The global neo-coronary pneumonia epidemic has increased the workload of healthcare institutions in various countries and directly affected the physical and psychological recovery of the vast majority of patients requiring hospitalization in China. We anticipate that post-total knee arthroplasty kinesiophobia may have an impact on patients’ postoperative pain scores, knee function, and ability to care for themselves in daily life. The purpose of this study is to conduct a micro-video intervention via WeChat to verify the impact of this method on the rapid recovery of patients with kinesiophobia after total knee arthroplasty during neo-coronary pneumonia.Using convenience sampling method, 78 patients with kinesiophobia after artificial total knee arthroplasty who met the exclusion criteria were selected and randomly grouped, with the control group receiving routine off-line instruction and the intervention group receiving micro-video intervention, and the changes in the relevant indexes of the two groups of patients at different time points on postoperative day 1, 3 and 7 were recorded and analyzed.P > .05). On postoperative day 3 and 7, there were statistical differences in Tampa Scale for kinesiophobia, pain, activities of daily living scale score and ROM between the two groups (P < .01), and the first time of getting out of bed between the two groups (P < .05), and by repeated-measures ANOVA, there were statistically significant time points, groups and interaction effects of the outcome indicators between the 2 groups (P < .01), indicating that the intervention group reconstructed the patients’ postoperative kinesiophobiaand hyperactivity. The level of pain awareness facilitates the patient's acquisition of the correct functional exercises to make them change their misbehavior.There were no statistical differences in the scores of kinesiophobia, pain, knee flexion mobility (ROM) and ability to take care of daily life between the two groups on the first postoperative day (WeChat micro-video can reduce the fear of movement score and pain score in patients with kinesiophobia after unilateral total knee arthroplasty, shorten the first time out of bed, and improve their joint mobility and daily living ability.This study has passed the ethical review of the hospital where it was conducted and has been filed, Ethics Approval Number: 20181203-01. With the aging of the world population, the number of patients who undergo total knee arthroplasty (TKA) every year is increasing rapidly, and the majority of them are middle-aged and elderly. Culliford found that the number of TKA patients in the United Kingdom has increased rapidly in the last decade, and it is predicted that by 2030, the number of TKA patients will reach 1.22 million, which is twice as many as in 2010. Based on the disadvantages of the procedure, such as high trauma and bleeding, patients tend to experience more severe pain after surgery, with up to 60% of patients in early severe pain.The knee joint is the largest and most complex complex joint in the human body and carries 4 to 6 times the longitudinal gravitational force of body weight. The incidence of kinesiophobia is 52.8%, which affects the patient's recovery after surgery. kinesiophobia is an irrational psychological state in which the patient, when faced with painful stimuli, has the misconception that activity or rehabilitation exercises will lead to re-injury or aggravate pain, and is therefore unwilling to actively engage in rehabilitation exercises. Kinesiophobia is an important factor in the prognosis of total knee arthroplasty, and in severe cases, it can affect the recovery of joint function and even lead to joint disuse and disability.Because of the special physiological structure and position of the knee joint, most of the patients will have severe pain after TKA. Faced with the stimulation of pain caused by multiple factors, some patients may think that activities or functional exercises will aggravate the postoperative pain or cause re-injury to the knee joint.,9 This study aims to help patients with kinesiophobia after unilateral total knee arthroplasty to carry out early rehabilitation exercises through short micro-videos in order to reduce their kinesiophobiaa and pain level, to help them master the correct functional exercises, to help improve knee function, and to speed up the rehabilitation.WeChat can be used to educate patients about the disease and can be communicated in various forms, such as voice, text and even video, which is more suitable for rehabilitation guidance during neocoronary pneumonia.22.1This study has passed the ethical review of the hospital in which it was conducting , and the project was established and supported by the Provincial Medical and Health Science and Technology Program (2020KY936) during the research process. Ethics-related contents were strictly observed in the study.2.2This study is a prospective, randomized, single-blind (subject), controlled clinical study. The purpose and procedure of the study will be informed and explained by the investigator and the nurse in charge before the start of the intervention, and it informed consent for the study will be signed after obtaining the patient's approval and understanding. This study does not additionally increase the risk of post-operative rehabilitation, and the relevant rehabilitation exercises in the study will be carried out in the company of a rehabilitation therapist, if any adverse reaction occurs, it will be immediately stopped and contacted and dealt with by the rehabilitation therapist and physician in the current ward, the relevant compensation measures and insurance by the hospital rules and procedures.2.3Patients who were admitted to our hospital for unilateral total knee arthroplasty from January 2020 to June 2020 during the period of neo-coronary pneumonia resistance, were selected by convenience sampling method and scored by Tampa Scale for kinesiophobia (TSK) within 24 hour after waking up from anesthesia according to the inclusion-exclusion criteria. One patient in the intervention group and 1 patient in the control group withdrew from the study, with a loss of follow-up rate of 2.5%, and the general information of patients is detailed in Table Inclusion criteria:(1)patients who met the American Rheumatism Association (ARA) diagnostic criteria for knee osteoarthritis and underwent total knee arthroplasty,(2)patients with TSK score >37 within 24 hours after surgery,(3)patients who underwent unilateral total knee arthroplasty for the first time,(4)patients who voluntarily participated in this study and signed an informed consent form.Exclusion Criteria:(1)patients with lower extremity thrombosis or previous history of embolism and need to restrict lower extremity activities,(2)patients with other lower extremity joint pathologies such as ankle and hip,(3)patients with illiteracy, confusion, mental or communication disorders,(4)patients who have participated in other similar studies.2.4(1)General information: including the patient's name, bed number, age, BMI, surgical location, education level, and marital status.(2) in 1990 and applied to chronic pain patients, and was later developed and validated by Hu in China.The TSK: This scale was proposed by Kori(3)Besides, the Pain Score, Joint Mobility, and Daily Living Skills Self-Care Scale was also included.2.5t-test and non-parametric rank-sum test; patients’ counting data were described by frequency and percentage, and statistical analysis was performed by karyotype test; patients’ monitoring data were analyzed by Repeated Measures ANOVA (Repeated Measures ANOVA). Trends in the indicator over time, where P < .05 is different.SPASS21.0 software was used to statistically and analytically analyze patients’ general information and related indicators by using Excel software to enter the database and adopting a 2-checking method. Patients’ measurement data were described by mean and standard deviation, and statistical analysis was performed by two independent samples 2.62.6.1The control group gave direct and regular verbal and face-to-face instructions to the patients, as follows: when the patients woke up from anesthesia, they were told to perform ankle pump exercise and quadriceps muscle contraction exercise, etc. They were instructed to increase or decrease the amount of exercise according to their state and degree of muscle fatigue; 1 day after the operation, they were instructed to bend their knee joints and straight leg raising exercise, etc. After that, the patients could adjust appropriately according to their rehabilitation situation. During this period, the patient's condition is closely observed and the vital signs are recorded regularly.2.6.2The intervention group used WeChat for online mobile phone micro-video broadcasting. The researcher could provide simultaneous cognitive belief education and exercise behavior essentials instruction next to the patient during the micro-video broadcast. Micro-video viewing is primarily the responsibility of the patient's charge nurse, and is scheduled for afternoon rounds by the charge nurse. The frequency is once a day, and the video can be given to the patient free of charge before discharge if the patient needs it. The micro-videos were disseminated in 3 parts: actionable exercise goals, detailed demonstration of movement and breakdown, and peer and health care support education. Patients were monitored on the first, third and seventh postoperative days to evaluate the dissemination effect, including the Tampa score for agoraphobia, knee mobility (maximum flexion mobility), pain classification, and Bartholomew's scale of self-care ability in daily life .Rehabilitation actions:(1)single-joint movement: choose ankle pump movement, ankle joint rotation movement of the 2 single-joint movement in the patient anesthetized awake immediately, both belong to the prevention of lower limb thrombosis rehabilitation actions easy to understand and the effect of a group of actions, the frequency of activities for 10 times/group, 10 groups/d.(2)Simple muscle exercise: instruct patients to perform quadriceps muscle contraction exercise, to lay a good foundation for the later early movement out of bed, to avoid thigh muscle weakness, the frequency of activities for 10 times/group, 10 groups/d.(3)Multi-joint movement: Patients mainly use the joint axis to pull the limb movement during joint movement, the joint chain refers to the composite chain composed of 2 or more parts of the human body connected through joints in a certain order.The straight leg raising exercise after TKA belongs to the most common type of exercise in the open kinematic chain, which is characterized by exercising single or several joints at the same time, mainly showing that the proximal end of the limb is fixed, while the distal end is movable. One type of rehabilitation, the main feature of which is the immobilization of the knee and distal joints of the affected limb while the patient moves the proximal part of the limb, is more similar to functional rehabilitation. The combination of the 2 allows for a maximum range of motion (ROM) of the limb, providing early, effective and safe rehabilitation.Paying attention to the rule of progression during rehabilitation exercises. The exercise follows the Tens rule, which consists of 10 seconds of contraction , and 10 seconds in between to allow the patient to rest. 10 repetitions, 3 sets a day.3P > .05), and there was a difference in kinesiophobia and pain scores between the 2 groups on postoperative days 3 and 7 (P < .01), and after repeated measures ANOVA, there was a difference in time point, group and interaction effect between the 2 groups (P < .01)  was less than that in the control group (43.297 ± 18.45), and the difference was statistically significant (P < .05).Patients should be accompanied by family members or medical personnel when they first get out of bed, and the walking distance after getting out of bed can be greater than or equal to 5 m with the help of a walking aid or family members, and the specific time started to be calculated immediately after the transfer from the anesthesia recovery room.P > .05), and there was a difference on postoperative days 3 and 7 (P < .01), and a further repeated-measures ANOVA showed that there was a difference in time point, group, and interaction effect between joint mobility and the daily living ability scale (P < .01)  scores in the intervention group compared with the control group on postoperative day 1 , and the 2 groups differed in time point, group, and interaction by repeated measures ANOVA (P < .01). The results showed that the kinesiophobia score and pain score of the intervention group decreased with the increase of the length of hospital stay compared with the control group, indicating that micro-video intervention can reduce the fear psychology of the kinesiophobia patients after total knee arthroplasty during COVID-19, so as to relieve postoperative pain, which was consistent with Doury's results. The reason is that, compared with traditional health education, micro-video health education focuses on the interaction between patients’ acceptance and feedback in the communication process, which can reduce patients’ kinesiophobia by eliminating their negative beliefs; secondly, micro-videos are produced systematically throughout the patients’ hospitalization period to strengthen their self-rehabilitation and maintenance behaviors by closely integrating the knowledge of kinesiophobia and knee replacement. to motivate them to switch from passive exercise to voluntary training to avoid adverse consequences such as weakened knee function, joint adhesions, and lower extremity thrombosis.Patients in the intervention group had lower pain scores and kinesiophobia scores than those in the control group on postoperative day 3 and 7 (P < .05), and the scores of joint mobility and self-care ability of daily life scale were higher in the intervention group than in the control group on postoperative day 3 and 7 (P < .01). The results showed that ROM and ADL of the intervention group and the control group increased significantly with the extension of hospital stay, indicating that micro-video intervention can promote the early and progressive functional exercise of the kinesiophobia patients after total knee arthroplasty during COVID-19, so as to promote rapid recovery. This result confirms that the rehabilitation exercise method provided by micro-video can enhance the strength of lower limb muscles of patients with kinesiophobia, which is conducive to timely independent walking. The results were consistent with Hande and Cai. With audio-rich and illustrated micro-videos for the intervention, the researchers’ timely follow-up during the patients’ exercise process helped to direct the patients’ attention from pain braking to active exercise, gradually transitioning from initial reluctance or fear of exercise to willingness to try until active rehabilitation exercise, increasing the patients’ participation in behavior management, visualizing the exercise outcomes, and gaining a sense of accomplishment in behavior management during the behavior remodeling process. Reach the set goal of postoperative knee function exercise as soon as possible to avoid poor knee function recovery in the patient.The mean time to get out of bed for the first time was 36.34 hours in the intervention group, which was better than the 43.27 hours in the control group (5The causes of postoperative pain after total knee arthroplasty are complex, and some studies have found that the arthroplasty surgery itself will cause patients to have strong psychological stress reactions, and these reactions and postoperative pain will affect each other, making the diagnosis and treatment of postoperative pain extremely difficult. Traditional rehabilitation instruction is usually nurse-led, but during neo-coronary pneumonia, the use of micro-video interventions can effectively avoid direct contact between patients and health care professionals. The research results showed that WeChat micro-video intervention could reduce the pain degree and kinesiophobia degree of patients with kinesiophobia after total knee arthroplasty during covid-19, and improve the ROM and the ADL. The shortcomings of this study were limited to observation during hospitalization, and there was a lack of mid- and long-term follow-up of patients after discharge from the hospital. In future studies, we may consider expanding the sample size, extending the time points of patient observation, and more scientifically evaluating the cognitive and behavioral adaptations of micro-communication on postoperative agoraphobic patients with TKA from a medical psychological perspective, so as to promote patients’ rapid recovery.All authors read and approved the final version of the manuscript.Conceptualization: Guanzhen Lu, Tingting Wu, Qin tan, Yan Zhong.Investigation: Zhe Wu, Lingmei Shi, Tingting Wu.Formal analysis: Tingting Wu, Guanzhen Lu.Writing – original draft: Guanzhen Lu, Tingting Wu.Writing – review & editing: Yan Zhong.


BackgroundInitial Glasgow Coma Score (iGCS) is a well-known predictor of adverse outcomes following chronic subdural hemorrhage (cSDH). Frailty, i.e. a reduced physiologic reserve, is associated with poorer outcomes across the surgical literature, however, there is no consensus on the best measure of frailty. To date, no study has compared frailty’s ability to predict cSDH outcomes versus iGCS. The goal of this study was to, therefore, examine the prognostic value of the 5- (mFI-5) and 11-factor (mFI-11) modified frailty index, and Charlson Comorbidity Index (CCI) versus iGCS following cSDH.MethodsBetween January, 2016 and June, 2018, patients who presented to the emergency department with cSDH were retrospectively identified using the International Classification of Diseases (ICD) codes. mFI-5, mFI-11, and CCI scores were calculated using patient baseline characteristics. Primary endpoints were death and discharge home and subgroup analyses were performed among operative cSDH. Univariate and multivariate logistic regressions were used to determine predictors of primary endpoints.ResultsOf the 109 patients identified, the average age was 72.6±1.6 years and the majority  were male. The average CCI, mFI-5, and mFI-11 were 4.5 ±0.2, 1.5 ±0.1, and 2.2 ±0.1, respectively. Fifty (45.9%) patients required surgical intervention, 11 (10.1%) died, and 48 (43.4%) were discharged home. In the overall cohort, while the only multivariate predictor of mortality was iGCS , the CCI  was a superior predictor of discharge home compared to iGCS . Conversely, among those who received an operative intervention, the CCI, but not iGCS, independently predicted both mortality  and discharge home . Neither mFI nor age predicted primary outcomes in multivariate analysis.ConclusionWhile frailty is associated with worse surgical outcomes, the clinical utility of the mFI-5, mFI-11, and CCI in cSDH is unclear. We show that the iGCS is an overall superior predictor of mortality following cSDH but is outperformed by the CCI after operative intervention. Similarly, the CCI is the superior predictor of discharge home in cSDH patients overall and following an operative intervention. These results indicate that while the iGCS best predicts mortality overall, the CCI may be considered when prognosticating post-operative course and hospital disposition. Chronic subdural hemorrhage (cSDH) is an increasingly common pathology encountered in modern neurosurgical practice given its high frequency among the elderly . The outFrailty, i.e. a reduced physiologic reserve, is an emerging concept across the surgical literature that aims to elucidate the differential effects of age versus the cumulative effect of multiple comorbidities on surgical outcomes. While frailty, as most often measured by the modified frailty index (mFI-11), has been associated with poorer neurosurgical outcomes, its effect among those with cSDH is unclear -6. To daStudy design and settingThis retrospective study was performed between January 2016 and June 2018 at a quaternary academic referral center  with high neurosurgical volume. Institutional Review Board Approval with a waiver of informed consent was obtained from New York Medical College & Westchester Medical Center (IRB 12921). All data were retrospectively collected using the electronic medical record system by trained and monitored data abstractors.Subject selectioncSDH patients were identified by reviewing the International Classification of Diseases (ICD) codes for subdural hemorrhage for all patients presenting to our emergency department in the study period. Inclusion criteria were patients 14 years or older who presented with a chronic subdural hemorrhage. Patients were excluded if they had a history of  neurosurgical procedure or were found to not have a chronic SDH on in-house imaging. We defined cSDH as any subdural hemorrhage with a chronic component including mixed, acute on chronic, pure chronic, or subacute SDH.Measures and endpointsFor each patient, demographics, smoking and alcohol abuse history, anti-coagulant or anti-platelet (AC/AP) drug use, GCS score, chief complaint, and cSDH characteristics , and presence of an isolated head injury were collected. The eleven-factor modified frailty index mFI-11) was calculated by assigning one point for the presence of each of the following pre-hemorrhage characteristics for a maximum of 11 points: hypertension requiring medication, congestive heart failure, myocardial infarction, previous percutaneous coronary intervention or angina, transient ischemic attack or cerebrovascular accident without neurological deficit, cerebrovascular accident with neurological deficit, peripheral vascular disease or ischemic chest pain, chronic obstructive pulmonary disease or current pneumonia, diabetes mellitus, non-independent functional status, and impaired sensorium  treatment), hospital length of stay (hLOS), ICU length of stay (ICU-LOS), deep vein thrombosis (DVT), pulmonary embolism (PE), pneumonia, tracheostomy, gastrostomy, and discharge GCS (excluding deaths).Statistical analysisNormal distributions were determined using an Anderson-Darling normality test. T-tests were used for normally distributed continuous samples and Mann-Whitney tests were used for non-normally distributed continuous samples. Continuous data were shown using mean ± standard error of the mean (SEM). Fisher’s exact tests were used for binary variables and odds ratios (OR) are shown with 95% confidence intervals (95% CI). Subgroup analyses were conducted among those who required an operation. Similar to prior studies, multivariate logistic regressions were performed via the enter method using known predictors of outcomes sex, prior subdural hemorrhage, craniotomy, AC/AP use, iGCS, and SDH thickness followed by forward conditional addition of either mFI-11, mFI-5, or CCI to the model. Age was not included due to collinearity with the CCI. No collinearity was detected in either model, as defined as a variance inflation factor of less than one or greater than 10. Statistical analysis was performed using Prism 8.3.0  and SPSS version 25 . Significance was defined as p<0.05.Demographics and baseline characteristicsOf the 429 records identified, 109 met inclusion and exclusion criteria Figure . As expeThe average CCI was 4.5 ±0.2 range: 0-11) and 42 (38.5%) had a CCI³6. The most commonly identified CCI characteristic, beyond age, was a history of uncomplicated diabetes  followed by a history of dementia   patients were admitted and 50 45.9%) required a surgical evacuation of SDH. Five (4.6%) patients developed a DVT, 1 (0.9%) a PE, and 5 (4.6%) pneumonia. Six (5.5%) patients required a tracheostomy tube and 9 (8.3%) a gastrostomy tube. The average ICU-LOS was 5.0 ±0.5 days (range: 0-22) while the hLOS was 9.0 ±0.9 days (range: 1-62). Ultimately, the average discharge GCS was 14.3 ±0.2, a plurality of patients were discharged home , and 11 (10.1%) patients died , had a higher iGCS , larger SDH thickness , and were more likely to have an isolated head injury , indicating careful selection of surgical candidates. Likewise, those that received an operation had decreased CCI  and mFI-11  but not mFI-5 (p=0.2580) scores compared to those who did not have an operation. There were no significant baseline differences in history of SDH, smoking or alcohol abuse history, AC/AP use, or type of SDH between those who did or did not receive an intervention  and ICU  length of stay but no differences in complications (p>0.05)  and was not independently predicted by any frailty measure Table . DischarSubgroup analysis of operative patientsStepwise multivariate logistic regressions, in the same manner as above, were performed among those who received an operative intervention. Among this group, the only independent predictor of mortality was the CCI  (Table Frailty predicts outcomes in a variety of surgical and non-surgical patients. Despite cSDH being a common neurosurgical condition associated with cerebral atrophy and advanced age, the utility of frailty has not been explored in this population. In this study, we show that frail patients, regardless of scoring system, are less likely to be discharged home compared to their non-frail counterparts. Along with iGCS, the CCI was independently associated with discharge home in multivariate analysis in the cohort overall and was the only independent predictor of this endpoint in patients who received an operation. Similarly, while mortality overall was best predicted by iGCS, the CCI was the only independent predictor of death in subgroup analysis of operative cases. These results indicate that the CCI may have clinical utility in predicting functional outcome in all cSDH patients and mortality among those who receive an operation. It is well known that patient comorbidities contribute to poorer prognosis following a neurologic insult. Frailty is an emerging concept that aims to quantify the cumulative effect of these comorbidities in order to more accurately prognosticate outcomes. In neurosurgery specifically, frailty has been associated with poorer outcomes following subarachnoid hemorrhage ,11, spinCareful selection of surgical candidates for cSDH evacuation incorporates a variety of factors including hemorrhage size, MLS, age, overall clinical history and exam, and the iGCS. In particular, the iGCS following cSDH is thought to be the factor with the highest prognostic utility ,22. In lWhile the mFI-11 is the most commonly used frailty measure in the literature, to date, no study has examined the mFI-11 or mFI-5 among patients with cSDH; an effect that may reflect a publication bias. Furthermore, while there have been previous studies investigating the relationship between the CCI and cSDH prognosis, there are conflicting results with some finding that the CCI is independently associated with cSDH recurrence , increasLimitationsThis study was chiefly limited by its retrospective design as outlined elsewhere  and by aWhile frailty is associated with worse surgical outcomes, the clinical utility of the mFI-5, mFI-11, and CCI versus the iGCS following cSDH is unclear. We show that the iGCS is an overall superior predictor of mortality following cSDH but is outperformed by the CCI after operative intervention. Similarly, the CCI is the superior predictor of discharge home in cSDH patients overall and following an operative intervention. These results indicate that while the iGCS best predicts mortality overall, the CCI may be considered when prognosticating post-operative course and hospital disposition.


Chronic post-thoracotomy pain is a debilitating condition after traumatic multiple rib fractures and surgery. We aimed to estimate the prevalence of chronic post-thoracotomy pain after traumatic multiple rib fractures in South Korea and explore factors associated with it. From October 2017 to June 2019, a cross-sectional survey of 100 adults, who had undergone thoracotomy due to traumatic fractures of two or more ribs 2 years to 3 months prior to the survey, was conducted in the regional trauma center in South Korea. In total, 80% and 65% patients reported any level and above moderate chronic pain, respectively. Quality of life was mostly below the normative value of the US general population. Forty-six percent patients had restrictive respiratory dysfunction, and 47% and 59% patients were classified as being at risk of above mild-level anxiety and depression, respectively. More than 70% of patients had a current opioid prescription. Multivariable logistic regression analysis showed weak evidence of association between acute, severe postoperative pain and chronic postsurgical pain . Collectively, chronic post-thoracotomy pain and associated incomplete recovery regarding respiratory, functional, and psychological outcomes were prevalent in patients with traumatic multiple rib fractures in South Korea. Patients who undergo surgical fixation of traumatic multiple rib fractures often experience disabling chronic postsurgical pain, which seriously limits activity of daily life and impairs quality of life3. The prevalence of chronic post-thoracotomy pain (CPTP) ranges from 25 to 91%, showing considerable heterogeneity, which possibly attributed to differences in the underlying pathophysiology, mode of injury if relevant, design of study, methods of classifying pain, and clinical context5. Given the high prevalence and the detrimental impacts on the functional recovery process and quality of life in the affected patients7, CPTP after traumatic multiple rib fractures deserve recognition both as a major clinical problem and as a significant public health burden9. Factors associated with CPTP may include demographic characteristics, such as age, gender, education, and socioeconomic status, and clinical characteristics, such as severity of injury, poly-trauma, comorbid conditions, preoperative pain level and acute postoperative pain level14. Knowledge on the prevalence of CPTP after traumatic multiple rib fractures and its associated factors are fundamentally important for developing risk-stratification strategies and identifying modifiable risk factors which likely contribute to the management and prevention of CPTP after traumatic multiple rib fractures and the informed decision-making process regarding appropriate pain management by relevant stakeholders 17. Currently, such information remains unclear in the South Korean population. To address this gap of knowledge, the study aimed to estimate the prevalence of chronic post-thoracotomy pain after traumatic multiple rib fractures in the South Korean setting and explore factors associated with it.The International Classification of Diseases 11th revision (ICD-11) defines chronic postsurgical pain or chronic traumatic pain as pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, i.e., at least 3 months after the initiating eventThe study was performed at outpatient clinics in the Regional Trauma Center at Pusan National University Hospital. Among the 678 outpatients, 161 eligible patients were asked to participate in the survey to achieve the anticipated 100 participant’s responses  . The proportion of patients with neuropathic pain was 51%. Table .Table 2PForty-seven percent patients were classified as having at least mild-level anxiety. More than half of the patients (56%) were classified as being depressive. Almost one in 10 patients was found to have a risk of severe anxiety and/or depression  who had undergone the pulmonary function test showed a restrictive respiratory pattern. A small number of patients (8%) showed an obstructive respiratory pattern. There was no difference in the respiratory function parameters between patients with and without chronic pain, when adjusted for age, sex, level of education, current smoking status, and injury severity scale (≥ 16 or not) 4. Patients with chronic pain had significantly worse quality of life than those without chronic pain in both physical and mental domains, when adjusted for age, sex, level of education, current smoking status, and ISS score  and 21% psychotropic drugs. Acetaminophen was prescribed in one patient  among respondents in patients who had undergone stabilizing surgery of multiple rib fractures and/or flail chests20. In a recent narrative review, the incidence of chronic pain after thoracic surgery, including either open or video-assisted thoracotomy (VAT), remained stable at around 50% over time21. Inconsistencies between previous findings may be attributable to clinical and methodological heterogeneity, including but not limited to, difference in definition of chronic pain, time-point of measuring pain, research design  or methods of data collection . Currently, no clear explanation for inconsistency of evidence seems available at the moment which justifies the further systematic investigation on the risk of CPTP in patients after traumatic multiple rib fractures.In our study, the prevalence of self-reported CPTP was 80% when classified as any level of pain and 65% when classified as moderate to severe level. Prevalence of pain after rib fractures and subsequent conservative management was 59% at 2 months post-injury22, which reported that the prevalence of probable or definitive neuropathic pain was 66% in patients with persistent CPTP. Whether the prevalence of neuropathic pain after thoracic surgery related to trauma differs from those for non-traumatic etiologies needs further investigation.The prevalence of neuropathic pain among patients who reported a moderate or severe level of chronic pain was consistent with that reported in a previous systematic review23, although these results need careful interpretation as respiratory function was measured at variable timepoints after discharge.We found no significant association between CPTP and pulmonary function test results. It is of note that the overall proportion of patients with restrictive respiratory dysfunction was almost 50% regardless of chronic pain, which may imply that the burden of respiratory dysfunction is common in patients who had received thoracotomy. In a single-center audit in South Korea involving 72 patients with traumatic multiple rib fractures who had PFT results 6 to 23 months from discharge, restrictive respiratory dysfunction  was present in 42% patients24. Patients without chronic pain also showed impaired quality of life in terms of PCS scores. Claydon reported that patients with multiple rib fractures faced challenges with rehabilitation throughout the entire recovery journey, which mainly arose from difficulties with coping with chronic pain and long-term restriction of lifestyle and functional abilities6. These findings suggest that limited physical function may present independent of chronic pain and can be an important outcome that deserves attention from healthcare professionals. Since chronic pain and poor quality of life may mutually affect each other in an intertwined way and not necessarily be captured by the questionnaire-based assessments25, triangulation of our findings by both quantitative and qualitative studies would help understand the potential complexity of association between chronic pain and quality of life in patients with chronic post-thoracotomy pain after multiple rib fractures.We found that quality of life was consistently lower in all domains than that of the reference population value and tended to be significantly lower in patients with chronic pain than in those without chronic pain. Our findings resonate with previous studies conducted in Australia, reporting that multiple rib fractures are associated with lowered quality of life over 2 years post injury in patients with multiple rib fractures regardless of surgical fixation surgery26. The US population-based cohort study revealed that the risk of opioid use 90 to 180 days after various elective surgery was 7.1%27. In our findings, a much higher proportion of patients were classified as prolonged users of opioids, which might be associated with a different clinical context and distribution of risk factors for chronic use of opioids. However, we could not exclude risk of overestimation as prescribed opioids might have not been actually consumed by patients. The prescribing pattern of physicians and pain-coping behaviors of patients are also related factors which should be explored in larger prospective studies.A recent systematic review found that the prevalence of continued opioid use after trauma or surgery was 4.3% (95% CI 2.3% to 8.2%)28. We found some weak evidence of an association between the experience of severe pain in acute stage trauma and CPTP. Heterogeneity in clinical, sociodemographic, and methodologic aspects might have contributed to the observed discrepancy. For instance, previous studies were mostly regarding patients who had undergone elective surgery28, in which the underlying pathophysiology, the degree of concurrent neural and bony tissue injury, and psychological impacts of traumatic events may be considerably different from those who had received non-elective surgery after trauma. Nurse records of acute-stage pain might have been documented inaccurately and may have affected the study findings. Time from surgery was various in our cross-sectional study, which may have contributed to the misclassification of CPTP. Therefore, our findings require careful interpretation and should not be regarded as confirmative evidence of no association between acute and chronic pain. Observed association between use of IV-PCA and chronic pain is possibly due to confounding by indication, as stratified analyses revealed no significant association between them.Acute pain intensity is known to be associated with chronic pain in patients with rib fracturesTo the best of our knowledge, this is a first descriptive cross-sectional survey investigating the prevalence of CPTP in patients with traumatic multiple rib fractures in South Korea. A dedicated, trained researcher measured outcomes using validated scales and instruments. Almost all patients provided results of the pulmonary function test, which may triangulate the validity of our findings on the impaired physical functions assessed by the subjective questionnaire. There were a few missing responses among the survey participants, which limits the risk of bias due to the non-response. The power of the study was enough to test the null hypothesis that the CPTP in patients with multiple rib fractures would be 25%. We adhered to the reporting guideline of observational studies in the design and reporting of the survey.29. It remains unclear whether trauma or surgery were solely responsible for chronic pain due to the absence of data regarding pain before trauma. Data acquisition was available only in patients who physically presented at the outpatient clinic. This may have introduced selection bias if the patients who have visited the hospital and underwent survey were systematically different from those who did not visit the hospital after surgery. Other logical barriers such as time constraints or unaffordability of the hospital visit should also be considered as potential source of non-presentation. In our study, the timepoint of measuring chronic pain was inconsistent, which would be a potential source of variance of the prevalence estimation. The survey was conducted in the single regional trauma center; therefore, the respondents may not represent the study population  and our estimations may not reflect the true population prevalence of chronic post-thoracotomy pain after traumatic multiple rib fractures. Although we asked participants to rate their pain focusing on the chest area, patients who were poly-traumatized and had injuries other than in the chest may not differentiate the pain limited in the chest region and the perceived overall bodily pain. Therefore, we could not exclude the risk of bias due to misclassification of CPTP. Findings on clinical outcomes should serve exploratory purposes due to the risk of type 1 error when multiple analyses were performed.Limitations are as follows: This is a cross-sectional study, which could not distinguish between prevalent (existing) pain and incident (new-onset) pain30. Valid ascertainment methods of acute-stage pain in patients undergoing surgery after traumatic multiple rib fractures should be developed, as routine clinical documents collected for non-research purposes may not be a reliable source of research data.To overcome aforementioned limitations, prospective investigation of incidence of CPTP in patients undergoing thoracotomy after chest trauma is highly warranted. Standard methodology and timepoints for measuring pain and other patient-relevant outcomes as well as its transparent reporting are necessary to produce comparable quality of data, which would be used for the reliable estimation of CPTP following traumatic multiple rib fractures. Burden of opioid and psychotropic drug use in this population should be addressed in further larger-scale studies, because of their potential harms when used long-term. Surveillance of chronic pain, quality of life, psychological comorbidity, and respiratory function after surgery to inform researchers and clinicians for providing the best-available care to patients are required. Return to work or social activity which reflects occupational and social aspects of recovery were not measured in this study and need to be addressed in future studiesChronic post-thoracotomy pain was prevalent in patients with traumatic multiple rib fractures in South Korea. Impaired respiratory function, suboptimal quality of life, depressive mood, and possible prolonged use of opioids were also common. There was some weak evidence of an association between acute postoperative pain and CPTP. Further prospective and population-representative studies are required for the reliable estimation of CPTP in South Korea.3. A secondary hypothesis was that acute-phase severe pain after injury is a significant risk factor of chronic persistent pain, based on previous studies that have highlighted the association between acute-stage severe pain and chronic post-thoracotomy pain after multiple rib fractures31.We hypothesized that the estimated risk of chronic post-thoracotomy pain after traumatic multiple rib fractures is 25%, the known baseline risk in patients who have undergone elective thoracic surgery for non-traumatic etiologiesWe used a cross-sectional design, which is less complex than other designs and appropriate enough for estimating the prevalence of chronic pain when limited information is available for the topic. We defined the study population as adults dwelling in South Korea who underwent thoracotomy  2 years to 3 months prior to the survey due to multiple rib fractures associated with blunt chest trauma. The survey was conducted in the regional Trauma center in Pusan National University Hospital (PNUH), which is located in the center of Busan City and covers traumatic injury cases in Busan City and the outskirts of South Gyeongsang Province from October 10, 2017 and June 11, 2019. The PNUH Trauma center was established on November 9, 2015. The cumulative number of patients with multiple rib fractures admitted and discharged in the center from inception to December 31, 2019 is approximately 1694.32. Patients who were unable to respond to the questionnaire with or without assistance of the caregiver or the researcher for reasons such as cognitive problems or only caregivers were present in the hospital were excluded in the survey.Adults aged ≥ 19 years who had undergone thoracotomy due to traumatic multiple rib fractures 2 years to 3 months prior to the survey were included. To be eligible, patients should have a diagnosis of fractures on two or more ribs (code S22.4) and/or flail chest (code S22.5) according to the International Classification of Diseases, 10th RevisionA structured data collection sheet was developed through discussion between authors. A dedicated, trained research assistant (YKS), who had not been involved in surgery or postoperative care, asked the patient about demographic characteristics and clinical outcomes via a face-to-face interview to avoid response bias. For brevity of the survey process, information available on the electric medical record (EMR) were not asked from the patient; it was extracted from the record by the research assistant or the study trauma surgeons. In most cases, approximately 10 to 15 min were required for the data collection in an interview. Pulmonary function test without bronchodilator administration using spirometry was performed by experienced independent technician assessors who were not aware of the chronic pain status in the respiratory disease center in the PNUH on the same day of the survey.Each patient was asked whether he/she felt any level of pain within the recent week. Patient who reported pain were asked to rate the average pain intensity felt at rest, during movement, lying down, and while coughing on the numeric rating scale (NRS) of 0  to 10 (worst pain imaginable ever) scores. Patients who expressed pain NRS scores of ≥ 4 points for any of the four situations were considered to have moderate-level chronic pain .33. It comprises of 5 items for pain and 2 for sensory testing, and the score ranged from 0 to 24 points. Patients with scores ≥ 12 points were considered to have a neuropathic mechanism underlying their pain in the chest area33. If a patient reported no pain, the scale was not administered and the level of neuropathic pain was scored as zero. A dedicated trained research assistant (YKS) performed the procedures and assessed the patients.To screen the patients with neuropathic pain, we administered a validated Korean version of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale to patients who expressed any level of pain in the recent weekv2) Health Quality of Life questionnaire was used to assess the quality of life in the recent 4 weeks34. This is a validated scale to measure general health quality of life in the general population of South Korea. Scores of health domain scales and component summary measures were standardized as T-scores using a metric with a mean of 50 and a standard deviation of 10 based on the 2009 U.S. general population samples, as indicated in the official user manual of SF-12v235. Standardized scores above and below 50 are above and below the average in the 2009 U.S. general population35.The Korean version of SF-12 Version 2 , mild (8 to 10), moderate (11 to 14), and severe (15 to 21) degree of anxiety and depression, respectively37.The Korean version of Hospital Anxiety and Depression Scale (HADS) was used to measure self-reported depression and anxiety in the survey participants38.We measured forced vital capacity of predicted value (FVC%), forced expiratory volume in one second of predicted value (FEV1%), and the ratio of FEV1% to FVC%. Restrictive respiratory dysfunction was defined as having FEV1/FVC ratio ≥ 0.7 and FVC% < 80% of predictive value. Obstructive respiratory dysfunction was defined as having FEV1/FVC ratio < 0.7 and FVC% ≥ 80% of the predictive value. Mixed obstructive-restrictive respiratory dysfunction was defined as having both FEV1/FVC ratio < 0.8 and FEV1% < 80% of the predictive valueAcute-stage pain intensity was defined as the severity of pain experienced by patients from the traumatic event to discharge from the thoracic trauma ward. As participants were unlikely to recall the intensity of acute-stage pain reliably, we used the highest pain intensity measured by a 0 to 10 NRS from the trauma-ward nurse records in EMR on admission to the thoracic trauma ward as a proxy of acute-stage pain intensity. Acute, severe pain, a dichotomized variable defined as pain rated ≥ 6 points, was generated as an exposure variable in multiple logistic regression analysis. Preoperative pain intensity measured in the emergency room was not used to avoid inaccurate and inconsistent pain assessment.A number of sociodemographic, clinical, and radiological covariates were obtained either in the survey questionnaire or the EMR. A priori confounders were age at the surgery, sex, level of education as a proxy of socioeconomic status, current smoking status, injury severity scale (ISS) score ≥ 16, and abbreviated injury scale (AIS) score ≥ 4 on chest as a proxy of severe traumatic injury. Other potentially relevant factors included bilaterality of the rib fractures, injury of the costal cartilages, preoperative chest tube insertion, and day of preoperative chest tube insertion. We tried to examine effect modification by sex, although this was not possible due to the smaller number of female patients. Potential confounders and effect modifiers were determined by the trauma surgeons and the researchers after literature reviews and discussions. Alcohol consumption was considered a behavioral covariate. Clinical covariates included the location of rib fractures , the number of fractured ribs, degree of dislocation  determined by trauma surgeons (KYW and CKL), removal of the plates, injury of costal cartilage, mode of injury , time elapsed from surgery (months), length of hospital stay , polytrauma, comorbidities identified at the injury, insertion of preoperative chest tube, period of chest-tube insertion, experience of epidural or intravenous patient-controlled analgesia (PCA) which were indicative for patients reporting acute severe postoperative pain, and adverse events or complications after surgery. Patients with multiple rib fractures but not having injuries of other body parts determined by AIS score, were considered to have isolated rib fractures . Patients who had multiple rib fractures and injuries in the other parts of the body  were regarded as having polytrauma.https://cris.nih.go.kr/cris/index.jsp).The Pusan National University Hospital ethics committee approved the survey . The research was performed in accordance with the Declaration of Helsinki and the guideline for Good Clinical Practice (GCP). All participants provided written informed consent. The prospective study registration number is KCT0002839  of chronic post-thoracotomy pain in patients with non-traumatic eventsFor descriptive data, the number and proportion of participants with the outcome of interest were presented. The chi-square test or Fisher’s exact test was used for categorical variables as appropriate. Continuous data were presented as mean ± standard deviation and/or 95% confidence interval. Non-parametric tests were performed, and median and interquartile range were presented when data were non-normally distributed. Binomial analysis was performed to test crude association between the presence of chronic post-thoracotomy pain  and confounders and covariates. Multivariable logistic regression was performed using a forward-stepwise approach to identify an association between history of acute severe pain and chronic post-thoracotomy pain, adjusted for a priori confounders and covariates, which showed statistical significance with chronic pain in bivariate analysis. Multi-collinearity issue was considered when building the regression model. Missing values in the health outcomes or exposure were not imputed. There was one missing value of acute pain intensity, and the record was excluded from the multiple logistic regression analysis.Supplementary Information.


Different pain syndromes may be characterized by different profiles of mediators reflecting pathophysiological differences, and these alterations may be measured in a simple saliva sample. The aims of the current study were to compare concentration of glutamate, serotonin (5-HT), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and substance P (SP) in saliva and plasma from a well-defined group of patients with chronic temporomandibular disorders myalgia  with a group of pain-free controls, and further investigate the relationship between these markers and clinical characteristics.n = 39), and matched healthy pain-free controls (n = 39) were included. Stimulated whole saliva and plasma samples were collected in the morning. Glutamate was analysed using a colorimetric assay, and 5-HT and SP were analysed by commercially available ELISA. Levels of NGF and BDNF were determined using multiplex electrochemiluminescence assay panel.Patients diagnosed according to the diagnostic criteria for TMD (p < 0.05). Salivary NGF (0.319 ± 0.261 pg/ml) and BDNF (3.57 ± 1.47 pg/ml) were lower in patients compared to controls (p’s < 0.05). Contrary, plasma BDNF, was higher in patients (263.33 ± 245.13 pg/ml) than controls (151.81 ± 125.90 pg/ml) (p < 0.05). 5-HT was undetectable in saliva. Neither plasma 5-HT, nor SP levels differed between groups. BDNF and NGF concentrations correlated to levels of psychological distress (p < 0.0005).Patients expressed higher salivary and plasma levels of glutamate  than controls  (The higher levels of salivary and plasma glutamate in patients with TMD-myalgia compared to controls strengthens its importance in the pathophysiology of TMD-myalgia. However, the lack of correlation to pain levels question its role as a putative biomarker. Patients with TMD-myalgia further had lower levels of salivary NGF and BDNF, but higher plasma BDNF. These results and their correlations to psychological distress warrant further investigations. Chronic masticatory muscle pain, i.e. temporomandibular disorder (TMD) myalgia, affects approximately 10% of the adult population, and is three times more frequent in women . It is cThere are several risk factors underlying TMD-myalgia, e.g. biophysiological, psychosocial, structural, postural and genetic factors , 5. DespGlutamate is the main excitatory neurotransmitter in the nervous system and is presented both in central and peripheral nerve endings. It has been demonstrated that glutamate is released peripherally and centrally in response to nociceptive stimulation and tissue or nerve injury –12. SeroBrain derived neurotropic factor (BDNF) and SP are other examples of neuropeptides that play significant roles in the development of pain and hyperalgesia , 22, 23.Most of the past studies on putative biomarkers of chronic pain have assessed plasma, cerebrospinal or interstitial muscle concentrations . RelativTherefore, saliva can reflect the physiological state of the body and reveal systemic as well as local conditions in the glands and surrounding structures. Saliva collection provides several advantages over blood , such asWith the growing interested in the search of biomarkers reflecting chronic pain pathophysiology, it could be hypothesized that TMD-myalgia is mirrored in altered saliva levels of certain neuropeptides and other pain-related mediators. The main aim of this study was therefore to compare the concentration of glutamate, 5-HT, NGF, BDNF, and SP in saliva and plasma from a well-defined group of TMD-myalgia patients with a matched healthy pain free control group. An additional aim was to investigate the relationships between these markers and pain ratings and psychological factors, as well as between saliva and plasma concentration of these mediators.Thirty-nine consecutive patients (mean + SD age: 28.8 ± 7.4 years) referred to the Specialist Clinic for Orofacial Pain and Jaw function, University Dental Clinic, Karolinska Institutet, Huddinge, Sweden were included in the study. Inclusion criteria were a diagnosis of myalgia or myofascial pain  according to the Diagnostic Criteria for TMD (DC/TMD) axis I with at least three months duration and an average pain intensity during the last 30 days of ≥ 3/10 on a numeric rating scale (NRS).Thirty-nine sex and age matched healthy controls (mean + SD age: 28.8 ± 6.9 years) were also included in the study. They had no current pain and were recruited though advertisement and among undergraduate dental students at Karolinska Institutet, Huddinge, Sweden.A power calculation showed that 37 participants in each group should be enough to detect a difference in biomarker level of 1.5 SD with 80% power and a significant level of 5%.Exclusion criteria for both groups were any conditions that could influence pain sensitivity, such as chronic widespread pain , systemic inflammatory disease , whiplash-associated disorder, neurological disorders, pain of dental origin, pregnancy or lactation, and high blood pressure. Medications that could interfere with analysis and pain sensitivity such as anticoagulant treatment and analgesic drugs, or that could interfere with pain perception such as antidepressants or anticonvulsant drugs were also considered exclusion criteria. Patients with factors that could influence saliva collection and composition, such as hypo-salivation, salivary gland diseases, poor oral hygiene, regular tobacco usage, several missing teeth, extensive prosthodontics rehabilitations, oral diseases and mucosal lesions were further excluded from further involvement in the study. All exclusions criteria were evaluated in each participant by taking medical history and through dental examination. One dentist (HJ) calibrated to a reference standard researcher (ME) according to the most recent DC/TMD criteria examined all the patients and controls to ensure they fulfilled all the terms.All participants underwent a general clinical dental examination and were evaluated by the Swedish version of the DC/TMD axis I and II . During The Patient Health Questionnaire (PHQ) is a diagnostic tool for mental health disorders used by health care professionals. Studies have found good correlation between PHQ diagnoses and those of independent mental health professionals. The PHQ-9 includes nine symptoms of depression and assesses the level of the depression by the frequency of the symptoms within the last two weeks. Scores range between 0 to 27, and scores of 5, 10, 15, and 20 are considered cut-off values for mild, moderate, moderately severe, and severe depression, respectively. The PHQ-15 includes 15 somatic symptoms or symptom clusters that account for more than 90% of the physical complaints. Scores range between 0 to 30, and scores of 5, 10, and 15 are considered cut-off values for mild, moderate, and severe somatic symptoms, respectively , 38.The Generalized Anxiety Disorder scale (GAD-7) assess generalized anxiety disorder symptoms and measures anxiety based on seven items. Total score ranges from 0 to 21, and scores of 5, 10, and 15 are considered cut-off values for mild, moderate, and severe anxiety, respectively .The Perceived Stress Scale (PSS-10) assesses how unpredictable, uncontrollable, and overloaded individuals find their lives during the previous month. Total score ranges from 0 to 40, where a higher score indicates greater perception of stress . In somePain Catastrophizing Scale (PCS) measures catastrophizing in the context of actual or anticipated pain. Total score ranges between 0 to 52, where higher scores indicate higher presence of catastrophizing thoughts. Previous studies have reported that a cut-off value of more than 30 points is associated with pain catastrophizing of clinical relevance .Jaw Functional Limitation Scale (JFLS) assesses the function of the masticatory system in three dimensions: mastication, vertical jaw mobility, and emotional and verbal expression. The scale consists of 20 items with each item is rated with NRS, where 0 corresponds to no limitation and 10 to severe limitation. Calculation of a global score (0–10) as the average of the ratings for eight of the items is recommended , a higheInsomnia Severity Index (ISI) is a short screening instrument used to measure the symptoms of insomnia. The scale score range between 0 to 28, with a score above 15 indicating clinical insomnia .All participants assessed their current pain intensity on the day of sample collection on a NRS. The scale ranges from 0 to 10, where 0 indicates “no pain at all” and 10 indicates “worst imaginable pain”.Graded Chronic Pain Scale (GCPS) was used to assess pain intensity and pain-related disability. Subscales scores for pain intensity and disability are combined to enable classification of chronic pain in grade 0 (no pain) to IV (high disability-severe limiting).The characteristic pain intensity (CPI) was also assessed (NRS) with the first three question of the GCPS. The pain intensity was calculated as the mean of the current pain intensity, and the average and worst pain intensity during the past month. The score was then multiplied by 10 to yield a 0–100 final score .2 was used with increase of pressure rate of 50 kPa/s.The pressure pain threshold (PPT) was assessed by an electronic pressure algometer . The device consists of a pistol grip and a rod with a pressure-sensitive strain gauge at the tip and a display unit. A circular padded probe with an area of 1 cmThe PPT was recorded at the most prominent point of the masseter muscle, and over a reference point on the tip of the index finger on the same side. The most dominate side was used. The participants were instructed to press a hand-held button as soon as the pressure turned into a painful sensation, whereby the pressure value was frozen on a digital display. The procedure was first verbally described and illustrated for the participant. The PPT was then recorded three times at each location. For analyses, the average threshold of the three recordings was used.The participants were instructed not to eat, drink or brush their teeth during minimum one hour prior to sample collection. All samples were collected in the morning between 7:30 and 12:00 am to reduce the influence of diurnal variation, with more than 80% collected between 9:00–11:00 am.Stimulated whole saliva was collected as earlier described by Jasim et al., 2016 and 2018 based on its simplicity, low variability, and significantly higher expression of several biomarkers , 42. PriTM P100 tube . The saliva and blood samples were gently mixed and directly centrifuged at 2500 x g for 15 min. The saliva supernatant and the plasma were alliquoted in 0.5 mL eppendorph vials and stored at − 70 °C until analysis.Directly after saliva collection, a venous blood sample was collected in a 8.5 ml BDThe concentration of glutamate in saliva and plasma was determined as described previously by Jasim et al. 2018 . BrieflyβNGF was measured) and BDNF using multiplex electrochemiluminescence assay panel from Meso Scale Discovery  according to the manufacturer’s protocol. Data were collected and analysed using MESO QUICKPLEX SQ 120 instrument , Rockville, MD, USA) equipped with DISCOVERY WORKBENCH® data analysis software . The limits of detection (LOD) were 0.036 pg/ml for NGF and 0.373 pg/ml for BDNF.Plasma and saliva samples were thawed on the day of analysis, blinded and randomly analysed for NGF (the active form For detection of SP the enzyme-linked immunosorbent assay kit (ADI-900-018), and for 5-HT the colorimetric competitive enzyme immunoassay kit (ADI-900-175) from Enzo Life Sciences  were used. The LOD for SP was 8.04 pg/ml and for 5-HT 0.293 ng/ml. Both kits were used according to the manufacturer instructions using 96 well plate. The plates were analyzed using a spectrophotometer .Statistical analyses were performed using Statistica version 13 . The Shapiro-Wiks test was used to test for normality for each distribution. Salivary and plasma SP were normally distributed, while salivary and plasma NGF, BDNF, 5-HT and salivary glutamate was normally distributed after logarithmic transformation. Only plasma glutamate was not normally distributed. Substances that were detected in more than half of the samples were included in the statistical analysis. All samples were within the detection limit, only three saliva samples expressed levels of NGF and 5-HT slightly below the detection limit.P < 0.05.For continuous variables with normal distribution independent t-test was used. For categorical variable or variables that were non-normal distributed, Mann-Whitney U-test was applied to study differences between groups. To test for significant correlations between saliva and plasma levels of normally distributed mediators as well as PPT, the Pearson’s correlation test was used. Otherwise, correlations between variables were tested for statistical significance with Spearman correlation test. Correlations were adjusted for multiple comparisons according to Bonferroni. Descriptive data are presented as mean and standard deviation (SD) or median and interquartile range (IQR). For all analyses, the significance level was set at Descriptive data of patients and healthy controls are presented in Table Patients showed significantly higher signs of psychological distress and decreased jaw movements compared to controls. Even if the levels were significantly higher in patients compared to controls, the patients expressed on average mild depressive symptoms and insomnia, moderate levels of somatic symptoms and perceived stress, and almost no clinically relevant pain catastrophizing Table .n = 66; p = 0.026) and plasma  levels of glutamate showed significant differences between patients and controls. Patients had significantly higher levels of glutamate both in saliva and in plasma compared to controls , but there were no sex differences in plasma levels.Salivary .5-HT was poorly detected in saliva samples (36%) and was consequently removed from further analysis. Plasma 5-HT could be detected in 66% of all the blood samples There were no significant differences in plasma 5-HT levels between the two groups . A similar pattern with lower levels of NGF in patients compared to controls was found in plasma but the difference was not statistically significant . There were no sex differences in saliva and plasma NGF levels.The levels of NGF in saliva and plasma are shown in Fig. No correlation existed between the saliva and plasma levels of NGF.n = 77; p = 0.028). Contrary, plasma BDNF was higher in patients compared to controls . There were no sex differences in saliva and plasma BDNF levels.BDNF expression differed significantly between groups in both saliva and in plasma, as reported in Fig. There was no significant correlation between salivary and plasma BDNF levels.n = 41; p = 0.084). The levels of SP in plasma were similar in both groups, without significant difference . There were no sex differences, and no significant correlation was found between salivary and plasma SP levels.SP was detected only in 52% of all the saliva samples but in almost all blood samples. The levels of SP in saliva and plasma are shown in Fig. s) between salivary levels of the substances and other variables among the two groups. There were no significant correlations for any substance among the patients, but BDNF showed moderate negative correlations to perceived stress, anxiety, and somatic symptoms among the healthy controls.Table s = − 0.462; n = 78; p < 0.001).In the groups combined, there was a moderate reverse correlation between NGF and somatic symptoms  plasma, which contains only a very small portion of 5-HT (< 5%), a too low sensitivity of the immunoassay to detect 5-HT is a probable explanation. 5-HT is more expressed in platelet rich plasma compared to saliva; thus, it was easier to detect with the immunoassay and measurable levels were found in two thirds of the samples. The plasma levels were higher in healthy controls compared to patients, but within normal reference values , 44. TheThe neuropeptide NGF regulates the development of the nervous system. The peptide has been recognized as a key mediator in chronic pain and has recently also been linked to depressive disorders , 46. BasSeveral studies suggest the involvement of BDNF in pain processing and peripheral as well as central sensitization , 47, 48,The inverse correlation between salivary BDNF and perceived stress, anxiety and somatic symptoms among the controls are somehow in line with previous observations of decreased plasma/serum BDNF in mood disorders . The lacSP is an important mediator in pain perception and is involved in the transmission of pain from the periphery to the central nervous system and increased levels in patients with TMD-myalgia could therefore be expected. However, we found no differences in SP concentration between patients and controls. Previous studies on the salivary levels of SP in chronic pain are inconsistent. Some studies have shown decreased levels of SP in BMS and chronic low back pain compared to healthy pain-free controls , 23. ConSP levels in plasma were similar compared to earlier studies , 42, whiSeveral substances enter the salivary gland from the blood by passing through the intercellular spaces by transcellular or paracellular diffusion, consequently saliva is often regarded as an ultrafiltrate of plasma and contains fractions of proteins derived from the blood stream , 49, whiThe present study has some limitations that need to be considered. The study was performed in adults between 18 and 40 years representing the peak of TMD prevalence; other age groups were not taken into consideration because of the possibility of age-variability . MoreoveA strength of this study is that the diurnal variation of substances was taken into consideration, since all samples were collected in the morning hours with a majority of the samples collected between 09 and 11 am. The saliva collection was also standardized and followed a specific protocol in order to decrease the inter- and intra-individual variability. And finally, the study population were properly examined to exclude systemic or oral conditions that may affect the salivary composition and biomarker levels. Patients were also diagnosed by a clinician calibrated to a reference standard researcher (ME) according to the most recent DC/TMD criteria to ensure the diagnosis of TMD-myalgia.The present study showed that patients with a diagnosis of TMD-myalgia had significantly higher levels of salivary and plasma glutamate as well as plasma BDNF compared to healthy pain-free individuals, suggesting that these may be indicative biomarkers for TMD-myalgia. However, the levels did not significantly correlate to subjective pain levels, so the possibility for them to serve as biomarkers for TMD-myalgia can be questioned and warrants further investigations. Patients further showed lower levels of salivary NGF, which correlated to psychological maladjustment. This association may propose NGF as a possible marker for studying psychological dysfunction in TMD myalgia. Further studies are however needed to elucidate the mechanisms for NGF in TMD-myalgia.


According to the analyses using continuous net reclassification improvement, the mCCI-A improved the net mortality risk reclassification by 44.0% , 41.6–46.5; p < 0.001). The mCCI-A facilitates better risk stratification of mortality rates in Korean inpatients than the CCI, suggesting that the mCCI-A may be a preferable index for use in clinical practice and statistical analyses in epidemiological studies.Weights assigned to comorbidities in predicting mortality may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified version of the Charlson Comorbidity Index (CCI) using an Asian nationwide database (mCCI-A), enabling the precise prediction of mortality rates in this population. The main data source used in this study was the National Health Insurance Service-National Sample Cohort (NHIS-NSC) obtained from the National Health Insurance database, which includes health insurance claims filed between January 1, 2002, and December 31, 2013, in Korea. Of the 1,025,340 individuals included in the NHIS-NSC, 570,716 patients who were hospitalized at least once were analyzed in this study. In total, 399,502 patients, accounting for 70% of the cohort, were assigned to the development cohort, and the remaining patients  were assigned to the validation cohort. The mCCI-A scores were calculated by summing the weights assigned to individual comorbidities according to their relative prognostic significance determined by a multivariate Cox proportional hazard model. The modified index was validated in the same cohort. The Cox proportional hazard model provided reassigned severity weights for 17 comorbidities that significantly predicted mortality. Both the CCI and mCCI-A were correlated with mortality. However, compared with the CCI, the mCCI-A showed modest but significant increases in the  Among the various methods used to predict mortality by weighting comorbidities, the Charlson Comorbidity Index (CCI) has been widely utilized by health researchers to measure the burden of diseases. In 1984, Charlson et al. identified the clinical conditions to be included in the index by reviewing 559 hospital charts of patients admitted to medical services at a single hospital and then assessed the associations of these comorbidities with the 1-year all-cause mortality2.Comorbidity is among the most important predictors of inpatient outcomes3, renal disease4, stroke5 and intensive care6. Nevertheless, there are several reasons to recalibrate and subsequently validate this index with inpatients to obtain better predictions of their mortality rates. First, because the management of inpatients and their comorbidities has advanced significantly over the past 30 years, the contribution of comorbidities to the mortality rate has likely also changed. Second, this index is not suitable for predicting long-term outcomes in general hospitalized patients because in the development of the CCI, only a small sample and the one-year mortality rate were considered. Therefore, this index should be recalibrated and revalidated using more recent data.The ability of this index to predict mortality has been validated in various disease subgroups, including cancer7, Davies index8, Khan index9, a modified version of the CCI in incident hemodialysis patients (mCCI-IHD)10 and a modified version of the CCI in incident peritoneal dialysis patients (mCCI-PD)11. However, indices created from these specific disease groups may not be optimal to use as a tool to predict the outcomes of generalized patients.The recalibration and validation of comorbidities indices have been performed in various disease group such as the index of coexistent diseaseTherefore, the present study aimed to develop a modified version of the Charlson Comorbidity Index (mCCI-A) using an Asian nationwide database that reflected the recent changes of mortality due to the development of medical technology and the difference in prevalence of diseases from racial differences and to compare its performance with the original CCI.The baseline characteristics of the entire cohort, development cohort and validation cohort are listed in Table In total, 74.43% of the subjects had one or more comorbidities. Among the 17 comorbidities, the most prevalent comorbidity was chronic pulmonary disease (47.56%), followed by ulcer disease (37.1%) and mild liver disease 24.05%) , congestive heart failure (CHF), dementia, any tumor and moderate or severe liver disease increased; the updated weights for acquired immunodeficiency syndrome (AIDS) and metastatic solid tumors decreased; and the updated weights for diabetes without complication, diabetes with end organ damage, hemiplegia, and moderate or severe renal disease did not change Fig. .The mCCI-A scores were calculated by summing the updated weights. The scores were applied to each patient in the development cohort. Based on the CCI and mCCI-A scores, we categorized both scores into the following 4 risk groups: ≤ 50th percentile, 50th–80th percentile, 80th–90th percentile and > 90th percentile. To determine the cut-off values of the comorbidity scores in each risk group, we generated a histogram to represent the distributions of the scores Fig. . The cutFigure The baseline characteristics of the validation cohort n = 171,214) are listed in Table 71,214 arc statistic and cNRI were calculated after adjusting for confounders in the following two analyses: univariate and multivariate. Significant differences were observed in the c statistics between the CCI and the mCCI-A in the univariate and multivariate analyses (Table p < 0.001), indicating that the mCCI-A facilitates a better risk stratification of mortality in Korean inpatients than the CCI. Figure To assess the discrimination ability of each index, the es Table . Additioc statistic and cNRI were calculated after adjusting for confounders in multivariate analysis in subgroups such as mild liver disease, chronic pulmonary disease, diabetes mellitus and moderate/severe renal disease patients composed of the total cohort. Significant differences were observed in the c statistics and cNRI between the CCI and the mCCI-A in multivariate analyses . Using ICD codes may be useful in exploratory data analyses14. In the 2000s, a retrospective cohort study was conducted using National Health Insurance claims data (2001–2002) to compare the performance of three comorbidity measurements  among inpatients hospitalized for Chronic Obstructive Pulmonary Disease and Acute Myocardial Infarction in Taiwan15. However, these studies had two limitations. First, these studies investigated specific disease groups rather than general patients. Second, the purpose of these studies was to demonstrate superiority among the existing methods or to apply the methods to the general population.Since 1987, the CCI has been used as a comorbidity index throughout the medical community, and there have been efforts to predict the outcome of the general inpatient population using the CCI since the 1980s to 2000s. In 1996, the CCI was applied to 33,940 inpatients with ischemic heart diseasePrevious studies have directly applied the CCI to patients using a weight equal to that in the original index for each CCI index. However, the recalibration and validation of the weights of the CCI index diseases are needed for several reasons. First, the original CCI does not reflect the significant progress achieved in the treatment of each comorbidity and medical advancements over the previous 30 years. Second, the extent to which the original CCI reflects long-term outcomes considered important is unclear because the “training” population used to develop the original CCI was created based on the one-year mortality rate in general inpatients. Third, the original CCI was developed based on a relatively small number of patients.16. A new comorbidity index was developed by assigning specific weights to the original CCI in this study. However, AIDS was excluded because no patients with AIDS were included in the sample. In 2011, a study updated the CCI and scores using Canadian administrative databases of 55,929 patients admitted to a medical facility in the Calgary region  (population 1.3 million)17. The authors excluded the 5 comorbidities found to have no statistical correlation with the mortality rates among the 17 comorbidities. The new index exhibited superior performance over the original CCI (c = 0.825 vs. 0.808). Although these two studies reflect the recent advances in medical management, there are limitations in that study. The evaluation of several comorbidities was limited (particularly AIDS), and there is still a need for further evidence regarding whether the index can be directly applied to Asians.In 1996, a study was conducted to update the CCI and scores using USA administrative databases of 6,326 patients who underwent bypass surgery, and the new index exhibited superior performance over the original CCI (c = 0.74 vs. 0.70)18. The authors emphasized the necessity for developing scales that can more accurately predict patient outcomes.In Asia, the CCI has also been applied to various disease groups to evaluate the various outcomes of patients. However, the usefulness of the original CCI remains controversial. A Japanese study revealed that the CCI had been used to predict the overall survival of patients with solid tumors; however, the CCI is not considered a significant predictor11. The first study involved 24,738 people who first started hemodialysis between 2005 and 200810. We developed the mCCI-IHD, which included 14 comorbidities with reassigned severity weights. In the validation cohort, compared with the CCI, the mCCI-IHD showed modest but significant increases in the c statistics at 6 months and 1 year. Compared with the CCI, the analyses using cNRI revealed that the mCCI-IHD improved the net mortality risk reclassification by 24.6%, 26.2% and 42.8% at 6 months and 1 and 2 years, respectively. The second study involved 7,606 people who first started peritoneal dialysis between 2005 and 200811. We developed the mCCI-IPD, which included 11 comorbidities with reassigned severity weights. In the validation cohort, compared with the CCI, although the mCCI-IHD showed no differences in the c statistics, the analyses using cNRI revealed that the mCCI-IHD provided a 38.2% improvement in mortality risk assessment.Previously, we updated the CCI and scores in hemodialysis and peritoneal dialysis patients using the National Health Insurance dataset in Korea11. Additionally, recent advances in the effectiveness of the treatment of metastatic cancer has led to a decreased mortality rate. This change is likely due to the decreased weights of metastatic cancer in this study. The second implication is that this study, based on the overall cohort of inpatients, overcame the limitations associated with the use of small sample sizes in previous studies. For example, AIDS was not considered in a previous study modifying the CCI due to the small sample size. However, in this study, obtaining the weights of AIDS was possible because of the large sample size.Based on the results of the previous two studies, we extended this study to the entire inpatient population. In this study, we modified the CCI using administrative data that included nearly all Korean inpatients who were admitted between 2002 and 2013 and developed a comorbidity index that provides better risk stratification. In addition, we performed a cross validation of the new index. Additionally, the superior performance of the new index over the original CCI was shown. Notably, this report has two major implications. First, in contrast to the previous CCI, the mCCI-A score reflects the current medical environment. Comparing the weights in the CCI with the weights in the mCCI-A, the increased weights of cerebrovascular disease, circulatory systems (MI and CHF) and nonmetastatic tumors are likely associated with the increased prevalence of these diseases. This tendency is consistent with recent studies investigating populations with specific diseases in Korea19. Second, although the use of administrative data has advantages, such as the conservation of time and resources and consistency in diagnosis, the diagnoses may be inappropriate due to physician preferences regarding diagnostic codes. Third, administrative data do not include biochemical parameters such albumin and hemoglobin, which could affect the survival rate. Fourth, new values for the weight of each comorbidity were derived in this study, but no expert agreement on them could be derived and will need to be considered later. Fifth, because this study was conducted for patients from 2002 to 2013, there is a limitation to the application of hospitalized patients after 2013. Last, although there were interactions between variables and comorbidities that we considered in our analysis, the interaction test was not conducted in our study.This study has several limitations. First, in contrast to collecting data through chart reviews, the determination of the prevalence of diseases is generally problematic using administrative data21. Briefly, The NHIS-NSC covers health insurance claims filed between January 1, 2002 and December 31, 2013. Of the eligible population in 2002 , 1,025,340 participants (2.2% of the target population) were randomly selected until 2013 and were followed until 2013 (for 12 years). All traceable identifiers were removed before publishing to protect patient confidentiality.In this study, 578,547 patients (56.4% of the NHIS-NSC) who were hospitalized at least once were analyzed longitudinally. Except for 7,831 patients who died immediately or same month as hospitalization after admission, the total number of patients in our cohort was 570,716.The main data source used in this study was the National Health Insurance Service-National Sample Cohort (NHIS-NSC) obtained from the National Health Insurance Service (NHIS) in South Korea. The NHIS-NSC database has been publicly available since July 2014 and contains a substantial amount of information regarding health care utilization, health screening, sociodemographic variables and mortality in Korean citizens. Detailed information obtained from the NHIS-NSC has been previously published22. To develop the modified index, we used the same comorbid conditions covered by the CCI, including MI, CHF, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease, diabetes, hemiplegia, diabetes with end-organ damage, any tumor (including leukemia and lymphoma), moderate to severe liver disease, metastatic solid tumors and AIDS. We retrieved all records of each patient from the National Health Insurance database prior to the date of the discharge to identify the comorbidities. A patient was considered to have a comorbid condition if the condition was present in the index admission records. The outcomes included all-cause long-term mortality within the follow-up period after admission. Additionally, the National Health Insurance claims databases were used to identify mortality. Death occurring between January 1, 2002 and December 31, 2013, was considered in the development and validation cohorts. However, patients with admission and death occurring in the same month were excluded. The demographic information of both cohorts included age, sex, region, and family income.Using the International Classification of Diseases, 10th revision (ICD-10), we identified the Charlson comorbidities among the secondary diagnoses based on all diseases that were diagnosed from both inpatient and outpatient services before discharge23. Then, the relative weights were truncated to integer values rounded to zero decimal places. The comorbidity score of each patient was calculated by summing the weights. Kaplan–Meier survival curves24 were generated to compare the performance of the CCI to the performance of the mCCI-A.First, to analyze the baseline characteristics of the study population, we merged the demographic and medical utilization data. A Cox regression analysis adjusted for age (quartile), sex, region and family income ratio was performed to develop new weights for the comorbidities. We obtained the adjusted HRs and 95% confidence intervals (CIs) after adjusting for age, sex, region, family income ratio, and all 17 comorbidities. The prognostic weights of the mCCI-A were computed by dividing the HRs associated with each comorbidity by the lowest HRsWe performed internal-validation partitioning of the main data set into two sets comprising 70% of the sample for training and 30% of the sample for testing using a random sampling function with the variable of death as a reference parameter. In total, 70%  of the sample was used for training to develop new comorbidity weights, and the remaining 30%  of the sample was used as a validation cohort.c statistic was calculated using the area under the receiver-operator curve25. To determine the statistical significance and 95% CIs of the c statistic, a Mann–Whitney test was performed with a contrast test. The continuous net reclassification improvement (cNRI) score obtained by performing logistic regression models was calculated to evaluate the reclassification26. For the binary response, i.e., death, the function improveprob in R was used to determine whether the predictions obtained from the model of mCCI-A significantly differed from those obtained from the model of the original CCI27. The cNRItotal is the sum of cNRIEvent and cNRINon-event, indicating the sum of the net proportions of subjects who died (Event) and who did not die (Non-event) were correctly reassigned a predicted risk.To assess the capacity of discriminating between the indices, a https://cran.r-project.org). In all analyses, p < 0.05 was considered statistically significant.The data were analyzed by using SAS 9.4 for Windows software  and R software version 4.0.0  of Seoul National University Hospital (1610-038-797), and the study protocol was approved by the IRB. Under IRB approval, the informed consent waived.


Triptans, specific symptomatic medications for migraine, are not effective ina proportion of patients, or in all attacks, hence the importance ofidentifying predictors of response. Our aim was to investigate theassociation between the efficacy of oral frovatriptan 2.5 mg and clinicalcharacteristics of migraine attacks.We enrolled 29 consecutive patients affected by migraine without aura at theHeadache Center of “Mondino” Institute of Pavia. Each patient was given adiary and asked to record prospectively the features of three consecutivemigraine attacks while using frovatriptan. A generalized estimatingequations approach was used to determine phenotypic features associated withthe pain free response at 2 hours.Participants provided complete data for 85 attacks. Thirty of these (34%)patients reported being pain free 2 hours after taking frovatriptan 2.5 mgintake. Unilateral pain, presence of phonophobia, presence of one or morecranial autonomic symptoms and presence of one or more premonitory symptomwere each associated with being pain free at 2 hours.The response to frovatriptan was associated with particular features of themigraine attack, either before or during the pain phase of attacks. The datasupport larger studies to explore detailed attack phenotyping, withparticular attention to early signs, to enable individualized treatment inmigraine. We excluded patients with migraine with aura to avoid anyconfusion with the premonitory phase. We also excluded patients with acontraindication to, or previous use of any triptan, use of opioids, use ofmigraine preventive medication, and history of psychiatric disorders.ad hoc headache diary and asked to record prospectivelythe features of three consecutive migraine attacks. Patients were instructed touse frovatriptan immediately after identifying a headache as a migraine attackregardless of pain intensity, and excluding those with an onset on wakening, andto fill their headache diary when they used their medication.Consecutive patients diagnosed with migraine without aura and prescribedfrovatriptan 2.5 mg p.o. as acute medication were included. They were providedwith an The following characteristics of migraine attacks were recorded: Location, quality (pulsating) and intensity  of pain; presence of the followingsymptoms: Nausea and/or vomiting; photophobia, phonophobia, osmophobia, cranialallodynia; cranial autonomic symptoms (CASs), including eyelid oedema, foreheadand facial sweating, conjunctival injection and/or lacrimation, nasal congestionand/or rhinorrhoea, miosis and/or ptosis; premonitory symptoms of yawning,tiredness, mood changes, neck stiffness, vertigo, nausea, photophobia,phonophobia, osmophobia, food craving, thirst, problems with concentration,speaking or reading in the previous 24 hours; and time of frovatriptan intakefrom pain onset.In order to assess cranial allodynia, patients were asked if a non-painfulstimulus, such as touching or washing, produced pain on their face or head.Pain intensity 2 hours after triptan intake and the duration of the attack,marked by migraine symptom resolution, were recorded in the diary. The efficacyof frovatriptan was assessed as pain resolution within 2 hours after medicationuse . In caseAll patients were asked to return to the Headache Centre either when they hadmanaged to record three consecutive attacks, or at the latest after 3 monthsfrom the initial visit.P < 0.05.Given the aim of establishing predictability of response to a triptan withinindividuals, the full analysis set was defined as patients who took treatment onthree attacks and provided clinical data on each attack. Variables are presentedas mean ± SD, median with interquartile range, or as frequency counts (%), asappropriate. To examine the relationship between phenotypic variables of theattack and the pain-free response to frovatriptan, we used a single generalisedestimating equations approach with an unstructured correlation matrix. Pain freeat 2 hours was set as the binary dependent variable and fitted with a logit linkfunction . The significance level was set atThirty-nine patients were enrolled. Ten patients failed to record data for threeattacks and were therefore excluded from data evaluation. The remaining 29 patientssuccessfully recorded the features of three consecutive migraine attacks whilstusing frovatriptan 2.5 mg, providing data for a total of 87 attacks. Data from twoattacks out of the 87 recorded were incomplete, therefore the final dataset included85 attacks.Of the included patients, 83% were female (25/29), mean ± standard deviation(range) age was 32.9 ± 8.3 (19–47) years. Mean age at migraine onset was 21± 11(5–47) years, duration of illness 16.0 ± 9.5 (1–30) years. The frequency ofattacks of migraine without aura per month was 3 . Prior tothe study, patients reported treating their migraine attacks with eitherparacetamol or non-steroidal anti-inflammatory drugs (NSAIDs). Twenty-sevenpatients exclusively suffered from migraine without aura attacks, while theremaining two patients reported infrequent episodes of tension-type headache andexperienced one tension-type attack each during the observation period.The frequencies of the different attack features are reported in Patients used frovatriptan after a mean period of 63 min following head painonset. At this time, median (IQR) pain intensity was 2 (1–3). At 2 hours, 35%(30/85) of attacks were rendered pain free.21 = 11.44, P = 0.001),presence of phonophobia , presence of one or more cranial autonomic symptoms and presenceof one or more premonitory symptom  were each associated with a pain-freeresponse.Modeling the clinical outcome at 2 hours after frovatriptan intake: Unilateralpain  and rizaIn contrast with our results, in an analysis of eletriptan and sumatriptan studies,the presence of photophobia in an attack predicted a poor response . MoreoveSome of the varying outcomes across studies predicting treatment outcome are likelydue to key design differences. First, in some studies ,8 patienFrovatriptan has been explored in a study showing that current major depressivedisorder was associated with response to medication, while generalized anxietydisorder, history of triptan intake, preventive medication and familiarity were not. However1B/1D receptors (The presence of both CAS and unilateral pain can represent an epiphenomenon ofintense trigeminal peripheral afferent activation, which may recruit peripheralneurovascular 5-HTeceptors . With reeceptors . PerhapsOne important limitation of our study was the small sample size. Our study aimedat screening a large set of variables on a very well characterized andunconfounded population in order to identify the relevant ones. As a feasibilitystudy with the novelty of exploring non-canonical migraine attack symptoms, wesought to push the envelope with deeper phenotyping. Thus the number ofparticipants was small for the breadth of phenotyping. A much larger study interms of participants will be required to clarify these questions. Anotherlimitation of this study design is that the complete phenotype of the attacksmay not have been expressed, as frovatriptan was used early after pain onset.The frequency of some features, such as nausea or photophobia, is reported atlower rates compared to other studies, accordingly .In this study, we have shown with the use of a prospective diary that unilateralpain, presence of phonophobia, presence of one or more cranial autonomicsymptoms and presence of one or more premonitory symptom were each associatedwith the response to frovatriptan in this exploratory work. All these featuresare manifest in the early phase of the migraine, when the attack is moretreatable by triptans. The results support exploring larger studies employingdeep phenotyping to optimise acute migraine treatment.Unilateral pain, presence of phonophobia, presence of one or more cranialautonomic symptom and presence of one or more premonitory symptom wereeach associated with a response to frovatriptan.Early identification of factors associated with a good triptan responsewould potentially offer a more tailored strategy for treating acutemigraine.