (n = 3). These data were collected by the app daily based on patient self-reports. In total, 93% of alarms were considered sufficiently relevant to call the patient and further investigate whether an action  was required.In total, 51 alarms were received in the TAU + app + alarm condition. The most frequent were related to recurrent headache (n = 6) generally perceived that the app was useful for pain management  and for their own comfort as health care providers. Importantly, they were keener on using the app version with alarms than the version without alarms.As indicated in We also investigated burden. On average, the physicians perceived that helping the patient download the app and guiding them during the first use required 13 min  and responding to all daily alarms  required 28 min in total . As reported in The present study aimed to compare the effectiveness of three monitoring approaches in patients with chronic pain, namely usual episodic monitoring, monitoring with an app without clinical alarms and monitoring with an app with clinical alarms. For one month, all patients received the usual treatment for their pain, but different effects on outcomes  were expected to emerge across monitoring conditions. Another goal was to investigate the opinion of health professionals about the app.In relation to the first goal and contrary to our expectations, monitoring with the app and alarms did not have a significantly greater impact on outcomes compared to the usual monitoring method or the app without alarms condition, both at the group and individual level. However, consistent with our hypotheses there was only a reduction in pain interference in the group of patients using the app with clinical alarms for telemonitoring. In addition, the analyses at the individual level showed that the proportion of patients reporting a clinically meaningful reduction  in almost all outcomes, namely pain severity, pain interference, fatigue, depression and anxiety, was higher in patients who were monitored using the app with alarms. Regarding the second objective, the healthcare professionals involved generally perceived that the app was useful for pain management in the sense that it improved treatment safety and effectiveness. They also believed that it increased their sense of comfort as healthcare providers. Importantly, they were more satisfied with the version of the app that included alarms. Regarding the burden of using the app, they reported that helping patients download the app and respond to alarms required some extra time, but they found this burden to be low or moderate.For several years, it has been argued that eHealth and particularly mHealth will inevitably change our health systems in general  and painOne of the findings regarding the implementation of mHealth in chronic pain management was that this system was well accepted by the pain physicians involved, which is critical for implementation purposes . ImportaIn relation to the utility of this new approach to monitoring, one of the main study goals was to explore whether the inclusion of telemonitoring  would lead to improved outcomes thanks to a rapid detection of poor treatment response, chronic low mood or high interference of pain on functioning. One problem was sample loss. Thus, even though a visual inspection of mean-level differences across conditions suggested somewhat larger improvements in the app + alarm condition in pain interference, sadness and anxiety, these results should not be overemphasized. Even the fact that pain interference only significantly improved in the app + alarm condition should be interpreted with caution due to sample size loss during the study. An interesting and more promising finding, however, was the fact that the percentage of patients reporting a clinically meaningful improvement in almost all outcomes, i.e., pain severity, pain interference, fatigue, sadness and anxiety was always higher in the app + alarm condition. This is important because, different from the analysis of changes at the group mean level, CSC is explored at the individual level. As noted in past research, while “managers and trialists may be happy for treatments to work on average, patients expect their doctors to do better than that” . At the An important finding in the present study was that the use of the app with alarms as adjunct to medical treatments for pain may as well provide some benefits on the functioning and mental well-being of individuals, again when explored at the individual level. Chronic pain is a very disabling and mentally distressing experience. Not surprisingly, musculoskeletal diseases, which were the type of conditions included in the present study, have become the leading cause of sick leave in Europe and account for approximately half of work-related illnesses  and the In addition to exploring the effectiveness of usual medical treatment in several conditions, this study aimed to investigate whether physical symptoms rarely experienced by the patient before treatment onset were minimized in the app + alarm condition compared to the group using the app without alarms. Of course, one thing to keep in mind is that there is no guarantee that these physical symptoms are actually due to the recently proposed pain treatment. By mentioning that patients should only report symptoms that they do not usually experience, we expected to reduce possible misinterpretation of symptoms. However, it is also possible for patients to experience unusual symptoms for reasons other than the onset of a new pain treatment . This limitation is difficult to address, so the results regarding the number of daily symptoms should be taken with caution. While acknowledging the previous, an important finding was that algorithms can be effectively created so that the determination of when an event becomes alarming  no longer depends solely on the interpretation of the patient. Of course, reporting of symptoms rather than signs requires patient self-report. However, the contribution of the present study is that an algorithm can be used to effectively send an alarm to professionals, so that action can be taken. Note that these alarms could be generated because of the ecological momentary assessment with the app, which current and past research has revealed to be feasible in terms of patient response rates .As a final remark, which may be important for implementation purposes, the study revealed that patient follow-up using phone calls was difficult and technical and phone-related problems are likely to occur when implementing mHealth. In relation the former, calling patients in the TAU condition for follow-up assessment was very time consuming and largely ineffective. Specifically, if often took several calls to get in contact with the participants and these were not always available to complete the survey at the time of the call. This occurred despite the fact that patients were informed that a follow-up call would be made one month after the baseline assessment. This supports the need for more flexible and patient-dependent assessment tools, such as smartphone apps. In this sense, patient daily self-monitoring eliminated the need for physician active monitoring, so only when the app algorithm detected an undesired event, this was notified to the physician and only then a phone call was made. In relation to technical problems, such as app malfunctioning or problems with the patients’ phone, such as crashing or low battery or memory, these did occur in the study and resulted in almost 20% of loss in sample size. Recent research into telemonitoring in chronic pain states that these technical problems are something we will probably have to accept . One lesTo the best of our knowledge, this is the first study to use an alarm-based telemonitoring system in a randomized controlled trial in chronic pain settings. Some study limitations, including loss of sample due to technical or phone-related problems or the reduced power in the analyses have been already discussed. However, in relation to sample size it is important to mention that the anticipation of a 10% drop-out was clearly insufficient. At least 25% should have been expected based on our results. We expect that this will help researchers when calculating the required sample size for similar future studies. It is also important to acknowledge additional shortcomings, such as the reliance on subjective outcomes only  and the focus on musculoskeletal pain only, which prevents us from generalizing the findings to specific populations or to all chronic pain populations. In relation to wearable devices, however, it is important to note that their inclusion in routine practice may be less ecological than the use of smartphones since the latter are much more frequently utilized by the population. Another shortcoming that should be acknowledged is that the required sample size was obtained based on an uncorrected alpha level of 0.05. Corrections such as Bonferroni–Holm  should bThe present study may contribute to the field of mHealth in chronic pain in a number of ways. First, the study showed that mobile apps can be effectively implemented for patient monitoring. In this sense, the Pain Monitor app allowed us to collect a large number of data associated with pain and treatment in an automated way. This information has never before been collected with this level accuracy . This is important given the heterogeneity both in the etiology and the treatment of chronic pain, as ecological momentary assessment could help us obtain a more accurate picture of treatment response which may help guide interventions in a more effective manner . Second,


Real-world data (RWD) play important roles in evaluating treatment effectiveness in clinical research. In recent decades, with the development of more accurate diagnoses and better treatment options, inpatient surgery for cervical degenerative disease (CDD) has become increasingly more common, yet little is known about the variations in patient demographic characteristics associated with surgical treatment.This study aimed to identify the characteristics of surgical patients with CDD using RWD collected from electronic medical records.P value <.01 was considered statistically significant. The RWD in this study were collected from the Orthopedic Department at Peking University Third Hospital, and the study was approved by the institutional review board.This study included 20,288 inpatient surgeries registered from January 1, 2000, to December 31, 2016, among patients aged 18 years or older, and demographic data  were collected at baseline. Regression modeling and time series analysis were conducted to analyze the trend in each variable . A P<.001), leading to a narrowing sex gap. The average length of stay for surgical treatment decreased from 21 days to 6 days and showed a steady decline from 2012 onward.Over the last 17 years, the number of inpatient surgeries increased annually by an average of 11.13%, with some fluctuations. In total, 76.4%  of the surgeries were performed in patients with CDD aged 41 to 65 years, and there was no significant change in the mean age at surgery. More male patients were observed, and the proportions of male and female patients who underwent surgery were 64.7%  and 35.3% , respectively. However, interestingly, the proportion of surgeries performed among female patients showed an increasing trend (The RWD showed its capability in supporting clinical research. The mean age at surgery for CDD was consistent in the real-world population, the proportion of female patients increased, and the average length of stay decreased over time. These results may be valuable to guide resource allocation for the early prevention and diagnosis, as well as surgical treatment of CDD. According to the evidence classification system for evidence-based medicine, the best evidence originates from randomized controlled trials (RCTs) and associated systematic evaluations. However, RCTs have some shortcomings, such as ethical limitations, small sample sizes, short observation times, narrow observation scopes, and high experimental costs . ComparaIn recent years, there has been growing interest in the prevention of various degenerative diseases. Essentially, all people who live a long life will develop degenerative disorders . With thYet, few large-scale clinical studies evaluating the demographic changes in the Chinese population receiving surgical treatments for CDD have been carried out. However, knowledge of these trends can be beneficial for medical care, surgical treatment strategy selection, and early disease prevention, and it might promote effective clinical management of this disease ,20.In light of the recently published guidelines from the US Food and Drug Administration on the communication of RWD and real-world evidence to support regulatory decision making, as well as promote evidence-based public health policies in China ,22, we cThis study was a retrospective analysis of electronic medical records (EMRs) on surgical treatments for CDD performed in the Orthopedic Department at Peking University Third Hospital (PUTH) between 2000 and 2016. The study was approved by the institutional review board (IRB00006761-M2018082). PUTH is a modernized and comprehensive upper first-class hospital that serves as a regional center for orthopedic care in northern China. Here, we designed a real-world study to analyze and assess the trends in the total number of inpatient surgeries for CDD, mean patient age at surgery, patient sex , and average length of stay (LOS) .Data on patients with CDD who were registered from January 1, 2000, to December 31, 2016, and who underwent inpatient surgical treatment in the Orthopedic Department at PUTH were collected via the health care system, and the associated data on the first page of the medical records were used. Eligible patients included Chinese patients aged ≥18 years with a principle diagnosis of CDD according to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code. Furthermore, inpatient surgeries were identified through ICD-9-CM procedure codes .In this study, inpatient surgery was defined as a surgical operation or procedure involving an overnight stay in an inpatient institution. A total of 20,288 inpatient surgeries for patients with CDD met the inclusion criteria during the study period. The additional data collected included patient sex, age at surgery, admission time, discharge time, LOS, discharge diagnosis, and surgery type.For all analyses, we used January 1, 2000, as the start of the study period because complete data were available from this year onward. We used R version 3.6.0  for all analyses. First, patient charts were reviewed to gain insights into clinical characteristics. Analyses of the mean age at surgery and number of inpatient surgeries were stratified by sex  and age .The mean age at surgery was calculated by averaging the patients’ data by either month or year. Median was used to measure the average LOS. Another key measure, the annual growth rate of the number of inpatient surgeries, was calculated as an increase in the number of operations divided by the total number of operations from the previous year.chi-square goodness-of-fit test to compare the number of inpatient surgeries across different groups (age and sex), and the t-test to compare the mean age at surgery. Additionally, the rank-sum test was used to compare the average LOS between male and female patients.We used the Time series analysis was used to assess the variation and trends in the number of inpatient surgeries over time. We aggregated the data on patients with CDD who were enrolled from 2000 to 2016 into a monthly time series based on the admission date and analyzed the overall trend. Generally, the growth in the number of surgical operations was not stationary but instead exhibited an ascending trend and seasonal behavior. We thereafter selected the Holt-Winters exponential smoothing model for time series forecasting . We specDetailed analyses were performed according to the following steps: (1) The number of inpatient surgery admissions by month from January 1, 2000, to December 31, 2015, constituted the training set, whereas the remaining records from January 1, 2016, to December 31, 2016, constituted the testing set. Both the training set and testing set were converted into time series. (2) As the seasonal fluctuation evident in the data is not strictly distributed, both additive and multiplicative methods were applied to train the model. (3) It was assessed whether the model was sufficient. The Ljung-Box (LB) test was used to evaluate the residuals of the fitted model, and the mean absolute percentage error (MAPE) was used to evaluate the forecast error. The mathematical expression of the MAPE is shown in P<.01 was considered statistically significant.A linear regression model was used to assess the variation and trends in the male-to-female ratio over the past 17 years, with demographic characteristics as dependent variables and the index calendar year as the independent variable. In this study, P<.001; The patient demographic characteristics are shown in P=.92, MAPE=16.44%; multiplicative method: LB test P=.03, MAPE=14.37%), and both methods were capable of predicting the seasonal peak in most months  of 11.13%. The number of inpatient surgeries fluctuated seasonally; it declined in January and February but always peaked in late spring, and the fastest monthly growth rate was always noted in March. Time series analysis was adopted to identify the underlying structure and function  of the surgeries for CDD were performed in patients older than 40 years. The number of CDD surgeries differed by age group and was especially high in patients aged approximately 50 years. Specifically, 76.4%  of the surgeries were performed in patients aged 41-65 years and 50.8%  were performed in those aged 46-60 years. The average age at the time of inpatient surgery was 52.58 and 52.92 years among male and female patients, respectively.t-test, P=.16). Overall, the mean age at surgery for patients with CDD remained consistent, except for a sudden increase in 2016. The overall proportion of surgeries performed in the elderly population (older than 70 years) over the past 17 years was very small ; thus, the mean age at CDD surgery was not affected by population aging  [Over the past 17 years, there was no statistically significant change in the mean age at surgery (yearly) among the patients with CDD (coefficient of variation=0.01) . In our in 2015) . Upon fuBoth the number of inpatient surgeries performed in male patients and the number of inpatient surgeries performed in female patients showed an increasing trend . InteresP<.001)  . Female P=.64). As the LOS in our study had a slight right-skewed distribution, we used the median to measure the average LOS.The LOS for the surgical treatment of CDD decreased by 15 days over the last 17 years , and the largest decreases were noted from 2000 to 2001 and from 2006 to 2007 . This reWe further observed an overall decrease in the LOS, and this trend might continue in subsequent years, but at a slower rate . MoreoveIn this real-world study, we assessed data on surgical treatments performed in patients with CDD at a hospital located in northern China from 2000 to 2016. The trends can be characterized by an increase in the number of inpatient surgeries performed for CDD over the past 17 years in PUTH, a consistent mean age at surgery, and a decreased average LOS for surgical treatment. In addition, inpatient surgeries performed among female patients accounted for an increasing proportion of the total number of procedures. Our study is one of the first retrospective studies to analyze the surgical treatment of CDD in a large Chinese population. Some of these findings were, in general, similar to those of previous studies that focused on other degenerative disorders in other countries ,32,33.The rapid development of information technologies, such as EMRs used in medical care systems, allows the timely and secure exchange of health information across physicians, hospitals, specialists, patients, and health care insurers; therefore, information technologies can significantly assist providers in obtaining meaningful information. The utilization of RWD retrieved from EMRs provides abundant opportunities for information-based improvements in designing and conducting clinical trials and studies in the health care setting to answer questions that were previously thought to be unanswerable. Previous studies have shown that real-world evidence derived from sources outside typical clinical research settings, such as electronic health records, can help with patient care, research on health care systems, and quality improvement ,34. An eIn this study, we focused on the use of EMRs for identifying trends in factors related to the surgical treatment of CDD. First, as we discussed above, surgical treatment was focused primarily on individuals aged 41 to 65 years, as the mean age at the time of inpatient surgery was 52.58 years for male patients and 52.92 years for female patients. A study in Norway showed that the average age difference was 1.4 years, as the mean age at the time of surgery was 50.8 years for female patients and 52.2 years for male patients . In the Second, the proportion of surgeries performed among female patients showed an increasing trend over the past 17 years in this study; more female patients than male patients with CDD were admitted for inpatient surgery, and the narrowing gap between the sexes was similar to the results reported in our previous study . NeverthThird, we also observed that the CDD patient group that received surgical treatment had a decreasing average LOS. This decreasing trend in the length of hospital stay following spine procedures was also reported in other studies , and thiFinally, a growing rate of surgery for CDD was observed in northern China over the past decade. In the context of an aging population, the prevalence of spine surgery will continue to increase owing to the progressive nature of CDD ,41,54. AThere were several limitations in this study. This was a real-world study investigating the surgical treatment of patients with CDD, who were admitted to one hospital and who underwent surgery at that hospital, and the single-center nature of this study may limit external validity. In addition, we were unable to measure several important outcomes following surgical treatment. For instance, the comorbidities of CDD in the aging population, as well as comparisons between different surgery types were investigated to a limited extent. These factors might affect our results, and we will analyze these factors in our future work. Additionally, we found that few patients with CDD underwent several inpatient surgeries. Moreover, there were sudden decreases in the monthly number of inpatient surgeries owing to fortuitous events, such as medical insurance settlement and celebration activities, and no details on these factors were provided in this research. Despite these limitations, our study presents certain variations and real-world trends in Chinese patients who underwent cervical surgery and addresses the potential factors that may have influenced inpatient surgery, which will have important implications in advancing health care resource allocation methods used in medical decision making. Unfortunately, assessment of benefits is not as straightforward as the term might suggest, and the line among effective, ineffective, and experimental treatments is often a personal decision made by an individual clinician. By assessing EMR data to estimate the trends in medical treatments for CDD, we can develop effective resource allocation strategies to maximize the benefits in the population.Through a large-scale real-world population study on surgical treatments for CDD in a hospital in northern China, we provide real-world evidence that CDD may increase the workload for hospitals in China. An increased number of inpatient surgeries was found, suggesting an increasing demand for specialists and medical assistants in the surgical management of this disease. We suggest that more attention should be given to the aging population, as well as the middle-aged female population. Additionally, more discussions and heightened awareness of cervical/skeletal health are needed. The decrease in LOS suggests improvements in surgical techniques and health care systems; however, more attention should be paid to surgical care and follow-up.


The purpose of this study was to investigate the relevant factors of pain after transvaginal mesh (TVM) surgery for the treatment of pelvic organ prolapse and to analyse the management and relief of the pain.A multicentre retrospective study of a clinical database of patients who underwent TVM surgery was conducted, and pain related aspects were analysed.P < 0.01). Forty patients underwent non-surgical treatment, with a relief rate of 40.0%, 33 patients received surgical treatment, 15 underwent partial mesh removal, and 18 underwent complete mesh removal, with a relief rate of 84.8%. The total relief rate was 88% within all 50 patients suffering from pain.A total of 1855 patients were included in the study. We divided the patients into two groups: pain-free (1805 patients) and pain (50 patients) group. The incidence of pain after TVM surgery was 2.70%, with a median occurrence time of 7.5 months. Pain mainly involved the vagina, perineum, buttocks, groin, inner thighs, and lower abdomen. Excessive intraoperative blood loss  and postoperative anatomic failure  were analysed as risk factors with statistical significance. Mesh exposure rate in the pain group was 38%, showing a significant difference between the groups (Excessive intraoperative bleeding and unsatisfactory postoperative anatomic outcomes can increase the risk of postoperative pain; mesh exposure is also associated with the pain. Most patients can get pain relief with proper management, more than half of whom may need mesh removal with differing approach. Pelvic organ prolapse (POP) is a common pelvic floor disorder among women, with population-based epidemiologic studies reporting the prevalence range from 2.9 to 34.3% in general population –4. WomenAlthough these devices have improved outcomes, the safety of synthetic mesh has been questioned owing to the surgical complications, prompting the US Food and Drug Administration to issue warnings about adverse events associated with the mesh . ComplicThe primary objective of this clinical analysis, therefore, was to identify patient and surgical factors associated with the development of pain after the TVM surgery. The secondary aim was to conduct a clinical analysis of the management and relief of the pain.In this multicentre retrospective study, patients who underwent TVM surgery for POP without hysterectomy were identified from the Pelvic Floor Medical Alliance of Northeast China and Inner Mongolia between January 2013 and October 2018. Patients were excluded if they had a history of chronic pain caused by endometriosis, vulvodynia, vaginismus, interstitial cystitis, or lower back conditions, since they have a higher risk of persistent postoperative pain and may not be ideal candidates for the synthetic material placement [Operations were carried out by experienced urogynaecology surgeons. Relevant demographic characteristics and surgical data were extracted from patient electronic medical records. POP stage examinations were performed before and at 3 months follow-up after the surgery with the patient in a lithotomy position, according to the International Urogynecological Association (IUGA)/International Continence Society (ICS) Pelvic Organ Prolapse Quantification (POP-Q) system . ObjectiPatients were recommended to be followed-up at 3 months postoperatively and every 3–6 months subsequently. Follow-up included evaluating anatomic outcomes, screening for mesh exposure or erosion by physical examination, and inquiring about complications such as pain, vaginal discharge, vaginal bleeding, and sexual dysfunction. The IUGA/ICS joint terminology and classification was used to assess the postoperative complications . PatientThe primary treatment of choice was non-surgical, including topical oestrogen, antibiotics, 1:5000 potassium permanganate sitz bath, biofeedback therapy, or a combination of the above. Patients in whom the conservative treatment was ineffective or who had the indications for mesh removal underwent surgery. Partial mesh removal was performed in cases of limited mesh exposure with no other bothersome symptoms and when mesh contracture was found. After irrigating with saline solution, we made an incision in the exposure or contracture site, removed the involved part of the mesh, and trimmed the edges of the vaginal epithelium. When the exposures were larger, presenting with severe symptoms, or mesh arms pierced the obturator space or ischiorectal fossa, the mesh was removed as much as possible. Complete mesh removal was performed by making an incision in the vaginal epithelium, dissecting the mesh from the overlying epithelium and underlying connective tissue, and closing the vagina with an absorbable suture. After the mesh and its arms were completely removed, a concomitant prolapse repair would be performed if needed. In cases of anatomic failure with obvious pain, we partially removed the mesh and reconnected the remaining part or performed complete mesh removal and reconstructed the normal anatomic structure with other repair procedures.The sample size calculation was conducted by Power Analysis and Sample Size Software version 15.0 for Windows. According to statistics, 2260 patients underwent TVM surgery in a specified period. Considering problems such as incomplete data and loss of follow-up, the actual number of patients included in the study was about 80% of 2260 patients . According to earlier studies, the incidence of pain is about 2% (1–3%) . When thP value < 0.05 was considered statistically significant.SPSS version 25.0 (IBM Statistics for Windows) was used for data analyses. Continuous variables are presented as the mean and standard deviation or median and ranges; categorical variables are summarised using number count and percentage. Independent samples t-test was used to compare continuous variables, chi-square or Fisher’s exact test was used to compare categorical variables, and Mann–Whitney U test was used to compare rank variables between the groups. For variables with statistical differences, logistic regression was used to determine the contributions of the indicators to increase the risk of pain. A A total of 2260 patients underwent TVM surgery for POP between January 2013 and October 2018. After the exclusion of 285 patients lost to follow-up, 97 with incomplete data, and 23 with baseline self-reported chronic pain, 1855 patients were included in this study. The median follow-up length with interquartile range was 24  months. Fifty (2.7%) patients reported postoperative pain and were classified into the pain group, and the other 1805 patients were classified into the pain-free group.P = 0.005). Differences in body mass index, parity, previous hysterectomy, previous POP surgery (without mesh implantation), and comorbidities including hypertension and diabetes mellitus were proportionally minor between the groups. Concomitant mid-urethral slings (MUS) for the treatment of stress urinary incontinence (SUI) were implanted in 244 (13.2%) patients, and no differences were noted between the two groups in concomitant MUS or surgical procedure. Moreover, patients in the pain group were likely to lose more blood during the operation .A description of baseline demographic characteristics and surgical data of both groups are shown in Table P = 0.038) and values of Aa, Ba, C  at 3 months postoperatively were significant. Thirty patients in the pain-free group and four patients in the pain group experienced anatomic failure with the stage II.The POP-Q stage and values  of both groups before and at 3 months after the surgery are presented in Tables P = 0.026) and lager POP-Q values  had a higher risk of suffering from pain, while age was not statistically significant (P = 0.146).Logistic analysis was performed on the contribution of each indicator to the risk of pain, including age, POP-Q values, and intraoperative blood loss. The combined effects of Aa, Ba, and C points were adopted for the assessment. The results showed that patients with greater blood loss .The period between mesh implantation and pain occurrence ranged from 1 to 31 months, with a median of 7.5 months. The pain was localised in the vagina, perineum, buttocks, groin, lower abdomen, or multiple sites  remains controversial. Studies have suggested that laparoscopic sacrocolpopexy and sacrospinous fixation in the treatment of primary VVP and transvaginal bilateral sacrospinous fixation in the treatment of recurrent VVP appears to be effective and safe for the improvement of quality of life and sexual function . As noteHealth-related quality of life (HR-QoL) is widely recognised as an important outcome measure following urogynaecological surgery . Taking This study had the following limitations: Firstly, pain was not directly measured with validated instruments, and the metric used for pain relief was based on subjective phrases in medical records at times. Secondly, since the mesh we used was mainly Prolift™, the factors of mesh itself  are not included in the study. Then, since the pain may occur years after surgery, longer-term follow-up might be required. Finally, the cases in this study came from specific regions, and it is unclear whether the conclusions can apply to patients in other parts of the world. This study had several limitations. First, pain was not directly measured with validated instruments, and the metric used for analysis of pain relief was based on subjective phrases in medical records at times. Second, since the pain may occur years after the surgery, longer-term follow-up might be required. Third, the cases in this study were collected from specific geographical regions, and it is unclear whether the conclusions can apply to patients in other parts of the world.Despite these limitations, the evidence of our study is strengthened by the relatively large number of patients and detailed data available from surgical and medical records. Moreover, this study investigated the relevant factors of postoperative pain, one of the inconvenient complications after the TVM surgery, the observations of which are relatively new to the available literature. The clinical practice shown in this study may provide important information about the strategy of the pain management following TVM surgery. In the future, we will carry out more in-depth studies on the mesh complications to provide more important reference for the postoperative management of TVM.The aetiology and development of pain after TVM surgery involves a variety of factors. Excessive intraoperative bleeding and failure with postoperative anatomic outcomes can increase the risk of pain, and patients with mesh exposure are more likely to develop this symptom. Patients can obtain pain relief with non-surgical or surgical management, more than half of whom need mesh removal with differing approach. More factors related to the postoperative pain remain to be explored. Through continuous research and improvement, we hope that TVM surgery can have better effects and safety.


We evaluated the correlation between these and other routine haemodynamic parameters, measured intraoperatively, with postoperative morbidity. Postoperative morbidity was measured using the Comprehensive Complication Index (CCI) and length of stay (LOS). Additionally we correlated CCI with the cardiac risk biomarker, preoperative NT-ProBNP.Postoperative morbidity occurs in 10–15% of patients undergoing major noncardiac surgery. Predicting patients at higher risk of morbidity may help to optimize perioperative prevention. Preoperative haemodynamic parameters, systolic arterial pressure (SAP) < 100 mmHg, pulse pressure (PP) > 62 mmHg or < 53 mmHg, and heart rate (HR) > 87 minThis is a retrospective analysis of patients in MET-REPAIR, a European observational study correlating self-reported physical activity with postoperative morbidity. Patients’ electronic anaesthetic records (EARs) including perioperative haemodynamic data were correlated with 30-day postoperative morbidity, CCI and LOS parameters. Statistical analysis to assess for correlation was by Kendall’s Correlation Coefficient for tied ranks (Tau-B) or Spearman’s Correlation Coefficient. Blood for N-terminal prohormone of brain natriuretic peptide (NT-proBNP) measurement was collected < 31 days before surgery.n = 50 patients were analysed. When stratified according to age > 70 years and ASA > 3, the duration of MAP < 100 mmHg, < 75 mmHg or < 55 mmHg were associated with a higher CCI  and duration < 75 mmHg was associated with prolonged LOS . The intraoperative duration of PP > 62 mmHg was associated with LOS . There was no correlation between preoperative NT-proBNP and either CCI or LOS.Data from In older and higher risk patients, duration of intraoperative hypotension by a variety of definitions, or PP > 62 mmHg, are associated with increased postoperative CCI and LOS. These findings warrant confirmation in larger databases with evaluation of whether real-time intraoperative intervention could reduce postoperative morbidity. More than 300 million surgical procedures are undertaken globally per annum , acute kidney injury (AKI) or death  > 62 mmHg or < 53 mmHg, systolic arterial pressure (SAP) < 100 mmHg or > 160 mmHg, heart rate (HR) < 55 or > 100 minBaseline preoperative haemodynamic parameters are challenging to standardise, and debate continues as to whether benchmark values should be taken from the preoperative assessment clinic or ward data, or immediately prior to induction of general anaesthesia. Multidisciplinary guidelines on intraoperative anaesthetic haemodynamic management highlight the absence of universally agreed intraoperative target blood pressure values  increasingly enables accurate, real-time documentation of variations and trends in these haemodynamic parameters in the intraoperative period during anaesthesia. Whether these intraoperative haemodynamic parameters during anaesthesia and surgery correlate with cumulative postoperative morbidity has not been evaluated. Therefore, among a study group of increased risk patients undergoing major noncardiac surgery, we correlated haemodynamic parameters measured electronically during anaesthesia with postoperative morbidity, measured by the Comprehensive Complications Index (CCI)  recruited for the European MET-REPAIR study, and retrospectively observed the correlation between intraoperative haemodynamic parameters and postoperative morbidity.In our hospital, we routinely record intraoperative haemodynamic parameters in an electronic anaesthesia record (EAR). We took a subset of patients  with 30-day postoperative morbidity, among increased risk patients undergoing major noncardiac surgery.Accordingly, as an enrolling centre for MET-REPAIR, we had a cohort of increased risk patients undergoing major noncardiac surgery, whose 30-day postoperative morbidity had been tracked. While preoperative and some intraoperative data have previously been shown to be correlated with these adverse outcomes  approval was granted for MET-REPAIR. Separately, IRB approval was granted for the present study, with a waiver of consent, because these patients had already consented to their perioperative clinical course and data being tracked and documented. The distinguishing feature of this study is the focus on their data recorded during anaesthesia. Sample size calculation was made based on convenience, meaning all of the available patients recruited between January 2019 and June 2019 who had completed their surgery and 30-day postoperative observation period were included for analysis.> 2 or a National Surgical Quality Improvement Program (NSQIP) > 1%. The NSQIP is in turn defined as the risk (%) of perioperative cardiac events using the American College of Surgeons (ACS) ACS-NSQIP prediction tool that was being used at the time of the MET-REPAIR study. Patients were also included if aged > 65 years and undergoing intermediate or high-risk procedures regardless of their RCRI or NSQIP scores according to ESA guidelines, and having given written informed consent.Inclusion and exclusion criteria reflected that of the MET-REPAIR study. Inclusion criteria were that patients were inpatients, > 45 years, undergoing elevated-risk elective noncardiac surgery. This was defined as either Revised Cardiac Risk Index (RCRI) Exclusion criteria were patients having emergency surgery, acute coronary surgery or uncontrolled congestive heart failure within the last 30 days, stroke within the last 7 days of planned day of surgery, and patients unable to ambulate due to congenital or chronic illnesses.The study was limited to the review of existing medical records of patients enrolled in MET-REPAIR in our centre. Data sources used included paper medical records, pre-anaesthetic assessment forms, intraoperative EAR and results of preoperative serum of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) samples.As part of the MET-REPAIR study, we had previously obtained data on patients’ preoperative maximum MET value from the Adult Compendium of Physical Activities. The validated Rockwood Clinical Frailty scale was used to assign patient-specific numbers based on the level of preoperative independence in the activities of daily living (ADL) and amount of weekly physical activity. This information was obtained retrospectively from patient-reported functional activities in the MET-REPAIR clinical research form section about the level of independence. The CCI is based on the complication grading using the Clavien-Dindo Classification and takes every complication event after surgery into account. An overall patient morbidity score is reflected on a scale, with higher values indicating more severe postoperative morbidity  and analysed for distribution. Descriptive statistics were calculated initially and expressed as mean (SD), median (25%–75% range) or number (%), as appropriate.p < 0.05 were deemed statistically significant.As much of the data were nonparametric, correlation between patient characteristics, intraoperative haemodynamics and postoperative CCI and length of stay (LOS) was conducted using the correlation coefficient for tied ranks (Tau-B), or Spearman’s correlation coefficient for NT-proBNP data. Values of Data from n = 50 patients were analysed, with baseline characteristics summarised in Table p = 0.03) while duration of PP > 62 mmHg was correlated with LOS only . There was no correlation between any haemodynamic parameter and duration of stay in the Post Anaesthesiology Care Unit (PACU). None of the Kendall’s Correlation Coefficient for tied ranks (Tau-B) values in the PACU reached statistical significance.A list of univariate correlations with postoperative morbidity, using the CCI and LOS are shown in Table n = 22) and > 70 (n = 28). This stratification is outlined in Table p = 0.004).The data were stratified according to age (years) < 70 , the MAP duration < 75 mmHg , and the MAP duration < 55 mmHg , were all associated with worse complications as measured by CCI. Similarly, ASA > 3 patients had a significant association between LOS and duration of pulse pressure (PP) > 62  or MAP < 75 mmHg .The data were then stratified according to ASA score, as shown in Table p = 0.005) and MAP < 75 mmHg . LOS also correlated with duration with PP > 62 mmHg  in this subset of patients.The stratification based on NSQIP scores is detailed in Table r = − 0.01, 95% CI − 0.30 to − 0.28, p = 0.93) or LOS . Neither was there any association between preoperative or postoperative creatinine and either CCI or LOS.There was no correlation between preoperative NT-proBNP and either CCI  and increased postoperative morbidity, expressed in terms of increased CCI or length of stay, among higher risk patients. There was also a positive correlation between duration of PP > 62 mmHg intra-operatively during anaesthesia and increased CCI. A PP > 62 mmHg may result from a high systolic arterial pressure or a low diastolic arterial pressure. While this is often attributed to age-related atherosclerosis, its significance in the intraoperative period is unclear, and the mechanism by which wide pulse pressure could cause organ impairment and hence postoperative morbidity is uncertain. Increased PP > 62 mmHg in the preoperative period has been shown to be an independent risk factor for overall postoperative morbidity and myocardial injury during noncardiac surgery in these increased risk patients, while SAP was not  and myocardial injury after noncardiac surgery (MINS)  in influencing postoperative outcomes became apparent when a prospective, randomised clinical trial of increased risk patients showed that maintaining intraoperative SAP > 90% of patients’ individual preoperative baseline reduced 30-day postoperative morbidity by approximately one-third  can reduce postoperative morbidity would be warranted.


We investigated the prognosis of patients with dry pleural dissemination (DPD) of non-small cell lung cancer (NSCLC) and the risk factors of developing to malignant pleural effusion (MPE).We retrospectively reviewed 104 patients with NSCLC and DPD, confirmed surgically from 1996 to 2016. Incidence rate and risk factors of MPE were analyzed statistically. The prognosis of NSCLC patients with MPE was evaluated using the Kaplan–Meier method.P = .16). No predictive factors for the development of MPE were identified. Fifteen (14.4%) patients underwent invasive procedures for the management of MPE.The most common histologic type was adenocarcinoma in 95 (91.3%) patients. The median follow-up duration was 65.5 months and the median survival time was 37.7 months. MPE developed in 51 (49%) patients, and the median effusion-free interval was 41.9 months. The median survival time of the patients with and without MPE was not different (41.3 vs 31.7 months, Almost half of all patients with NSCLC and DPD experienced MPE, and 14.4% patients developed symptomatic MPE requiring invasive procedures. MPE in DPD did not affect the survival in NSCLC patients. DPD is detected in 1.2% to 2% of clinically resectable lung cancer patients.,6 A few studies showed relatively better prognosis of DPD compared with MPE and several studies reported favorable outcome after pulmonary resection in patients with surgically diagnosed DPD.–6 However, the prognosis of DPD regarding the development of MPE and survival, especially in the era of targeted therapy, is still unclear.Pleural dissemination is one of the important modes of metastasis and a poor prognostic factor of non-small cell lung cancer (NSCLC). However, it can progress to MPE which impairs quality of life and requires invasive procedures. If DPD is detected intraoperatively in lung cancer patients, there is a chance to perform any intervention to prevent MPE. Intraoperative talc poudrage is a suggestive modality to prevent MPE, and the thoracoscopic talc poudrage has been reported to be the most effective method to prevent recurrence of MPE in a patient with expandable lung.–11 We investigated the pattern of progression of DPD to MPE and the prognosis of NSCLC patients with surgically confirmed DPD.Another clinical issue is how to manage patients with DPD. DPD does not induce any symptoms and specific treatment directed to DPD itself is not necessary.2A total of 104 NSCLC patients with surgically confirmed DPD from February 1995 to March 2016 were reviewed retrospectively. All patients had a pathological diagnosis of pleural seeding of primary NSCLC. Patients with MPE diagnosed preoperatively or related with combined malignancies other than NSCLC were excluded. The data about age, sex, body mass index, histologic type, clinical stage based on the 8th edition of the TNM classification, location of tumor, visceral pleura invasion (operation finding), underlying diseases, presence of epidermal growth factor receptor gene (EGFR) mutation or echinoderm microtubule-associated protein-like 4 (EML4) – anaplastic lymphoma kinase (ALK) gene fusion, extent of tumor resection, oncologic treatment, recurrence, the presence of MPE, and survival were obtained by reviewing medical records. The effusion-free interval (EFI) was defined as the duration from the day of operation to the day of radiologic detection of MPE. The overall survival was defined as the duration from the day of operation to the day of death by any causes or the day of the last follow-up in months. Effusion-free survival was defined as the duration of survival without evidence of MPE. Resection of the primary tumor in patients with limited DPD was decided by the surgeon considering the location of the tumor and the pulmonary function. Talc poudrage was not performed in the study cohort. First-line oncologic treatments consisted of platinum-based cytotoxic chemotherapy and tyrosine kinase inhibitor (TKI). Surveillance after treatment was conducted by chest x-ray and computed tomography. Positron emission tomography was performed when recurrence was suspected clinically or radiologically. The last follow-up date was August 30, 2018.2.1 The pleural effusion developed in the immediate postoperative period was not counted as MPE.MPE was diagnosed radiologically or histologically. In patients with a large amount of effusion or respiratory symptoms related with effusion, therapeutic interventions including thoracentesis or invasive intercostal drainage (percutaneous catheter drainage or tube thoracostomy) were performed, and the MPE was confirmed histologically. In the patients with a small amount of effusion without symptom, MPE was diagnosed radiologically, and the intervention and subsequent cytologic diagnosis were exempted.2.2P ≤ .2 in univariable analyses were included in the multivariable analysis conducted by the Cox proportional hazard model. Prognostic effects of age (≤60 vs >60), sex, smoking status (never vs ever), histologic type (adenocarcinoma vs others), clinical T stage (T1/2 vs T3/4), tumor resection, visceral pleural invasion, targetable mutations, and TKI therapy on EFI were tested. Patients were divided into 2 groups . This study was approved by the Institutional Review Board of Seoul National University Hospital, Seoul, Korea . This study complied with the Declaration of Helsinki.Follow-up duration was calculated using the reverse Kaplan–Meier method. The effusion-free survival time and overall survival time were calculated using the Kaplan–Meier method. Prognostic factors for EFI were evaluated using the log-rank test for univariable analysis. Parameters showing 3The mean age was 60.9 ± 12.5 years (range: 30–86 years), and 56 patients (53.8%) had pleural nodules in computed tomography. Adenocarcinoma  was the dominant histology and 42 (40.4%) patients had targetable mutations . Platinum-based cytotoxic chemotherapy was the standard first-line regimen and was performed in 77 patients (74.0%). TKIs were used as a first-line regimen in 27 patients (26.0%) with targetable mutation and as a second-line regimen in 13 patients (12.5%) with the targetable mutation. Additional 12 patients (11.5%) without the targetable mutation had TKI as a salvage treatment for a brief period. Two patients with EML4-ALK gene fusion did not have TKI therapy. Baseline characteristics of the patients are described in Table The median follow-up duration was 65.5 months and the median overall survival time was 37.7 (interquartile range [IQR]: 22.2–64.9) months. The overall survival rates at 3-year and 5-year were 51.4% and 29.3%, respectively.MPE developed in 51 (49.0%) patients   Fig. . Table 4P = .87).Among 51 patients with MPE, 23 (22.1%) patients underwent interventions for the management of MPE and subsequently got the cytologic diagnosis of MPE. Eight (7.7%) patients were treated with a single episode of thoracentesis. Invasive intercostal drainages were performed in 15 (14.4%) patients, percutaneous catheter drainage in 9 (8.7%) patients, and tube thoracostomy in 6 (5.8%) patients  and the median survival time of patients with the targetable mutation was longer than that of patients with wild-type genes (52.3 vs 34.8 months).DPD is an earlier manifestation of pleural dissemination of NSCLC and can be detected radiologically, or surgically in patients without access to radiologic imaging. The reported prognosis of patients with intraoperatively diagnosed DPD is relatively favorable. Okamoto et al reported that the median survival time was 25.9 months and the 5-year survival rate was 23.7% in patients with intraoperatively diagnosed DPD. MPE reduces the quality of life and requires invasive procedures.,15,16 Its prevalence is approximately 16% at initial diagnosis in patients with advanced NSCLC. Finally, 40% of patients with NSCLC experience MPE during their lifetimes and approximately half are treated invasively.,18MPE is an advanced form of pleural dissemination in NSCLC. Li et al reported that MPE developed in 18.6% of 43 patients with intraoperatively diagnosed DPD (without radiologic evidence) during the 3-year follow-up period. In the present study, MPE developed in 49% of patients with DPD of NSCLC and the median interval to MPE was 42 months. The moderate prevalence rate of MPE in the present study might be due to our decision to include patients with DPD with and without radiologic evidence.There are few reports about the relationship between DPD and MPE. Kim et al reported that MPE developed in all 19 patients with radiologic DPD, and the mean interval to MPE was 19 ± 16.7 months. In our study, adenocarcinoma was not associated with EFIs. Also, the EGFR gene mutation and TKI therapy were not associated with EFIs. Tumor burdens of patients with radiologically positive DPD and radiologically negative DPD were different. However, the presence of radiologic evidence of DPD was not associated with EFIs (P = .61). Resection of the tumor was performed in 33.7% of patients and was a significant predictive factor for EFIs following univariable analysis . A reasonable explanation for this finding could be that tumor resection may have prevented or delayed further intracavitary progression. However, it is premature to recommend preventive tumor resection because it was not a significant factor and tumor resection was decided subjectively considering tumor size and location, pulmonary function, node metastasis status, and extent of pleural dissemination.We investigated predictive factors for MPE in patients with DPD to guide preventive treatment for MPE. No clinicopathologic factors predicted the development of MPE. Wu et al studied the association of lung adenocarcinoma and MPE and reported that patients with MPE at initial diagnosis had more EGFR gene mutations than a patient who had MPE after disease progression.P = .16). This finding suggests that the patient who succumbs to death by systemic progression of a disease other than MPE would be less likely to experience MPE. Between-group comparisons presented in Table The MPE and no-MPE groups showed statistically similar overall survival with a trend of more prolonged survival in the MPE group (41.3 vs 31.7 months,  It would be beneficial if a simple procedure could prevent MPE because many patients with DPD are at risk for developing MPE. The talc poudrage is the most effective method for managing symptomatic MPE and can be performed simultaneously as the patients are confirmed with DPD intraoperatively. The reported success rate of talc poudrage in patients with MPE related to lung cancer is between 82% and 91%.–11 Although disease status and the condition of patients with symptomatic MPE and asymptomatic DPD are different, the efficacy of talc poudrage in DPD may be similar to that of symptomatic MPE. Therefore, prophylactic talc poudrage may be considered to prevent the development of MPE in patients with DPD of NSCLC. In this study, however, the actual proportion of patients who needed an invasive procedure for MPE was 14.4% in their course of disease. In other words, the potential beneficiary of preventive intraoperative talc poudrage was 14.4% in patients with DPD. Thus, we think intraoperative prophylactic talc poudrage in NSCLC patients with DPD is not recommended. Furthermore, there was no predictive factor for the development of MPE.MPE induces respiratory symptoms, decreases quality of life, and is associated with significant social and medical costs. and it is an intrinsic limitation of studies about management of MPE. Thirdly, the study duration was long, and oncologic treatments evolved rapidly during the study period. Thus, we suspect that patient outcomes would be much better in recent patients. Finally, we considered any asymptomatic effusions as MPEs, although cytologic examination was omitted. Effusions in patients with NSCLC can be paramalignant, and our assumption is subject to criticism.,22 However, all patients with asymptomatic effusions in this study initially had pathologically proven DPD. Their post-effusion survival was similar to patients with cytology-positive MPE. Therefore, the definition of MPE in this study may be appropriate.This study had several limitations. First, this was a single institutional retrospective study and the number of cases was not enough to provide a higher level of evidence. However, it should be noted that all the patients suffering from DPD were reviewed, and this study can provide meaningful understanding about the fate of DPD in the real world. In order to obtain higher level of evidence, a multi-institutional prospective cohort study should be conducted. Secondly, modalities for the management of MPE had been selected largely based on the patient's subjective symptoms and this strategy might have resulted in selection bias. However, symptom-based management is a generally recommended strategy5MPE had developed in about half of patients with DPD of NSCLC and only a small portion of patients needed invasive intercostal drainage for the management symptomatic MPE. MPE in DPD did not affect the survival in NSCLC patients.Conceptualization: In Kyu Park, Woojung Kim.Data curation: Woojung Kim, Samina Park.Formal analysis: Woojung Kim.Investigation: Woojung Kim.Methodology: In Kyu Park, Samina Park.Project administration: Woojung Kim.Resources: In Kyu Park, Chang Hyun Kang, Young Tae Kim.Software: Woojung Kim.Supervision: Samina Park, Chang Hyun Kang, Young Tae Kim.Validation: Samina Park, Young Tae Kim.Visualization: Woojung Kim.Writing – original draft: Woojung Kim.Writing – review & editing: In Kyu Park, Chang Hyun Kang, Young Tae Kim.Woojung Kim orcid: 0000-0001-9530-8638.


Additionally, such positive effects were maintained at follow-up with a high treatment effect . Conclusion: MT plus ST showed reduction on perceived pain (3 points decrease), higher PPT (of at least 1.0 kg/cm2), improvement of disability caused by pain (4.4 points decrease), and positive perception of change (EG: 50% felt “much improvement”), compared to ST alone.Background: Isolated manual therapy techniques (MT) have shown beneficial effects in patients with temporomandibular disorders (TMD) but the effect of the combination of such techniques, together with the well-stablished splint therapy (ST) remains to be elucidated. Objective: This study was conducted to ascertain whether a combined program of MT techniques, including intraoral treatment, plus traditional ST improves pain and clinical dysfunction in subjects with TMD. Methods: A preliminary trial was conducted. 16 participants were assigned to either the MT plus ST-Experimental Group  or the ST alone—Control Group . Forty-five minute sessions of combined MT techniques were performed, once a week for four weeks. Three evaluations were conducted: baseline, post-treatment, and one-month follow-up. Outcome measures were pain perception, pain pressure threshold (PPT), TMD dysfunction, and perception of change after treatment. Results: EG showed significant reduction on pain, higher PPT, significant improvement of dysfunction and significantly positive perception of change after treatment ( Temporomandibular disorders (TMD) are defined by a set of clinical signs that affect the temporomandibular joint (TMJ), the masticatory muscles, and related structures involved in the movements of the TMJ .It has a prevalence of over 5% , and is Different treatment options for TMD are currently available: (a) splint therapy (ST), which has been widely studied and its efficacy proved ,8,9; thuIn this regard, a relationship between TMD and cervical dysfunction  has been highlighted by several authors, explained by the topographic arrangement between the cervical spine and the trigeminal nerve . Thus, uTherefore, isolated MT techniques have shown beneficial effects in patients with TMD, but the effect of the combination of such techniques, together with the well-stablished ST remains to be elucidated. Thus, a combined therapy of the currently broadly used ST, and articular/myofascial techniques applied both at the TMJ and the cervical level would allow the clinicians to address joint and myofascial pain, functional limitation and cervical mobility, all of them important variables that have an impact on people who suffer from TMD.In the present study, we aimed to ascertain whether a program based on a combination of MT techniques, which have shown beneficial effects when applied isolated, plus the traditional treatment of ST in subjects with TMD decreases pain, improves pressure threshold, dysfunction, and positively influences perception of change on patients when compared to the application of ST alone.The sample included participants who suffered from TMD, diagnosed by dentists applying the DC/TMD , and werA preliminary randomized controlled trial was carried out from May 2018 to August 2018. The participants were randomly allocated by a statistician to two different groups: the experimental group (EG), in which a protocol of accessory mobilization and myofascial MT techniques and ST was applied, and the control group (CG), who received ST alone. Participants belonging to the EG were treated for four weeks (one 45-min session per week). To analyze the effect of the intervention, three evaluations were carried out: at baseline (T0), post-treatment (T1), and at follow-up  (T2).www.clinicaltrials.gov (registration number: NCT03555201).The treatments were applied by an experienced physical therapist, with the necessary training and the study was carried out in the laboratories of the Physical Therapy Faculty of the University of XXXX. Participants provided informed consent following an explanation of the study aims and procedures before entering the study. The current preliminary clinical trial was conducted following the Consolidated Standards of Reporting Trials (CONSORT) statement . The EthPatients were randomly assigned to the EG or CG by an assistant who did not participate in the trial. Sequentially numbered envelopes were prepared with random assignment. The assessment files were placed in sealed opaque envelopes. Another assistant from outside the study proceeded with the assignment of the treatment. Coding, analysis, and interpretation of results was done by an external assistant.Both groups used a personalized occlusal splint for all the duration of the study (8 weeks) and only the EG also received the articular and myofascial MT protocol (4 weeks), which consisted of ten different techniques as described in Splint therapy: The splints were manufactured individually prescribed by a dentist, who made additional adjustments if necessary. It consisted of conventional occlusal splint molded with irreversible hydrocolloid  for the fabrication of a Michigan-type splint with canine and protrusive guides as well as a flat occlusal surface for contact with the antagonist teeth. Patients were instructed to use their occlusal splints 12 h a day for the duration of the study .MT treatment: The protocol consisted of a combination of ten techniques applied on the cervical, suboccipital, and temporomandibular areas: (1) neck accessory mobilization technique on C7 vertebra ; (2) mobPain: Assessed with the Visual Analogue Scale (VAS), in which the patients marked their level of pain intensity on a 10-cm horizontal line (0 = no pain to 10 = maximum pain) in relation to the last week. When pain was unilateral, only one side was registered, when bilateral, patient was asked to indicate a global score of pain. The VAS has shown high validity and reliability for the assessment of the patient’s pain intensity (CI 95% = 0.96–0.98) . Partici2) which induces pain was measured by pressure algometry (Wagner Instruments FDK 20). The patient was seated, and the masseter, temporal, and sternocleidomastoid muscles were assessed bilaterally, performing three measurements in each muscle, with a period of thirty seconds rest between them. The average of the three scores was obtained for analysis. The reliability of pressure algometry procedure was found to be high : 0.82–0.97) [Pain pressure threshold (PPT): The minimal pressure (kg/cm82–0.97)  and mode82–0.97) . When teDysfunction Index of TMD: It was assessed by the Helkimo Index which includes the following five clinical signs and symptoms : (i) impaired range of mandibular mobility; (ii) TMJ function impairment; (iii) muscle pain; (iv) TMJ pain during palpation; and (v) pain during mandibular movement. The total score is based on the sum of the score of the five items, with 25 being the maximum score. The index classifies the individual as follows: absence of TMD signs and symptoms (0 points), mild TMD signs and symptoms , moderate TMD signs and symptoms (5–9 points), and serious TMD signs and symptoms (10–25 points) .Change perception: Assessed at T2 with the Patient Global Impression of Change Scale (PGICS), which evaluates the change perceived by the subject after treatment. This scale has seven affirmations depicting a patient’s rating of overall improvement . Therefore, the lower the score, the higher the improvement perception .p-values were obtained using 150 permutations) [2 statistic [d) [p-value < 0.05.Descriptive results of continuous data were expressed as mean and standard deviation while categorical data were described as frequencies and percentages. In order to test treatment effect we applied in standardized data, a non-parametric permutational multivariate analysis of variance (PERMANOVA) with a repeated measure design that included three factors ,31: facttations) . These ptatistic  was usedstic [d)  was calcOf the twenty-five prospective participants, sixteen individuals were eligible, agreed to participate, were randomly assigned to a group, and completed the study . Seven participants did not meet inclusion criteria and were excluded: three participants had surgical history in TMD area, three had previous physical therapy, and one participant had used analgesics or muscle relaxants. Two participants voluntarily abandoned the study for personal reasons. p > 0.05) in morphometric and pain variables, except for Body Mass Index and Head Pain Location.Therefore, sixteen patients were considered for analyses in the study, with a mean age of 29.9 (±12.4) years, being mostly women . Participants were classified with myofascial pain  and myofascial pain with referral  according to DC/TMD. Participants of both groups had pain for at least four years, with a weekly frequency and of moderate intensity. The pain focused mostly on the jaw and cervical area. Clinical profiles of participants for both groups are shown in 1, 14 = 5.4, p = 0.002) and the interaction between treatment*time factor explained 11.3% . When considering the EG, pair-wise comparison showed significant differences between T0 and T1  and between T0 and T2 , but not between T1 and T2 . These results indicate that the EG experienced a significant general improvement after the treatment in relation to the CG. Moreover, the effect of that treatment was maintained significantly throughout the time of experimentation.When each of the factors of the study were analyzed, the treatment factor explained significantly 27.4% of the variance (Fp = 0.001) and this improvement was maintained at T2 (p = 0.001), with the treatment factor explaining 33.2% (R2) of pain improvement with a large effect size (f2: 0.50). No differences were found within the CG. In relation to the differences between groups, statistical changes were found for VAS at T1 and T2, with a large effect . None of the participants communicated any use of medication due to an acute increase in pain in the TMJ region for the duration of the study. The ANOVA analysis showed significant differences between groups for all measured variables at T1 and T2 . The resp = 0.001), so it improved from being practically in a severe level of dysfunction to a moderate one, staying at this level at T2 (p = 0.02). CG on the other hand showed no statistical within group differences; thus, remained at values close to severe dysfunction throughout the time of experimentation, with all participants being at moderate or severe levels. In the EG at T0 50% of the participants had a severe level of dysfunction and 50% had a moderate level, then at T1 and T2 none of the participants had a severe level, and they were all between moderate to low level of dysfunction (The Helkimo Index results showed a significant decrease of 4.4 points in the EG between T0 and T1 (function .2) of the improvement of the algometry variable for the three muscle groups, with a moderate to large effect size depending on the muscle . Thus, the between groups differences were statistically significant for all the measured muscles both at T1 and T2. Algometry results for EG show significant increase for all of the muscle groups at T1: masseter muscle significantly increased at least 1.0 kg/cm2 (p = 0.001), temporal muscle showed a significant increase of at least 1.9 kg/cm2 (p = 0.001), and sternocleidomastoid muscle significantly increased at least 1.3 kg/cm2 (p = 0.001). For the CG generally at T1 and T2 results were maintained or decreased when compared with T0, and no within groups statistical differences were found.In relation to PPT , Regarding the effect of the treatment over time, it was noted that for the EG at T1 the VAS and the Helkimo decreased significantly, and the algometry of the three muscle groups increased significantly and these improvements were maintained at T2.p = 0.005). Moreover, 50% of participants of EG felt “much improvement” after the treatment, whereas 50% of CG felt “minimally worse”.Finally, PGICS scale showed that after the completion of the whole study (T2) EG perceived a greater change after treatment  and this difference between groups was significant , severity, dysfunction, and perception of change in individuals with TMD when compared to the traditional treatment based on ST alone. These results highlight that MT combined with ST can be a more effective treatment than only ST. In addition, the positive effects of MT are maintained over time, since we observed improvements even at follow up.To the best of our knowledge, this is the first study to evaluate the potential effects of adding a protocol including several MT techniques to the traditional ST for TMD. This protocol included both accessory mobilization and myofascial techniques applied to the TMJ and the cervical region, in order to address the most relevant clinical aspects of TMD.The results of this study showed significant improvement of pain measured by VAS in the participants of the EG compared to the CG. The EG results at T1 and T2 for VAS when compared with T0, both showed significant improvement, although not with the same intensity. Moreover, the EG experienced an improvement beyond the minimum clinically significant difference in pain severity  . It is nThe neuro-anatomical basis which may explain this relationship between the neck and the head may be related to the trigemino-cervical nucleus caudalis in the spinal grey matter of the spinal cord at the C1–C3 level, where there is a convergence on the nociceptive second order neurons receiving trigeminal and cervical inputs . This toNoteworthy, PPT improved significantly for the three studied muscle groups only in the EG, while it did not improve in the CG. Thus, the combined treatment applied to the EG was more effective in improving the PPT than the traditional ST; thus, suggesting that it may have improved the nociceptive stimulus on painful tissue  related Regarding the improvement of the dysfunction assessed by the Helkimo Index, taking into account that this index assesses clinical signs related to both pain and mobility, our results indicate that the combination of MT techniques with ST allowed to improve the two main limitations of TMD. Although the use of ST has shown positive effects in subjects with TMD in previous studies  by addinConsidering that the Helkimo Index assesses range of mandibular mobility, pain during mandibular movement, and function impairment, among other symptoms, the improvements achieved in our study may be explained by to the MT protocol, rather than the ST. The applied MT treatment included techniques, such as non-thrust joint mobilization, which have been found to improve extensibility of non-contractile tissue and increase range of motion while decreasing pain and disability via peripheral, spinal, and supraspinal mechanisms . Moreovep < 0.001) [In line with our results, other authors who have applied isolated manual or soft tissue techniques have also reported clinical improvements in individuals with TMD. In this regard, a previous study showed that soft-tissue techniques were more effective than ST to improve mandibular range of motion in subjects with TMD . Further< 0.001) . Taken tAnother important aspect was the participant’s perception after the treatment, which can reveal relevant information of the beneficial effects of a given therapy. To date, most studies on TMD have proven the effectiveness of treatment from the physical condition dimension, while, in the present study, the perception of change was also taken into account. Our results showed significant differences between groups in relation to the patient’s belief about the efficacy of treatment, with the EG patients perceiving between minimum and much improvement, and the CG perceiving between no change and minimally worse. Although the PGICS scale has been widely used in chronic pain clinical trials , it has As for limitations, the main one is the small sample size which is a usual situation in physical therapy. Nevertheless, we performed an ad hoc statistical design (PERMANOVA). Among its advantages is that it is robust to non-normal data and allows controlling the emergence of false positives. Another limitation of the study is the source of participants, which was mainly from dental practices, which biases the selection of participants. Thus, our results must be taken with caution and further studies with larger sample sizes, which would allow subgroups according to disorders, would be recommended to confirm our promising results. One of the strengths of this study is that, although there are many previous studies that evaluate MT in pain, which we consider needed, we also included the level of dysfunction and the change that the subject perceived after being treated. In addition, reproducible, simple, and gentle techniques applied in the cervical region and in the TMJ have been included.The results of the present study suggest that a combined protocol based on MT plus ST tend to improve pain, pain-induced disability, and the patients’ self-perception of change in individuals with TMD. Moreover, such positive effects are maintained after one-month follow-up. These results reinforce the effectiveness of a multimodal treatment provided by a multidisciplinary team collaborating in the therapeutic approach for TMD patients.