Relevant information was collected 1 day before surgery and 1–3 days after surgery, and the occurrence of CPSP was followed up by telephone at 3 months after surgery. Data on clinical characteristics and peripheral blood leukocyte miRNAs were used to establish a nomogram for predicting CPSP using least absolute shrinkage and selection operator (LASSO) regression methods. The area under curve (AUC) was used to determine the recognition ability of the nomograms. The model was subjected to correction and decision curve analyses. Four variables—body mass index (BMI), history of chronic pain, miR 550a-3p, and visual analog scale (VAS) score on postoperative day 2 (VAS2d)—were selected according to LASSO regression to build the nomogram. The nomogram demonstrated adequate calibration and discrimination in the prediction model, with an AUC of 0.767 . The calibration plot showed the best fit between model predictions and practical observations, suggesting that the use of the proposed nomogram to predict CPSP is beneficial. A nomogram consisting of BMI, history of chronic pain, miR 550a-3p, and VAS2d predicted the risk of CPSP after VATS in patients with lung adenocarcinoma.Chronic postsurgery pain (CPSP) refers to persistent or repeated pain around the incision after surgery. Different from acute postoperative pain, the persistence of CPSP seriously affects the quality of life of patients. CPSP has a considerable global impact due to large surgical volumes. Although the development of video-assisted thoracoscopy (VATS) has reduced the risk of CPSP, it still seriously affects patients’ quality of life. Clinical recognition of CPSP at an early stage is limited; therefore, we aimed to develop and validate a nomogram to identify the significant predictive factors associated with CPSP after VATS in patients with lung adenocarcinoma. We screened 137 patients with invasive adenocarcinoma of the lung from among 312 patients undergoing VATS. In this prospective study, patients were divided into the CPSP ( Chronic postsurgical pain (CPSP) refers to persistent or recurrent pain around the surgical scar for >3 months after surgery . In contLung cancer is one of the most common malignant diseases, with a high incidence and serious impact on human health and life . SurgicaIn recent years, a number of retrospective studies have investigated the associated risk factors for the development of CPSP after VATS, including body mass index (BMI), history of pain, and acute postoperative pain , 16–19. Notably, patients with CPSP have significantly decreased physical function and poor quality of life after lobectomy . TherefoThe nomogram prediction model was based on multivariate regression analysis to integrate multiple predictors, thus circumventing the effect of collinearity on the outcome and allowing more accurate prediction of each variable . Therefon = 52) and the non-CPSP group (n = 85).This prospective study [2019 Fuyi No.2 Ethical Review (No.208)] passed the ethics review of the 90 Second Affiliated Hospital of Fujian Medical University. A prospective design was used to screen 312 patients who underwent VATS between June 2019 and April 2021 (registration ChiCTR2200057092). Based on the intraoperative pathological results, 158 patients with adenocarcinoma were reserved for continued observation. Twelve patients were re-hospitalized within 3 months of discharge, and nine subjects were lost to follow-up for various reasons. After considering the exclusion criteria, 137 patients were included in the final study and divided into two groups according to the presence or absence of CPSP, namely the CPSP group (Inclusion criteria were as follows: (1) American Society of Anesthesiologists (ASA) grade I–III; (2) No other malignant tumors; (3) No neurological dysfunction; (4) No history of surgery within the past year; (5) Willing to cooperate with follow-up testing and sign the informed consent form.Exclusion criteria: (1) Transition to open surgery due to various reasons; (2) Postoperative pulmonary complications, secondary surgery, and re-hospitalization within 3 months for other reasons; (3) Failed to complete the study due to various reasons.via telephonic follow-up 3 months after surgery.All patients were visited in the ward 1 day before surgery to record their general information, including sex, age, body mass index (BMI), ASA grade, sleep quality, anxiety state, history of chronic pain, and presence or absence of hypertension and diabetes mellitus. Data on operation time, duration of drainage, and white blood cell count 1 day before and after surgery and postoperative pain scores on postoperative days 1–3 were recorded. Quantitative information on peripheral leukocyte miRNAs was also collected 1 day before surgery. The occurrence of CPSP (VAS > 0) was recorded The International Association for the Study of Pain  and receThe State–Trait Anxiety Inventory was used to assess anxiety. The Pittsburgh Sleep Quality Index was used to assess sleep quality. The pain score was assessed using the VAS, with scores ranging from 0 (no pain) to 10 (intolerable pain).Isolation of peripheral leukocytes: the blood of the patient was collected 1 day before the operation, and the fresh whole blood was added into the centrifuge tube containing the separation solution. After centrifugation at 3,500 rpm at 18°C for 20 min, the lower solution was collected. The collected solution was further subjected to red blood cell lysis, the supernatant was discarded, and the leukocyte pellet was collected. Trizol reagent  was added, mixed well, and stored at −80°C.RNA extraction: the leukocytes were lysed, and total RNA was extracted by chloroform extraction, isopropanol precipitation, and ethanol washing and precipitation.Small RNA library construction and sequencing: three samples were randomly selected from each of the two groups and handed over to Shanghai Ouyi Biomedical Technology Co. Ltd.  to complete the construction of the small RNA library and high-throughput sequencing. The difference of miRNA expression between the two groups was detected.−ΔΔCt algorithm.RT-PCR validation: the three miRNAs  with the most significant differences were verified by RT-PCR. The method consists of three steps: miRNA isolation , reverse transcription into cDNA , and RT-PCR performed on cDNA . Three replicate wells were created for each sample. Relative amounts of expression were analyzed using the 2t-test, Wilcoxon rank-sum test, Pearson's chi-square test, or Fisher's exact test, as appropriate. The least absolute shrinkage and selection operator (LASSO) regression method is used to select data dimensions and prognosis factors. A nomogram model was constructed based on the multivariate unconditional logistic regression analysis results .The median and value represent discontinuous data and continuous data, respectively. Between-group comparisons between patients with and without CPSP were employed to unpaired  results . The deg results . StatistA total of 37.9% (52/137) patients included in the study developed CPSP after VATS. Most patients with CPSP presented mild pain, of which 34.6% (18/52) presented with stabbing pain, while the rest presented with dull pain. The basic information and clinical manifestations of all participants included in the study are shown in To establish a predictive model for the occurrence of CPSP after VATS, the LASSO regression technique was used to perform multivariate logistic regression analysis of the above four variables. After calculation, the area under the curve (AUC) of nomagram predicted patterns was 0.767 (95% CI: 0.679–0.856). We constructed a nomogram personalized implement for predicting the probability of CPSP after VATS .P-value from the Hosmer–Lemeshow test was insignificant at 0.808, indicating the predicted value is completely consistent with the observed value without statistical bias.The prediction pattern has good calibration effect . The P-vDCA was performed to evaluate clinical effectiveness of the nomogram. Decision curves revealed that the threshold probability of CPSP after VATS in patients with lung adenocarcinoma was 25%–100% according to the nomogram . TherefoIn the present study, we established a nomogram to predict the occurrence of CPSP after VATS in patients with lung adenocarcinoma. The nomogram contained four variables—BMI, history of chronic pain, miR 550a-3p, and VAS2d. This predictive model had good discriminative ability, calibration, and clinical usefulness.The etiology of CPSP after VATS is multifactorial and may involve various relevant factors, including both patient and treatment factors. Some reported predictive and risk factors for the development of CPSP after VATS include BMI, type of VATS, operative time, drainage time, and acute postoperative pain , 37, 38.Studies have revealed that BMI is not associated with postoperative pain after general, orthopedic, or neurospinal surgery . HoweverA preoperative history of chronic pain, and acute postoperative pain also increases the risk of developing CPSP after VATS. However, this preoperative history of chronic pain may not be related to lung tumors because the patients we included were all early-stage lung adenocarcinomas with no obvious clinical symptoms, and most of the sites involved in their chronic pain history were the lower back, did not involve pain in the chest. Similarly, several clinical trials have reported the correlation between preoperative pain history and CPSP , 30. In Finally, we found that elevated miR 550a-3p expression in peripheral leukocytes was a supplementary predictor of the risk of CPSP development after VATS. miRNA are non-protein-coding RNA with critical regulatory roles in various processes under normal and diseased conditions . Some stHowever, the limitation is ubiquitous, and this research is no exception. First, this nomogram of the risk of CPSP after VATS was established based on data from a prospectively designed study in the region; therefore, the scope of inclusion is limited by regionality. Second, confounding factors for pain may not have been included in our study. Some of the other complexities of each case, including different surgeons/anesthesiologists, unique incisions, and various effects of different postoperative procedures on pain, were not considered. Finally, we cannot rule out patient-specific health conditions during telephone interviews and surveys, which may have complicated the presentation of pain. Moreover, the potential regulatory mechanism of peripheral blood leukocyte miR 550a-3p expression in CPSP should be further explored. Despite these limitations, this study is the first to develop a nomogram diagnostic method to predict the risk of CPSP after VATS in patients with lung adenocarcinoma.The nomogram composed of BMI, history of chronic pain, miR 550a-3p, and VAS2d predicted the risk of CPSP after VATS in patients with lung adenocarcinoma. Further studies are needed to validate our nomogram in different populations. This nomogram may be a valuable complement to the current prediction of CPSP after VATS, which can be advantageous for individual CPSP prediction and clinical decision making after surgery.


Two analgesic strategies have been described for pain treatment after the pectus excavatum surgery: the patient-controlled intravenous analgesia (PCIA) and ultrasound-guided intercostal nerve block. In this prospective, randomized and double-blinded trial and the short and long-term outcomes were compared in patients after surgery.  The children were randomized to either the intercostal or control group. Ultrasound-guided intercostal nerve block was with 0.25% ropivacaine and 5 mg dexamethasone in the intercostal group, while the control group was with 0.9% normal saline. The block was performed in the intercostal space corresponding to the lowest depression of the sternum and repeated bilaterally in the spaces above and below. Postoperatively, the children in the two-groups received PCIA with fentanyl for 48 hours. The primary outcome was a pain score on the postoperative day 1, as measured by the Visual Analogue Scale (VAS). p < 0.001), 1.7 on postoperative day 1 (p < 0.001) and 0.7 on postoperative day 2 (p=0.015). The opioid consumption was significantly lower in the intercostal group during the postoperative 48 hours (p < 0.05). The anxiety and QOL scores in the intercostal group were significantly improved on some points of time (p < 0.05). The incidence of adverse events was markedly lower in the intercostal group during the postoperative 48 hours (p < 0.05).  Sixty children undergoing the Nuss procedure were enrolled in the trial. The mean differences in VAS scores between the two groups were 3.2 in the PACU ( Our results suggest ultrasound-guided intercostal nerve block with PCIA may be more effective than PCIA alone in children who underwent the Nuss procedure. Pectus excavatum is a common congenital chest wall deformity that occurs in 0.1% of live births .Many analgesic strategies have been described to manage postoperative pain after the Nuss procedure, such as patient-controlled intravenous analgesia (PCIA), multimodal analgesia, thoracic epidural block, paravertebral block, and intercostal block. Epidural analgesia is established as a safe and effective method for postoperative pain management in children. However, the risks of thoracic epidural analgesia challenge its superiority in pain treatment. They are infection, nerve damage, drug error, and local anesthetic toxicity . Unlike PCIA is a well-established method for relieving postoperative pain in children and adolescents , which iAn intercostal nerve block is considered less invasive than epidural blockade and is relatively simple to perform and successful in children who have undergone thoracic and upper abdominal procedures . The advA retrospective cohort study of adolescents and young adults who underwent the Nuss procedure showed that some of them suffered from chronic postsurgical pain . In our http://www.chictr.org (ChiCTR1800018040). The exclusion criteria were as follows: patients requiring additional surgery, history of analgesic administration  24 hours before premedication, history of coagulation disorders or allergic to local anesthetics, history of renal insufficiency or American Society of Anesthesiologists (ASA) physical status of higher than II, inability to understand PCIA device use, or parental objection to intercostal nerve block. The day before surgery, all children and their parents were informed about the trial process and signed inform consent in the anesthetic assessment office. The children  scheduled for the Nuss procedure at Xinhua Hospital were randomized to the intercostal or control group  and prospectively registered at ol group .μg/kg, and rocuronium 0.6 mg/kg. After that, the trachea was intubated with an appropriately sized tracheal tube , and sevoflurane  in nitrous oxide  was administered as an anesthetic. Remifentanil (0.2 μg/kg/min) was continuously injected intravenously as an intraoperative analgesic. Patients received intravenous ondansetron hydrochloride 0.1 mg/kg before recovery. In this study, ropivacaine was used because it has less motor blockade effects and less cardiac toxicity than bupivacaine . However, ropivacaine alone is associated with a shorter duration when used for nerve block. Dexamethasone when combined with ropivacaine can prolong the nerve block time of local anesthetics [All children were premedicated with midazolam 0.3 mg/kg and acetaminophen 15 mg/kg (maximum 650 mg) orally. After obtaining intravenous access, all subjects were anesthetized with intravenous midazolam 0.1 mg/kg, propofol 3 mg/kg, fentanyl 2 sthetics . TherefoAfter intubation, the patient was placed in supine position, and an ultrasound-probe  was used to scan the thoracic wall laterally from the midaxillary line and identify the required anatomic landmarks. The ribs were identified as hyperechoic streaks, while the pleura appeared as hyperechoic lines between and below the ribs. The anesthetist used a 22-G short-bevel needle to introduce 0.25% ropivacaine hydrochloride  and 5 mgμg/kg/h and a 0.25 μg/kg bolus dose with a 30-minute lockout period. All children were also given NSAIDs orally.Postoperatively, the children in the two-groups received PCIA with fentanyl for 48 hours. The PCIA settings were a basal infusion of 0.5 μg/kg was administered as a rescue analgesic. PCIA press number, rescue analgesics, total fentanyl consumption, and analgesia-associated side effects, including respiratory depression (defined as a respiratory rate <8 bpm), requirement of naloxone, and/or peripheral oxygen saturation <90% as evaluated by an author, urinary retention, pruritus, nausea, and vomiting were recorded during the first 48 hours after surgery. The anxiety scores, depression scores, and quality of life (QOL) were measured preoperatively and on postoperative day 7, month 1, month 3, month 6, and year 1. After discharge, the children would be followed up at the outpatient clinic 6 months later, while other times were by telephone or WeChat.Postoperatively, all participants were transferred to the postanesthesia care unit (PACU). When the children regained consciousness, a blinded research team member assessed their postoperative pain levels by using VAS in both groups. The additional VAS pain scores were assessed on preoperative day 1 (baseline) and postoperative day 1, day 2, day 7, month 1, month 3, month 6, and year 1. If the pain score was ≥4, fentanyl 0.2 Using the sealed envelope technique, the patients were randomized into one of the two groups: the control group and the intercostal group. The two anesthetic techniques were explained to all patients before they were randomly allocated to one of the groups. An anesthesiologist took care of randomization and prepared all local anesthetic solutions, drugs, and PCIA pumps. Other anesthesiologists, patients, medical staff members, and the statisticians were unaware of the treatment groups.The primary outcome included pain scores on postoperative day 1, as measured by VAS. Children assessed their pain level using an 11-number scale varying from 0, which indicated no pain, to 10, which indicated unbearable pain. The pain scores were noted every 6 hours, and we averaged each 24-hour period postoperatively. The secondary outcomes included pain-related, mental health, QOL, and safety. Pain-related outcomes included VAS scores at other time points, PCIA press number, rescue analgesics, and total fentanyl consumption at 48 hours postoperation. Mental health included anxiety and depression at every time point during the first postoperative year. Safety-related outcomes included assessment of adverse effects. In the study, the screen for Child Anxiety-Related Emotional Disorders (SCARED) was used to evaluate anxiety, Children's Depression Inventory (CDI) was used to assess depression, and Pediatric Quality of Life Inventory version 4.0 Generic Core Scales (PedsQL4.0) was used to value QOL. The higher the SCARED score, the higher the anxiety and a total score ≥23 is considered to indicate the presence of anxiety. CDI is the most widely used self-rating scale for children aged 7–17 years. A total score ≥20 is considered as indicating the presence of a depressive disorder, and the higher the score, the more severe the depression . The Pedβ was 0.8. Using the one-sided value of α = 0.025, the sample size of each group should be at least 24. Accordingly, 60 children were enrolled, while the dropout rate was 20%.PASS (version 15) was used to calculate the required sample size based on the pain scores on postoperative day 1 as the primary outcome variable. The result of preliminary study showed that the difference value of pain on postoperative day 1 was 1.4 between the two groups, the standard deviation for the intercostal group was 1.64, while the same in the control group was 1.73. The power of test 1 − U-test was used for comparing the PCIA press number, rescue analgesics, and total fentanyl consumption. For data with normal distribution, we calculated the mean differences in scores between the two groups and their 95% confidence interval (CI), while we obtained median differences and 95% CI for data with nonnormal distribution. Age, body mass index, and duration of surgery were compared using 2-tailed t-tests, while the incidence of analgesia-associated side effects was compared using 2-tailed Fisher's exact test. A 2-sided P value of <0.05 was considered statistically significant. Data are represented as either ratio (percentage) or mean (SD) or median (IQR).SPSS (version 22) was used for conducting statistical analysis. The data collected contained both continuous and categorical variables. The normality of the data was evaluated using the Kolmogorov–Smirnov test. Data with normal distribution were summarized as means and SD, while data with nonnormal distributions were summarized as medians and IQR. Repeated measures ANOVA test was conducted to compare the changes from baseline in the VAS pain scores at PACU and postoperative day 1, day 2, day 7, month 1, month 3, month 6, and year 1. The same statistics were used for anxiety, depression, and QOL. Mann–Whitney n = 2), refusal to participate (n = 5), inability to understand how to use the PCIA device (n = 5), or inability to confirm availability for follow-up (n = 4). Eventually, 60 patients were successfully randomized to assign to the intercostal (n = 30) or control group  in the PACU, 1.7 (p < 0.001) on postoperative day 1, and 0.7 (p=0.015) on postoperative day 2  (p < 0.05)  . In the  < 0.05) . CDI sco < 0.05) . The Ped < 0.05) .p=0.03) and in the postoperative 48 hours  than the control group . And, after postoperative 3 months, the postoperative pain basically disappeared, and only a slight pain was observed in a few patients. To the best of our knowledge, most of the studies have focused on acute pain after pectus excavatum surgery, and this is the first study to follow-up postoperative pain for one year.α [Pectus excavatum is the most common congenital chest wall deformity, but little is known about the influence of the Nuss surgical procedure on the mental health of patients. In each group, surgery could help improve the mental health of patients, which was consistent with that of the previous study , 23. Theα . The strThe incidence of analgesia-associated adverse reactions was markedly lower in the intercostal group in during the first 48 postoperative hours, which may result from the difference in opioid consumption between two groups. Intercostal nerve block might cause adverse events, such as pneumothorax, peritoneal penetration, and abdominal viscera. However, under the guidance of ultrasound, its effectiveness and safety showed great improvement.We believe one of the strengths of our study is the monitoring of the outcomes, which were assessed for one year after the surgery. A majority of the randomized controlled trials have followed up intercostal nerve block in patients for a short-term period, with recent studies following patients for 24 h , 48 h 2, or up tHowever, this study has some limitations. First, we did not take the educational level, psychological traits, and compliance of the patients when planning the follow-up phase of the study, and many children came from remote country villages. Second, we did not assess the severity of pectus excavatum, the occurrence of postoperative surgical complications, the time to return to normal activity, and the patient's satisfaction: all these items may also influence the child's mental state and the presence of postoperative pain. Third, our primary outcome was the pain scores on postoperative day 1, which were used to calculate the required sample size. Our study was thus probably not powered enough (not enough patients included) to evaluate differences in other items over a long period of time. Fourth, future studies using a liposomal local anesthetic with a prolonged effect could be performed to better evaluate its effect on acute and long-lasting postoperative pain. Finally, we only studied the children aged from 10–16 years old in the present study. In future studies, the age range of patients could be expanded to find possible difference among children of preschool, school-age, and adolescence.In conclusion, our results demonstrated that the ultrasound-guided intercostal nerve block with adjuvant of dexamethasone might control acute pain and anxiety and improve QOL better. Our study suggests that ultrasound-guided intercostal nerve block with PCIA might be more effective than PCIA in children who underwent the Nuss procedure.


Articular pain improvement was reported in 71% of joints treated. Improvement in chewing quality at the end of the entire injection cycle was found in 63% of patients. The equations for the linear regression models for painless mandibular abduction (five applications of PRP) and maximum mouth opening (the first four applications of PRP) were x + 34 (R2 = 0.89) and 0.6x + 43.6 (R2 = 0.96), respectively. Improvement in these domains was found in 78% and 53% of patients, respectively. The strongest correlations were found between pain and chewing efficiency (−0.95), pain and painless mandible abduction (−0.96), and painless mandibular abduction and mastication efficiency (0.94). Conclusion: PRP injections into TMJ cavities should be considered as a low invasive, highly accessible form of treatment for various TMDs causing pain and mandible movement limitation.Background: Temporomandibular joint disorders (TMDs) are manifested, inter alia, by pain and limited scope of the mandibular abduction. Among the treatment strategies for these ailments, intra-articular injections of autologous blood preparations, including platelet-rich plasma (PRP), are administered. This prospective case series was aimed at assessing the effectiveness of repeated platelet-rich plasma (PRP) administration to the TMJ cavities in terms of reducing articular pain and increasing the mobility of the mandible. Material and methods: 40 consecutive patients diagnosed with TMJ pain qualified for the case series. The entire treatment program consisted of five PRP administrations and a summary appointment. Regression was analyzed for (1) intensity of spontaneous pain; (2) effectiveness of spontaneous pain relief; (3) mastication efficiency values; (4) painless mandibular abduction; (5) maximum mouth opening. The correlations between the abovementioned variable series were analyzed. Results: The mean spontaneous pain decreased consistently with successive PRP administrations in line with the regression model: −0.4x + 4.2 (R Temporomandibular disorders (TMDs) are a common but very general diagnosis ,2. AccorPaired TMJs, equipped with an extensive system of muscles and ligaments, are responsible for the mobility of the mandible ,4. Each The most commonly used methods for treating TMD include pharmacotherapy, physiotherapy, splint therapy, surgery, and intra-articular injections ,5. The lGood results of HA supplementation to the inside of the joint cavity may justify intra-articular injections in order to supplement and improve the composition of the synovial fluid ,9,10,11.The use of autogenous centrifuged blood products has a positive effect on wound healing . PRP andThis prospective case series was aimed at assessing the effectiveness of repeated platelet-rich plasma administration to TMJ cavities in terms of reducing articular pain and increasing the mobility of the mandible.Participants in the case series were administered PRP obtained from their own blood into the cavities of the temporomandibular joints in accordance with modern medical indications. The regional bioethics committee approved the case series program. In accordance with the consent of the committee, there was no placebo group or any other control. The report was designed based on the STROBE protocol and checklist .The case series program was conducted in 2020–2021 at the Department of Maxillofacial Surgery, Hospital of the Ministry of Interior, Kielce, Poland. The qualification period covered two full months from the beginning of August to the end of September 2020. In total, the entire program consisted of 6 medical appointments including 5 therapeutic appointments and a summary appointment. At 5 therapeutic visits, the surgeon (M. Sie.) administered PRP to one or both TMJs, according to prior qualification. At the summary appointment, the patient was examined by an orthodontics specialist (B. C.-N.). The therapy was carried out according to an individual schedule for each patient. The intervals between injections, for organizational reasons, ranged from 7 to 10 days. The summary visit was carried out about a month (±7 days) after the last PRP administration. After this time, each of the patients, in accordance with the assumptions of the program approved by the bioethics committee, could return to other analgesic therapies including pharmacotherapy, physiotherapy, and splint therapy. Therefore, it was not possible to conduct further follow-up visits to assess the effect of intra-articular injections alone.Surgical management at therapeutic visits consisted of (1) disinfecting the skin of the forearm with an alcohol-based Kodan Tincture Forte Colorless ; (2) collecting 8 mL of peripheral venous blood from the elbow flexion; (3) centrifugation of the collected blood to PRP ; 4) disinfecting the skin of the preaural area with the agent as above; (5) injecting 0.4 mL of the obtained PRP into the upper portion of TMJ according to the protocol described in our previous paper [ disinfecConsecutive patients referred to the Maxillofacial Surgery Clinic for intra-articular PRP injections were qualified for the case series. All patients were referred by orthodontics specialists who stated indications for treatment with the use of PRP. The orthodontists diagnosed all patients in within the 3rd subsection of the 1st edition of the ICOP classification, i.e., TMDs [In order to characterize the case series, data on the sex and age of the patients were obtained in the course of a medical interview. Each of the patients specified how long they had been experiencing soreness in the temporomandibular joint or joints. Medical data from the referral were collected on the diagnosis and the qualification of each joint in each patient for injection. At each of the 6 visits, the patient quantified the current pain on visual analog scales (VAS) for the right and left TMJs as well as the overall mastication performance immediately before the intervention. This scale took integer values from 0 to 10. At each of the medical visits, the range of painless mandibular abduction and nonsupported manually maximum mouth opening were examined. Each time, 3 successive measurements were performed in order to calculate an arithmetical mean.The evaluation of the indications and results of the therapy was separated from the individual stages of the treatment. Referral for PRP injections was considered by the orthodontist from our research team (B. C.-N.). This orthodontist confirmed the qualification for injections and ruled out general contraindications. Then, the surgeon (M. Sie.) ruled out local contraindications and administered PRP without knowing the details of the diagnostic process and indications for injection. Finally, the orthodontist (B. C.-N.), who intentionally did not attend individual therapeutic visits, examined the patient and summarized the results of the therapy. The data were analyzed by the authors who deliberately did not participate in the diagnosis, qualification, therapy, or its summary .Due to the wide discrepancy in epidemiological data regarding the incidence of TMJ dysfunction and pain, it was difficult to estimate the desired sample size. The available budget allowed for the implementation of a full treatment program in 40 patients. Therefore, it was assumed that the case series would be continued until full therapeutic cycles were achieved in 40 consecutive patients.np) gave 1 value for each visit of each patient, i.e., 6 values per patient (p0 − p5). On their basis, during subsequent visits (n), the effectiveness (enp) of the therapy was assessed, expressed by the formula:ep5 expressed the overall pain relief effectiveness.The characteristics of the case series included the quantitative variables of age, duration of ailments, and the number of joints qualified for treatment in each patient. Subjective assessment of spontaneous pain (nm) was determined analogously on the same VAS at each visit (m0 − m5). The increase in mastication efficiency (enm) was determined by the formula:em5 expressed the overall increase in mastication efficiency.The mastication efficiency (na) and maximum mouth opening (no), 3 consecutive measurements were made for each patient at each appointment. The mean values of these 3 measurements were taken as quantitative variables, thus giving one na value and one no value per one visit of one patient, i.e., a0 − a5 and o0 − o5 per patient. The effectiveness of the therapy in relation to the maximum painless abduction (ena) of the mandible and the maximum opening of the mouth (eno) was calculated as follows:ea5 and eno expressed the overall increases in painless mandibular abduction and maximum mouth opening, respectively.For maximum painless mandibular abduction (np); (2) effectiveness of spontaneous pain relief (enp); (3) mastication efficiency values (nm); (4) painless mandibular abduction (na); (5) maximum mouth opening (no). The correlations between the variable series p0–5, m0–5, a0–5, and o0–5 were analyzed. In the case of missing data, the closest value of a given variable was used, e.g., missing or illegible information on the amplitude of mandibular abduction at the last appointment was supplemented with the value from the penultimate visit. Data analysis was performed using the OriginLab software  and Google Sheets .Regression was analyzed for the (1) intensity of spontaneous pain (Forty-two patients were referred for treatment under the research program. We confirmed the indications for PRP injections in 41 of them (the indications for treatment subsided before the initiation of therapy in one patient). One of the patients who started the therapy did not complete it. This patient withdrew from the research program after two bilateral intra-articular PRP administrations due to the ineffectiveness of its pain relief. Initial diagnosis indicated serous TMJ inflammation as manifested by chronic pain. Pain values in this patient were 5 and 8 before the first injection, 6 and 9 before the second, and 6 and 10 after week 1 on the right and left VAS, respectively. Due to the ineffectiveness of the therapy, the patient returned to the referring orthodontist in order to change the treatment strategy. Thus, 40 patients met the criteria for inclusion in the analysis.The group of 40 patients consisted of 36 women and 4 men. The age of the participants ranged from 14 to 78 years. The median age was 33, and the mean was 37.5. Patients were diagnosed in stages II, III, and IV on the Wilkes scale: 28 (70.0%), 7 (17.5%), and 5 (12.5%) of them, respectively. Three patients did not report how long they had suffered from TMDs. Among the remaining 37 participants, the duration of the symptoms ranged from approximately 1 to 30 years, with the median being 4 years and the mean 6 years and 5 months. In 30 patients, both joints were qualified for treatment, and in 10 only one of the TMJs. Thirty-three right and thirty-seven left joints were treated, for a total of seventy joints treated with PRP injections.Due to an oversight by the investigators, seven patients did not subjectively assess the severity of joint pain and chewing efficiency at the last visit. In all cases, the data from the previous five visits were complete. In accordance with the adopted methodology, the data from the fifth visit were used each time as the values for the sixth visit. In three patients, the pain-free and maximum jaw abduction values were not correctly measured at the last visit. Similarly, in line with the adopted assumptions, the data from the penultimate visit were used. Three patients did not report symptom duration, and their responses were not taken into account in the pooled analysis of this variable. One patient did not report the severity of joint pain on the second visit; thus, data from this patient’s first visit was copied.The variables defined on the basis of the VAS, i.e., spontaneous pain and mastication efficiency, took 11 predetermined values that were integers ranging from 0 to 10. The mean mandibular abduction determined on the basis of three consecutive measurements was determined in millimeters and ranged from 15.0 to 54.3. The lowest of these extreme values was recorded on the first visit and the highest on the last visit. Similarly, the maximum mouth opening ranged from 23.0 to 57.3 mm. As with painless abduction, the lowest value was measured at the first visit and the highest after the end of therapy.R2 = 0.98) can, in this case, be described by the equation:The mean of subjective spontaneous pain calculated from the values for the 70 treated joints decreased consistently with successive PRP administrations  took the form:The same figure also shows the effectiveness of the therapy in relieving subjective pain . Again, The actual improvement, expressed as the difference in pain scores at the end and start of therapy, was reported by the patients relative to 50 of the 70 joints treated . In the The case with the greatest increase in pain in the course of therapy (by 3 points on the VAS) can probably be explained by a measurement error. According to the adopted test method, the reference pain value was the one recorded before the first administration of PRP, in this case 5 points. However, the analysis of medical records showed that the previous (not taken into account in our case series) value of pain from this joint was nine. Such a large discrepancy may indicate an unreliable assessment of the patient or an error in understanding the content of the order. It should also be added that in the same patient a decrease in pain by 5 points in the case of the other joint was shown.R2 = 0.8) expressed by the equation to the increase in the mean chewing efficiency:The mean of subjectively assessed VAS chewing performance in the treated 40 patients increased with the successive administrations of PRP , in this case, can be described by the following equation:The mean range of painless mandibular abduction for the 40 patients gradually improved over the course of the therapy  was fitted to all mean values of maximum mandibular abduction:The mean maximum mouth opening gradually increased in 40 patients by the four first PRP injections  and decreased after the fifth administration . The oveR2 = 0.96) was more accurate and can be described by the equation:For the first four administrations of PRP, the linear regression model , mastication effectiveness (m), painless mandibular abduction (a), and maximum mouth opening (o) at six medical appointments showed a number of relationships  between the initial joint pain and the effectiveness in this domain of intra-articular PRP administration applied five times. In the analyzed cases, the average pain reduction on the 11 point VAS was 0.4 per each administration of PRP. In the course of the case series program, the average dynamics of the decrease in pain value did not decrease, which may suggest that the continuation of the therapy could be effective in the context of the entire case series. In 42 examined joints, pain after five injections was less than the average pain after three and four injections, which is presumably a group of potential beneficiaries of continued treatment. In 13 joints, the value of pain calculated in this way increased, which may mean that the limit for repeated PRP administrations was exceeded, and constant values were achieved for 15 joints. A large number of injections per joint (five repetitions) allows for a preliminary drawing of the assumption that the number of injections may be dependent on the resolution of pain and pain-related ailments , which is an individual matter for each patient.There was quite a weak correlation (−0.36) between the initial subjective assessment of mastication and the effectiveness of its improvement. The negative value of this variable suggests that, on average, the worse the patient assessed his chewing before starting treatment, the better the effect. Analogous calculations for painless (−0.44) and maximum (−0.49) mandibular abduction showed moderate negative correlation. Therefore, it should be assumed that the change in the mobility of the mandible in the course of PRP administration into TMJs cavities depends to some extent on the initial values of the variables. This relationship is clearer in the physical examination than in the subjective assessment of chewing. Most of the patients in the case series improved their chewing efficiency (63%) and maximum jaw abduction without pain (76%). This confirms the analgesic effectiveness of the PRP intra-articular administration. Approximately half of the subjects (53%) experienced an increase in the maximal range of mouth opening, suggesting that there is a potential for PRP to overcome mechanical obstacles to abduction, possibly in the inflammation reduction mechanism. The discrepancy between the number of patients with increased mandibular mobility and the corresponding value without pain (25% of patients) additionally emphasizes the analgesic effect of the therapy.The sources of potential bias or imprecision of our case series lie mostly in the absence of a control group, the short follow up, and small group of patients. The group was composed of patients with TMJ complaints, who required treatment and decided to participate in the project provided that they would be treated. For this reason, already in the assumptions of the project, the possibility of comparing the tested method with therapies expected to be less effective or a placebo was rejected. Injecting the healthy side as a control in treated patients was not chosen for ethical reasons. The small size of the case series and the lack of a control group were also caused by the financial limitations of patients and the lack of funding for the project. Therefore, it cannot be ruled out that future randomized controlled trials will show similar results for placebo or other injectable groups. Further randomized controlled trials are required to better control the study confounders and provide the deep analyses comparing clinical outcomes after TMJ injections with different solutions or medications. The observation period was forced due to the assumption that after the study all of the patients would return to their initial therapies. The variables of the assessment of mastication efficiency and mandible mobility did not allow for an assessment for individual joints but for individual patients. This means that they were analyzed irrespective of whether the application was one-sided or two-sided. Only the variables concerning articular pain were interpretable for each joint separately.The golden standard in treatment of painful TMDs with limited mouth opening has not been set yet. There is still an ongoing search for an effective, predictable and fast-acting method. Therefore, conducting more clinical trials, as well as drawing specific conclusions, is essential for achieving the objective summary that could lead clinicians in their work.The therapy turned out to be the most effective in decreasing the overall spontaneous pain. This was also shown in recent studies investigating the application of PRP injections into TMJ cavities. Hegab et al. stated pain and mandible mobility improvements after PRP injections alone in treating TMJ osteoarthritis . HoweverPatients with various TMDs constitute 31% of the adult population according to a meta-analysis from 2021 by Valesan et al. . They moResults obtained in this case series are in line with the most recent literature summaries in a form of meta-analyses and/or systematic reviews in the discussed field ,34,35,36The precise mechanism underlying the actions of PRP in improving pain and MMO remains unclear. However, it is known that major growth factors and growth factor families from PRP, such as tissue growth factor-β (TGF-β), insulin-like growth factor 1 (IGF- 1), bone morphogenetic proteins (BMP), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), take part in the process of OA healing ,43,44. TPRP is an injection agent that is not manufactured but has to be prepared individually from the patient’s own blood sample. Obtaining PRP from autologous blood has the advantage that the raw material for its production is available to every patient and it is a free resource. Furthermore, this ensures a significantly low risk of allergic reactions or adverse effects caused by the injectate. However, it also contributes to extending the duration of the procedure as well as requiring the use of additional equipment, such as a centrifuge, while alternatives, such as HA, are simply sold in the form of a formulation in vials. Moreover, it should be borne in mind that PRP, as a blood product, is as good as the substrate from which it was prepared, which should be taken into account in poorly nourished patients, those on an unconventional diet, or those suffering from autoimmune diseases.According to our research and the literature analysis, PRP injections into TMJ cavities should be considered as a low invasive, highly accessible form of treatment for various TMDs causing pain and mandible movement limitation. Treatment with five administrations of PRP had a more pronounced immediate analgesic effect (improvement in 71% of joints) than in the domain of maximizing maximum mouth opening (improvement in 53% of patients). Improvements were seen in the majority of patients in the subjective chewing performance and pain-free abduction domains directly related to joint pain in 63% and 76% of patients, respectively. In the case series, each subsequent administration of PRP reduced pain on the VAS (0–10) by 0.4, increased chewing efficiency on the VAS (0–10) by 0.3, and increased pain-free abduction by approximately 1 mm. Further research is required, particularly investigating larger groups of patients with longer follow-up periods.


The needle insertion pain to perform hemodialysis is the main challenge and a common problem that requires pain management techniques for patients’ comfort.This study aimed to compare the effects of cooling and lidocaine sprays on needle insertion pain in hemodialysis patients.In this randomized cross-over clinical trial study, the hemodialysis patients were selected through convenience sampling according to inclusion criteria and randomly assigned to three intervention groups using the block randomization method. Each patient received three interventions in a cross-over design: Cooling spray or 10% lidocaine spray or placebo spray. There was a 2-week wash-out time between each intervention. The pain score was measured four times for each patient by the Numerical Rating Scale.Forty-one hemodialysis patients were included. The results showed a significant interaction between time and group (p < 0.05), so only observations of time 1 with adjustment for baseline values were used to evaluate the effect of the intervention. Patients receiving cooling spray reported 2.29 less pain score on average compared to placebo ; Also, patients receiving cooling spray reported a 1.61 lower pain score than those receiving lidocaine spray, but this difference was not statistically significant .The cooling spray was effective in reducing the needle insertion pain. Although it was impossible to compare the pain scores at different times and following different interventions, the present study results can help supplement the existing knowledge regarding cooling and lidocaine sprays. Pain is defined as an unpleasant sensation and emotional experience , and it The HD is the most frequently used renal replacement therapy, and an arteriovenous fistula (AVF) is the gold standard for vascular access in these patients . It is tOn the other hand, a painful procedure can instill a sense of distrust in medical staff; the patient’s pain intolerance also increases the risk of occupational accidents, such as inserting an infected needle in the nurse’s hand , 15. TheFor pain reduction, some methods have been suggested and studied, including the use of topical anesthetics, such as lidocaine , distracThe injectable anesthetics are not used for venipuncture or intramuscular injection alone because their injection is as painful as venipuncture or injection . AnestheAnother form of topical analgesic includes sprays. One of the most well-known types of these sprays is lidocaine spray. Lidocaine spray is used for the topical anesthesia of mucous membranes and skin. The beginning of its practical effect and its easy-to-use method has led to its widespread use, compared to other methods . A new tFurthermore, the existing evidence on the usefulness of cooling sprays is of medium quality and cannot be relied on . TherefoThis study was a single-center, open-label, randomized, three-period, three-treatment, sequence crossover clinical trial carried out within May 2019 to October 2019. The research setting was the Hemodialysis Ward of Imam Ali hospital in Bojnurd, North Khorasan province, Iran.The research population included all patients under treatment with HD, meeting inclusion criteria, and hemodialyzed in the Hemodialysis Center of Imam Ali hospital in Bojnurd, Iran, through an AVF. The inclusion criteria included age of over 18 years, alertness, the ability to speak and understand Persian or the presence of a Persian-speaking translator, no pacemaker or known heart problem, the onset of HD at least 3 months ago, no known allergies to lidocaine, no damaged skin, no use of analgesics and opioids during the last 24 h, no history of using lidocaine cream or products in the past, HD through an AVF, no history of antiarrhythmic drugs , and HD three times a week. The exclusion criteria included the occurrence of skin allergy or abnormal reaction at the vascular access site, not referring for HD in the next session, and lack of venipuncture with the first attempt in each stage.The convenience sampling method was used in this study. With the effect size of 0.81 obtained from Asgari et al.’s  study, uBefore the first intervention, informed and written consent was obtained from the patients, and the pain rating scale was trained. The first needle insertion was considered the primary intervention for all patients, and the vascular access procedure was performed without any intervention. The pain score was determined and recorded one minute after needle insertion by the Numerical Rating Scale (NRS). Each patient received one of the interventions in the next HD session (2 days later), including cooling spray (ethyl chloride), 10% lidocaine spray, or placebo spray. Patients who first received a cooling spray  received lidocaine spray 2 weeks later and placebo spray 4 weeks later. Patients who first received lidocaine spray received the placebo spray 2 weeks later and the cooling spray 4 weeks later. Patients who first received placebo spray received cooling spray 2 weeks later and lidocaine spray 4 weeks later , 30  model was used to analyze the data and evaluate the sequence, period, and carry-over effects. Crossover design is a type of longitudinal study, and the LME model has been widely used to analyze the data in longitudinal studies .Patients were entered into the model as a random effect (nested in different sequences) to control within-subject effects. The sequence effect, period effect, carry-over effect (in the form of the interaction between time and group), and treatment effect with adjustment for the baseline values of outcome were examined.This analysis was performed using SPSS software (version 24). The tests were considered two-tailed, and the significance level was set to 0.05. The LME analysis method is robust to the minor violation of the normality assumption. Therefore, this method can be used for the NRS score variable  –36. Due According to the inclusion criteria, 41 patients under treatment with HD were included in the study. None of the patients was excluded and left the treatment half-finished. The mean and standard deviation of age and HD treatment duration were 52.98 ± 14.10 and 3.8 ± 3.1 years, respectively. In addition, 25 patients (61%) in this study were male. The results showed a significant interaction between time and group (P = 0.007). In other words, there were carry-over effects. The period (P = 0.67) and sequence (P = 0.36) effects were not significant (Table Cooling spray group (A) first (Time 1) received cooling spray; then after 2 weeks (Time 2), the group received lidocaine spray; finally, after 2 weeks (Time 3), the group received placebo spray. Lidocaine spray group (B) first (Time 1) received lidocaine spray; then, after 2 weeks (Time 2), the group received placebo spray; finally, after 2 weeks (Time 3), the group received cooling spray. Placebo spray group (C) first (Time 1) received placebo spray; then, after 2 weeks (Time 2), the group received cooling spray; finally, after 2 weeks (Time 3), the group received lidocaine spray.As shown in Fig. The present study was conducted to compare the effects of cooling and lidocaine sprays on needle insertion pain in HD patients using a crossover design. Because pain is subjective and pain is what the patient tells us according to the literature, it is difficult to compare patients’ pain scores to each other. On the other hand, patients undergoing HD frequently experience needle pain, which also affects their perception of pain; as a result, comparing the pain score of patients after receiving various interventions to themselves creates a more accurate picture of the effect of the intervention on pain control. Therefore, a crossover design was used in this study in a way that the participants can be compared to themselves, controlling for any possible confounding variables.Moreover, this crossover design allows the comparison of various interventions. Although it was impossible to compare the pain scores at different times and after different interventions due to a carry-over effect, the present study results can help supplement the existing knowledge regarding cooling and lidocaine sprays. On the other hand, despite a two-week wash-out time, a carry-over effect in the crossover design was a significant issue that requires further investigation and more evidence on time needed to wash out the effects of similar interventions on pain in future studies.The interventions’ effects were compared for the first time, controlling for baseline scores. Although the results showed no significant difference between cooling spray and lidocaine spray interventions, the difference in the scores of the two interventions was significant. More reliable results can be obtained by conducting further studies with a more extended wash-out period and a larger sample size.The effects of cooling spray and lidocaine in various forms have been investigated in different studies, and different results have been reported. For example, Page and Taylor’s study on venous cannulation-induced pain showed that the pain reduction of cooling spray was less than topical lidocaine . AdditioMoreover, Dalvandi et al.’s study revealed that the pain after receiving a cooling spray was significantly less than the control group (in the case of cannulation without any intervention) and more than the EMLA cream . The afoThe results of Moon et al.’s study investigating the effectiveness of cooling spray and lidocaine injection in propofol injection pain showed that both groups receiving cooling and lidocaine sprays experienced less pain than the control group; however, there was no significant difference between the two groups of lidocaine and cooling sprays in terms of pain score . A studyLimited studies have shown that cooling spray is ineffective in reducing pain , 40, whiThe NRS has inherent time and shortcomings. Furthermore, additional contributors to patients’ pain, such as catastrophizing tendencies, might be evident if additional or different rating scales were used to better clarify the patients’ phenotype.Because HD patients need to be connected to the dialysis machine after needle insertion, it was difficult to evaluate the pain score immediately after the needle insertion; therefore, this evaluation was carried out in all patients within one minute after the needle insertion into the skin. The issue of whether the pain scores one minute after the needle insertion can be different from the score reported by the patient immediately after the needle insertion needs further investigation.To the best of our knowledge, a limited number of studies compared the effect of cooling and lidocaine sprays in a crossover design. Therefore, compared to other studies, one of the advantages of this study is that it exposed a group of patients to three forms of intervention. On the other hand, the investigation of the sequence, period, and carry-over effects is one of the advantages of this study. The presence of a carry-over effect despite the 2-week wash-out period can raise one of the most important issues for further investigation in the field of pain studies.This study has some limitations. Pain is subjective, and its evaluation can be associated with problems. On the other hand, patients undergoing HD treatment frequently experience needle pain that affects their perception of pain. Repeating a painful procedure  might also shape patient expectations and preferences, and any intervention insulted by these issues might produce nocebo or placebo effects. The characteristics of vascular access can also be effective in pain perception. An attempt was made to cover this limitation using a crossover design. However, due to the significant carry-over effect, it was not possible to compare the scores after different interventions at different times in one group, which is another limitation of this study. Moreover, blinding was not possible in this study due to the cooling nature of the cooling spray and the apparent difference between lidocaine and placebo sprays. However, an attempt was made to ensure that covering lidocaine and placebo sprays was the same. Another limitation of this study was the small sample size.The results of this study indicated the effectiveness of cooling spray in reducing pain caused by HD needles. Due to its cost-effectiveness, immediate effect, and non-invasiveness, cooling spray can be an appropriate option for reducing pain in various techniques that are associated with pain. Since both interventions performed in this study were non-invasive techniques, these results can be helpful to be compared to other invasive pain reduction methods and make the right choice with fewer complications and more non-invasiveness. It is recommended to perform further studies to determine the wash-out period after non-invasive pain control interventions. In addition, it is required to carry out supplementary studies to compare the effects of lidocaine and cooling sprays.


Atypical femoral fracture (AFF) is a rare complication in patients with osteoporosis undergoing long-term bisphosphonate therapy. The most common symptom of incomplete AFF is nonspecific thigh pain, which is often difficult to distinguish from other causes.We present two cases of AFF misdiagnosed as lumbar radiculopathy. Both patients visited our hospital for thigh pain, and in both cases the findings of lumbar spine magnetic resonance imaging showed substantial nerve compression. These patients had been treated for lumbar radiculopathy, but localized symptoms became conspicuous and femoral radiographs revealed complete AFF. The initial radiographs were reviewed retrospectively and revealed slight lateral cortical thickening in the affected femur, denoting a missed incomplete AFF. Internal fixation with intramedullary nails was performed.AFF may mimic lumbar radiculopathy. Therefore, clinicians should consider AFF as a differential diagnosis in older patients with lumbar canal stenosis who are undergoing long-term bisphosphonate therapy and present with thigh pain. Bisphosphonates are the most commonly prescribed medications for osteoporosis that prevent osteoporotic fractures . SeveralThe mean age of patients with surgically-treated, bisphosphonate-related AFF is reportedly 70 years, with groin and thigh pain being the most common symptoms . FurtherTherefore, the epidemiologic features and symptoms of AFF and lumbar radiculopathy are similar and these two conditions may coexist. However, missed incomplete or nondisplaced AFFs are at high risk of further displacement and may negatively impact the hospital stay, systemic or local complications, and/or mortality . Thus, aA 67-year-old woman visited our hospital with a chief concern of left anterior thigh pain for 1 month without any specific history of trauma. The patient had a history of systemic lupus erythematosus (SLE) and osteoporosis, for which she had been administered a proton pump inhibitor (PPI), 10 mg prednisolone, and monthly alendronate for 5 years.The patient had long-term sensory disturbance in the lower extremities owing to the peripheral neuropathy associated with SLE. The patient reported no rest pain in the left lower extremity, but reported pain during weight-bearing and walking. Further, mild weakness of the iliopsoas and quadriceps muscles was observed, probably because of pain and long-term disuse.Metabolic studies and tests yielded normal results except for 25-dihydroxyvitamin D . Her initial radiographical examination included a lumbar spine series and antero-posterior (AP) pelvis and revealed degenerative changes with reduced disc height at L1-2 . The initial radiographical examination included a lumbar spine series and revealed decreased disc height and grade 2 spondylolisthesis at L4-5 (Fig. An 83-year-old woman with a history of breast cancer and osteoporosis visited our hospital with a chief concern of left lateral thigh pain for 2 weeks. She had been receiving PPI and monthly alendronate for 10 years for the management of osteoporosis. The patient had no obvious sensory disturbance or muscle weakness. She had no rest pain in the left lower extremity, but had pain during weight-bearing and walkingLCS is often difficult to diagnose as a large number of differentials can mimic this condition, including herpes zoster, peripheral arterial disease, peripheral neuropathy, , 9 and pAFF is a type of stress fracture called an insufficiency fracture that develops over time, most commonly after prolonged suppression of bone remodeling by the bisphosphonates . RepetitA systematic review found that the mean reported age range of patients with bisphosphonate-related AFF who had surgical treatment was 66.8–74.2 years . In the Although the presence of the dreaded black line on the initial radiographs is a radiologic feature indicative of stress fracture nonunion,  the dreaDelayed or missed diagnosis of AFF, especially in the case of an incomplete fracture, may negatively impact the patient’s prognosis, as seen in the two cases presented where the fractures both progressed from incomplete to complete. Banffy et al. reported that five of six incomplete AFFs progressed to complete AFF, and patients who underwent surgery for incomplete AFF had shorter hospital stays than those of patients with complete AFF . CarefulIn summary, we reported two cases of AFF mimicking lumbar radiculopathy. Clinicians should consider AFF as a differential diagnosis in older patients with LCS who are undergoing long-term bisphosphonate therapy and present with thigh pain.


Symptomatic irreversible pulpitis is a common dental disease for which root canal treatment (RCT) has been the standard treatment. However, in many countries, RCT is considered a high-cost treatment that is not covered by public healthcare services; this forces patients to have dental extraction as their only option to relieve pain. In the last decade, several investigations have provided evidence that an alternative treatment known as full pulpotomy (FP) could be an alternative for patients who could not afford the cost of an RCT. Nevertheless, evidence is lacking on the success rate that could be obtained if it is performed in a public dental care clinic (PDCC). The present investigation has two main objectives. To be the first approach of a multicentric feasibility study to find out whether an FP performed by a general practice dentist (GPD) in a PDCC could be suitable and establish its success rate and patient satisfaction. Patients attending a PDCC with symptoms of irreversible pulpitis were invited to participate. FP was performed and followed up at 1, 3, 6, 9, and 12 months. The treatment success was assessed by combining three variables, patient satisfaction, clinical, and radiographic outcomes. Forty-one patients from 17 to 78 years old received the intervention. In total, 97.5% were completely satisfied with the treatment and were considered successful since none of the clinical or radiographic variables were present in any of the follow-ups. An FP performed by a GPD in a PDCC could be suitable as a routine treatment for symptomatic irreversible pulpitis due to the excellent success rate and patient satisfaction. In Mexico, a country with more than 126 million inhabitants, 93.3% of adults suffer from dental caries [It is well known that financial constraints affect oral and general health. Tooth extraction is a typical result of irreversible pulpitis ; evidentIn addition to the lower economic costs of such vital pulp therapies, including full pulpotomy (FP), other advantages come with them such as the reduction in operative time, the preservation of tooth structure , as wellIt is an interesting consideration to offer FP as a routine treatment for symptomatic irreversible pulpitis or carious pulp exposure in the PDCC of Mexican public healthcare services to the population that cannot afford an RCT. However, to formally raise this proposal, it is necessary to evidence the possibility of it being undertaken repeatedly by general practice dentists (GPD) using the available instruments, materials, and a workflow with an adequate success rate and patient satisfaction through the realization of a multicentric feasibility study, but first, a single center feasibility study (pilot study) is necessary. Then, the present investigation has two main objectives. It is the first approach of a multicentric feasibility study to find out whether the FP performed by a GPD in a PDCC of the Mexican public healthcare services could be suitable and establish the success rate of this proposal and patient satisfaction. This investigation was designed as a longitudinal prospective single-arm cohort study. The sample size was established by convenience and based on similar sample sizes in studies investigating the outcome of vital pulp therapies after at least one year. Ethical approval (code number: JS1/ENS/450/19) was obtained from the bioethics committee of the Ministry of Health of the State of Querétaro (Mexico), and the authorization was granted to perform the procedures in the “Centro de Salud -La Negreta- Jurisdicción Sanitaria N° 1 del Estado de Querétaro”. One GPD (J.V.V.T.) was theoretically and practically trained by an experienced endodontist (R.G.S.L.T.) in a 5 h lesson. Five fundamental topics were covered. 1. Pulp diagnosis, including pulp sensitivity tests, 2. Access cavity preparation with emphasis on the complete removal of the pulp chamber roof, 3. Hemostasis and application of the MTA with emphasis on adequate thickness and compaction, 4. Final restoration with amalgam, and 5. Explanations to the patient to solve doubts.All the patients from 17 years old attending the PDCC with severe and/or spontaneous pain or deep caries in a permanent premolar or molar tooth were selected for possible enrollment . The excA numeric rating questionnaire was also used to record pain intensity (0 = no pain to 10 = worst pain imaginable). To invite the patient to participate, they should fulfill the following inclusion criteria: Preoperative symptoms of irreversible pulpitis, such as spontaneous pain or pain exacerbated by thermal stimuli, lasting for a few seconds to several hours, interpreted as lingering pain compared with a control tooth , and whiAll patients were treated in one visit by the same previously trained GPD. Firstly, local anesthesia was injected with 4% articaine with 1:100.000 epinephrine . After applying the rubber dam , disinfection of the tooth was performed using 2.5% sodium hypochlorite (NaOCl). Restauration, caries, and weak tissues were removed, and the endodontic access was prepared with a high-speed N° 4 carbide bur . When confirmed that pulp tissue was supplied with blood, most of it was removed with a sterile high-speed diamond bur  under sterile saline solution irrigation and amputated to the canal orifices level using an endo excavator . If there was no bleeding, RCT was indicated and the patient was excluded. If bleeding occurred, hemostasis was achieved by rinsing the cavity with saline solution and applying small cotton pellets soaked in 2.5% NaOCl for a maximum of 10 min. White MTA  was mixed according to the manufacturer´s instructions and placed against the wound after hemostasis using an amalgam carrier  and packed using an amalgam standard condenser . The material was adapted to be 2 to 3 mm thick, and a moistened cotton pellet was placed directly over the MTA. After 15 min, the cotton was removed, and the tooth was restored with amalgam. A postoperative periapical radiograph  was taken after restoration with a radiographic holder Rinn XCP  to maximize the reproducibility of the radiographic paralleling technique. General care instructions were given to the patients, and three analgesic intakes  were recommended. The endodontist supervised all the procedures, registering the time needed to perform them without his intervention. In addition, the patients were asked about their satisfaction with the treatment duration. The possible answers were: “Less than I expected,” “Just what I expected,” “More than I expected,” and “Much more than I expected.” Twenty-four hours and seven days after the procedure, patients were contacted by phone to record pain intensity, tenderness to mastication, need for intake of analgesics (more than the recommended), and satisfaction with the effect of the treatment. The possible answers for their satisfaction level were: “Very satisfied,” “Satisfied,” “Neither satisfied nor dissatisfied,” “Dissatisfied,” or “Very dissatisfied.” All the patients were scheduled for five follow-ups, and their satisfaction with the effect of the treatment was recorded. Clinical variables were persistent or spontaneous pain, tenderness to percussion or palpation, tooth discoloration, abnormal mobility, swelling, periodontal pocket, or sinus tract related to the treated tooth and evaluated at 1, 3, 6, 9, and 12 months. Radiographic variables were evidence of periapical radiolucency, furcal pathosis, or root resorption observed at the 3, 6, and 12 months radiographs, which were digitized by one member of the group (R.G.S.L.T) using a digital camera  at a resolution of 1600 × 1200 pixels. Contrast and brightness were automatically adjusted using Adobe Photoshop 7.0 software , and digital black box images were positioned on the coronal third of the teeth so only the medium and apical thirds of each radiographic images were shown for evaluation to three previously calibrated observers who were blind to the aims of the study. All clinical and radiographic data were reviewed separately by two experienced endodontists (T.D. and R.A.D.P). A treatment was considered a success if none of the clinical or radiographic variables were present at the one year follow-up.The interexaminer consistency for radiographic variables was performed by the kappa coefficient (>0.81) using the statistical package IBM SPSS . Descriptive analyses were performed for quantitative variables including mean and standard deviations, while qualitative ones were expressed as frequencies and percentages. Forty-one patients received the intervention in 35 molars (16 maxillary–19 mandibular) and six premolars (four maxillary—two mandibular) teeth. Their clinical characteristics are summarized in All the participants reported preoperative moderate or severe pain and tenderness to mastication. Twenty-four hours after the treatment, 87.8% of the patients reported no pain, and only one reported tenderness to mastication. On the seventh day, 97.5% reported no pain, and 100% reported the absence of tenderness to mastication. During the first days, 97.5% were completely satisfied with the treatment. Only one patient reported severe pain and tenderness to mastication on the third day. She was excluded and RCT was indicated. Therefore, forty patients were followed from this point.One patient reported slight tenderness to mastication at one-month follow-up, and an occlusal adjustment was performed. After three months and all subsequent follow-ups, 100% of the participants reported the absence of pain, and 100% reported being “Very satisfied” with the treatment. All cases were considered clinical and radiographic successes . TherefoIn addition, regarding the treatment performance, it was registered that the complete workflow could be easily followed and applied by the GPD and was completed within 45 to 60 min. In total, 80.5% of the patients considered the duration of the treatment “Less than I expected,” 14.7% “Just what I expected,” 4.8% “More than I expected,” and 0% “Much more than I expected.” 100% of the invited patients accepted participating in the study and assisted in their follow-ups. Pain is considered the most common cause that prompts patients to seek dental care; this was evident in this study since 58.5% of the participants reported severe pain while the rest had moderate pain. In general, spontaneous or lingering provoked pain is accepted as indicative of irreversible pulp tissue changes . HoweverThere is no doubt about the relevance of RCT; in fact, we are living through the most rapid and extensive technological evolution in endodontics with some remarkable developments in technologies including endodontic imaging, root canal preparation, disinfection, and filling . All theIn Mexico and several other countries, an RCT performed by a specialist and assisted by current technology is considered a high-cost treatment that is not covered by public healthcare services . The finSeveral studies indicated that FP might also lead to favorable outcomes in treating symptomatic teeth with irreversible pulpitis ,47,48. FTo consider the FP as an alternative to RCT, postoperative pain and the clinical and radiographic outcomes are fundamental. The treatment success in this study was assessed by combining three variables, patient satisfaction, clinical, and radiographic outcomes. A very high success rate (97.5% at 12 months considering the patient who was excluded three days after the procedure) was obtained in this study and it was consistent with the reports from previous studies evaluating the outcome of pulpotomy in mature permanent teeth ,32,47,48Patient satisfaction regarding the effect of the treatment was assessed at each evaluation. At the first examination after 24 h, 90.3% of patients reported being “very satisfied”; the percentage increased to 97.5% after seven days. This was important and influenced the great acceptance from the patients who came to request attention at the PDCC, principally because of the opportunity to avoid tooth extraction. A 100% attendance rate was achieved at all follow-up visits and after one year, this lessened to a certain point what we recognize as the main limitation of this pilot study, the reduced number of participants. For a long time, it was suggested that FP is only adequate in young and immature permanent teeth because the rich blood supply of the pulp may contribute to high success rates  comparedThe high success rate achieved in this study, which is expected if FP is performed routinely, is also related to some factors. For example, cases with apical rarefaction that could influence and reduce the success of endodontic treatment  were excAnother critical factor was the intraoperative inclusion criteria of observing bleeding from all root orifices after eliminating coronal pulp and a maximum of 10 min until the bleeding had stopped. This proposal arose after observing that this is a variable topic, as studies have used hemostasis periods ranging from 2 to 25 min ,62,63,64Concerning the quality of coronal restoration, it is another critical factor that influences the success of endodontic treatment . It can Amalgam or resin composite were the only restorative options because Mexican public healthcare services could not provide custom crowns or inlays, and patients could hardly pay for them in private practice. In addition, it is well known that many patients with temporary restoration do not permanently restore their teeth once the pain has disappeared. For that reason, it was decided to restore the teeth with amalgam in the same session, as it requires less technical skills from the operator and still has more longevity and a lesser number of secondary caries compared to resin composite restorations ; in thisOn the other hand, considering the limitations of this study; the fact of only including systemically healthy patients delimits the results to this population, and therefore it is necessary to investigate whether the excellent success rate of this proposal can also be present in patients with systemic diseases, such as diabetics, or the immunosuppressed. We also believe that the high success rate in this study was due in part to the fact that the specialist supervised all the procedures, and although he did not intervene directly, his presence could even influence the GPD to follow the workflow and respect the selection criteria strictly. This could be a limitation if FP is implemented as a routine treatment in the PDCC. From the perspective of the GPD, the plain identification of bleeding and its hemostasis in each root canal of a multicanal tooth was indicated as the only critical component during the performance of the treatment. In fact, after analyzing the case of the patient who was excluded days after the treatment, it was indicated that there was doubt regarding the bleeding of one canal, possibly because this radicular pulp was inflamed or even necrotic. Therefore, emphasis should be given to the importance of following the workflow and strictly adhering to the selection criteria during the training of the GPD. This first approach of feasibility study demonstrated an excellent success rate and patient satisfaction when a GDP performed the FP in a PDCC in Mexico. It could be suitable as an option for symptomatic irreversible pulpitis or caries pulp exposure. The multicentric feasibility study will indicate if it can be successfully replicated with the same results to definitely establish if it could be considered as a routine treatment in the PDCC. This proposal could be replicated by public healthcare services from other countries that have the same needs and limitations.


Low back pain is the leading cause of years lived with disability worldwide. Chiropractors employ different interventions to treat low back pain, including spinal manipulative therapy, although the mechanisms through which chiropractic care improves low back pain are still unclear. Clinical research and animal models suggest that spinal manipulation might modulate plasma levels of inflammatory cytokines, which have been involved in different stages of low back pain. More specifically, serum levels of Tumor Necrosis Factor-alpha (TNF-α) have been found to be elevated in patients with chronic low back pain. We aimed to investigate whether urine from chronic low back pain patients could be an appropriate medium to measure concentrations of TNF-α and to examine possible changes in its levels associated to chiropractic care.t-test. Simultaneously, pain intensity and disability were also evaluated before and after care. Paired t-tests were used to compare mean pre and post urinary concentrations of TNF-α and clinical outcomes.Urine samples were collected from 24 patients with chronic low back pain and TNF-α levels were analyzed by ELISA before and after 4–6 weeks of care compared to a reference value obtained from 5 healthy control subjects, by means of a Welch’s p < 0.001), which were significantly lower after the period of chiropractic treatment (p = 0.03). Moreover, these changes were accompanied by a significant reduction in pain and disability (both p < 0.001). However, levels of urinary TNF-α were not correlated with pain intensity nor disability.Significantly higher baseline levels of urinary TNF-α were observed in chronic low back pain patients when compared to our reference value (These results suggest that urine could be a good milieu to assess TNF-α changes, with potential clinical implications for the management of chronic low back pain. Low back pain (LBP) is a common condition that is currently considered to be the first cause of years lived with disability worldwide, impacting most adults at least once in their lifetime . LBP hasMost cases of LBP are described as being non-specific, implying that the etiology of the patient’s complaints is unknown and cannot be attributed to a single tissue or pathology . A growiin vitro production of TNF-α was found to be increased (and positively correlated to that of interleukin 1β) in CLBP when compared to healthy control and acute LBP individuals  in the pathogenesis and in possible treatment strategies of chronic LBP (CLBP) . TNF-α iividuals . Animal ividuals .in vitro production of pro-inflammatory mediators, including TNF-α  in San Lorenzo de El Escorial, Spain. All experimental procedures conformed to the standards set by the latest revision of the Declaration of Helsinki and ethical approval was granted by the Madrid College of Chiropractic Research Ethics subcommittee before starting recruitment.All participants in this study were recruited from the patient population of the Clinic upon initial evaluation by one of the investigators who supervised the patient recruitment. Any patient presenting for care with CLBP was screened for inclusion and exclusion criteria and all deemed eligible were offered to participate in the study. Patients who accepted signed specific informed consent forms for the study before entering the protocol. Patients were to be recruited with the following inclusion criteria: being between 18 and 75 years of age and a clinical presentation of chronic non-specific LBP  . PatientIn parallel, a sample of healthy volunteer participants without LBP or any other health concern was recruited. In this case, the only inclusion criterion was to be between 18 and 75 years of age, and the main exclusion criteria were the existence of any acute or chronic health condition, particularly if it could influence or modify inflammatory status. This included having experienced or having sought medical care for LBP in the last year, and having received SMT in the previous 6 months. Participants included in the control group signed an informed consent before urine sample collection.Patients participating in the study underwent a customized chiropractic care plan consisting in each encounter of a case history, physical assessment and multimodal care , the latAt the end of the treatment period, a complete physical re-evaluation of the patient was performed, including evaluation of the main outcome measures, described in the following sections. Care was purposely not modified for the sake of the study. The control group did not receive any type of treatment. The inclusion of this group aimed at defining a reference value for urinary TNF-α in a healthy population, in order to confirm that persons with CLBP have higher than normal urinary TNF-α levels. TNF-α levels are presumed to remain relatively stable, nearing zero in the absence of active or chronic inflammation . ReferenBoth patients and healthy participants provided an initial urine sample (first micturition of the morning) before any treatment was initiated. Control subjects provided a unique urine sample at the beginning of the study as the only outcome measure, since they did not receive any treatment and the levels of TNF-α do not seem to change significantly over time in the absence of active or chronic inflammation . PatientPatient-reported outcome measures (PROMs) were used to evaluate pain and disability. Both were measured at the beginning and upon completing the treatment period . Patientt-tests were used to compare the mean of the CLBP group to this reference value, both pre- and post-treatment. This adaptation of the t-test is known to be robust against type I errors  before and after exposure to chiropractic treatment. In order to assess for correlations between concentrations of TNF-α, pain intensity, disability and number of visits, Spearman’s rank correlation coefficient was calculated by using before and after treatment values and percent changes. Finally, the potential interaction of treatment variables other than SMT (exercise and medication use) was analyzed by comparing the mean variations in TNF-α levels (ΔTNF–α), NRS-11 (ΔNRS–11) and ODI scores (ΔODI) in participants following a home exercise program or using pain medication, versus participants who did not. Differences in these variables were based on pragmatic differences in the treatment approach. Due to unequal sample sizes and variances, Welch’s t-test were used for these comparisons. Values presented in the results section represent mean ± standard deviation. For all before and after comparisons, effects sizes were computed and reported by means of Cohen’s d. A p value threshold of 0.05 was considered statistically significant for all analyses.In order to detect possible differences in normalized TNF-α (TNF-α to creatinine ratio) urinary concentrations between patients with CLBP and healthy controls, the mean value was calculated from the latter and used as a reference value. Further, Welch’s I errors . UrinaryTwenty-four patients (14 men and 10 women) CLBP met the inclusion and exclusion criteria, accepted to participate in the study by providing PROMs and urine samples, and concluded the treatment period. All participants included in the study were new patients to the Clinic and had never received chiropractic care prior to the study. Four additional patients were initially recruited but after further scrutiny, 2 of them did meet one of the exclusion criteria  and another 2 did not complete the treatment period, thus, their data were excluded from the analyses. Treatment consisted of a mean of 8.4 individual visits (ranging from 3 to 13 visits), delivered during a mean of 39.4 days (ranging from 19 to 76 days). As far as the control group is concerned, 5 healthy subjects (3 men and 2 women) were recruited for the study. The mean concentration of TNF-α in urinary samples of healthy participants was found to be 0.4 ± 0.9 pg/ml, and when corrected for urinary volume, the ratio to creatinine was 0.4 ± 0.8 pg/mg see .p = 0.0006).Before initiating care, mean urinary TNF-α concentration was 7.9 ± 11.3 pg/ml and the mean ratio to creatinine was 6.0 ± 7.0 pg/mg see . These lp = 0.015).After completing the period of chiropractic care, the mean concentration of TNF-α in urine was 3.6 ± 5.5 pg/ml, and the ratio to creatinine was 2.8 ± 4.5 pg/mg. These levels were still significantly elevated when compared to our reference value (p = 0.03), Cohen’s d = 0.55. These results are illustrated in Urinary concentration of TNF-α corrected for volume was significantly lower after the period of chiropractic care compared to baseline  was noted for the treatment group, d = 2.33 . Moreoved = 1.17 .p = 0.01) and after treatment . Of interest, there was also a moderate significant correlation between the number of visits and the change in NRS-11 . However, no other variable was correlated to the number of visits . No significant correlations were observed between TNF-α urinary levels at any stage or percent changes before and after treatment with any other variables analyzed .Spearman’s rank coefficient highlighted a moderate significant correlation between NRS-11 and ODI scores before , pain intensity (p = 0.3) and disability (p = 0.8). Out of 24 patients, seven received recommendations for a home exercise program apart from SMT. Patients following and not following a home exercise program showed similar reductions in TNF-α levels (p = 0.4), pain intensity (p = 0.8) and disability (p = 0.1) , one of them was also taking Pregabalin and another one Tramadol. No significant differences were observed between patients using pain medication and those who were not, for variations before and after treatment in TNF-α levels (p = 0.1) .To the best of our knowledge, this is the first study to measure TNF-α levels in urine samples of CLBP patients. In this cohort of 24 patients with CLBP, urinary concentrations of this cytokine were significantly elevated when compared to a reference value from healthy controls. Urinary TNF-α levels were lower after chiropractic care compared with the baseline values. This was accompanied by lower levels of pain and disability after chiropractic care compared with the levels before. However, clinical variables and TNF-α levels were not correlated. While this study cannot make any causal connection between changes in TNF-α and treatment, future studies with a control group should be able to determine whether chiropractic care may relieve pain and decrease disability in patients with CLBP through modulation of the pro-inflammatory cytokine network.d = 0.55). Similarly, Wang et al. found a significant difference in the proportion of participants with elevated levels of serum TNF-α positive when comparing healthy subjects and CLBP patients before treatment  in the SMT group  function , which cd = 2.33 and 1.17 for pain and disability respectively), which could also be considered clinically significant. Indeed, pain intensity ratings showed a 68% reduction in pain intensity from baseline, largely exceeding the proposed threshold of 30% . In our cohort, medication use did not yield a significant effect on TNF-α levels or pain intensity, yet NSAIDs can alter cytokine levels, conducing to a measurement bias . FurtherTo confirm our preliminary findings would require conducting further research. It is not possible to conclude that any of the measured effects are the direct consequence of the care received, unless a second CLBP group is included that will be randomly assigned to receive a different intervention, a sham intervention or no intervention at all. Moreover, our control group for urinary TNF-α levels was small when compared to the CLBP group and only one measure was taken at the beginning of the protocol. A second measure at the end of the protocol would allow to measure and control for non-specific changes in TNF-α levels. More data is needed in order to explore the potential for urinary TNF-α and other cytokines to become biomarkers for CLBP that could be quantified in clinical practice.To our knowledge, this is the first study to suggest that urinary levels of TNF-α can be found elevated in patients with CLBP when compared to healthy individuals. The results obtained in this preliminary study suggest that a non-standardized period of chiropractic care could have a significant impact on pain and disability levels, as well as on urinary concentrations of pro-inflammatory cytokine TNF-α in CLBP patients. These potential benefits should be further investigated in a proper randomized controlled trial design, with at least one control group that will not receive chiropractic care. Therefore, results from the current study should be interpreted with caution. Further research to elucidate the mechanisms and role of different conservative interventions for CLBP is an essential upcoming step.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Madrid College of Chiropractic Research Ethics, Real Centro Universitario Escorial María Cristina. The patients/participants provided their written informed consent to participate in this study.CG-M: conceptualization, methodology, investigation, formal analysis, and writing – original draft preparation. MR-S and LL: investigation, formal analysis and manuscript revision. FC-B: investigation, resources, and manuscript revision. DN: conceptualization and writing- review and editing. LÁ-G: conceptualization, supervision, and writing- review and editing. MP: supervision, funding acquisition, and writing- review and editing. AO-DM: conceptualization, methodology, funding acquisition, supervision, writing- review, and editing and approval of final version. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.