Pre- and post-instrumentation pain was rated utilizing Visual Analog Scale (VAS) with a spectrum of 0–100 mm. The descriptive statistics and one-way ANOVA with 95% confidence intervals were used for statistical analysis. The mean VAS scores before instrumentation were consistent in all three groups. At 6, 24, 48, and 72 h, patients with root canals instrumented by SAF had the lowest post-instrumentation mean VAS score, followed by XPS. For all time intervals, the patients in the HKF group had the highest VAS score. The full-sequence SAF instrumentation resulted in less post-operative pain than the XP-endo plus protocol, while manual instrumentation with K-files resulted in the highest post-operative pain.This investigation aimed to examine the post-operative pain experienced following single-visit root canal treatment using the XP-endo shaper sequence (XPS), full-sequence self-adjusting file (SAF), and manual K-files (HKF). A randomized equivalence parallel design, double-blinded clinical study was conducted on 120 patients with symptomatic irreversible pulpitis, with or without clinical signs of apical periodontitis. Only teeth with fully formed roots and no periapical lesions were incorporated in the study. Patients were apportioned to one of three groups ( The term “post-endodontic pain” describes any uncomfortable feeling or tenderness that transpire after an endodontic treatment. The prevalence of such pain has been estimated between 25% and 40% of cases. Furthermore, regardless of pulp status or peri-radicular condition, the frequency of post-operative pain recorded in patients is approximately 50–60% .Debris expulsion from the apical foramen in the course of the biomechanical preparation of the root canal has been associated with post-operative pain . Such deIt has been observed that different file systems, which use different preparation methods, such as rotary or reciprocating files, may result in varying levels of post-operative pain. The tip diameter, file designs, taper, and preparation method all can have an effect on the pain response .When slender root canals with an annular cross-section are considered, rotating and reciprocating files may adequately clean the root canal and its walls. In the case of oval root canals, on the other hand, rotating files leave much to be desired . This coThe SAF was developed primarily to solve the issue of root canals with non-round cross-sections. It attempts to address diverse pitfalls of rotary and reciprocating files when manipulated in root canals with variable cross-sections. The SAF is a NiTi instrument, which has the shape of a hollow tube made of thin-walled lattice. When inserted into the canal, it can be squeezed from its 1.5 mm diameter to the proportions of a #20 K-file ,11. The Previously, the manufacturer instructions indicated the need to prepare a glide path for the SAF using a manual #20 K-file. This instruction recently changed to recommend motorized glide path preparation using a pre-SAF orifice shaper (#40/0.10), pre SAF 1 (#15/0.02) in cases of narrow/calcified canals, and pre SAF 2 (#20/0.04), which should allow a 1.5 mm SAF to be manually inserted to working length prior to its activation. This new sequence of instrumentation has been termed “full-sequence SAF” .During instrumentation, the newly developed XP-endo Shaper plus guidelines involves three junctures: (i) K-files (#10 and #15) are utilized to generate a glide path. Thereafter, (ii) the XP-endo Shaper and (iii) XP-endo Finisher are utilized. These two instruments are spun at 800 RPM with pecking movement patterns to reach working length .The XP-endo Shaper file (#30/0.01) consists of Max wire NiTi alloy and has a zigzag shape. The tip terminus has six cutting blades that flow smoothly to the shaft and features an inactive, bullet-like apical section. The instrument is impacted by body temperature, which enhances it to an austenitic juncture, allowing it to operate in a snake-like manner. It is first employed as a piercing instrument in the root canal, and then 15 pecks are added to the working length after the working length is established. After XP-endo Shaper instrumentation, the resultant root canal size is #30/0.04 . The semThe apical outflow of debris caused by the manufacturers’ proposed protocol for the two adaptive file systems was compared to conventional root canal instrumentation with K-files in vitro . It was The reflected randomized clinical trial adopted ethical norms including the World Medical Association Declaration of Helsinki  and the PRIRATE 2020 standards . The stuA total of 200 consecutive patients aged between 18 and 65 years were screened between 14 September 2020 and 17 March 2021 for the selection criteria. Patients diagnosed with symptomatic irreversible pulpitis with or without clinical signs of apical periodontitis, with fully formed mature roots and an absence of periapical lesion, with respect to maxillary and mandibular first molars, were included in this study. Pulp vitality was confirmed using a cold test , and an electric pulp test. A preoperative periapical radiovisiograph  was also taken for the tooth in question.Exclusion criteria included patients with non-vital teeth ; cases of previous endodontic retreatment, second and third molars, and intentional root canal treatment were also excluded. Further exclusion criteria were cases with periapical radiolucent lesion, root resorption, immature/open apex, root caries, and gross decay that were considered non-restorable as well as teeth with mobility and complex anatomy. Also excluded were patients who declined to cooperate in the study, those who had taken medication in the 12 h before the operation, such as analgesics or nonsteroidal or steroidal anti-inflammatory drugs, pregnant and breastfeeding patients, patients with any uncontrolled systemic disease, and patients younger than 18 or older than 65 years. Thus, in total, 120 patients were incorporated and randomized to three study groups.www.random.org, accessed on 25 March 2021): Group 1 = XPS, Group 2 = SAF, and Group 3 = HKF. The staff nurse enclosed the randomized order of instrumentation procedures in opaque separate envelopes, which were later opened by the operator on starting endodontic treatment. All procedures were performed by two skilled operators (endodontists). Before commencement of this trial, a standardization protocol was established by the operators. The protocol for each instrumentation system was calibrated for the operators. The operators could not be blinded, as each instrumentation system had to be implemented in its unique way. The patients and outcome assessor were blinded to the groups of the study.After being versed about the trial and providing written consent, the patients were randomly assigned to three groups using a computer-generated simple randomization method , the use of which was first explained to the patient and used for both preoperative and postoperative pain assessment. Patients with a preoperative pain level of a minimum of 50 (>50) according to the VAS were included. The randomization and allocation of participants to different groups with analysis is explained in detail in Local anesthesia   was administered. Following rubber dam application, an access opening was prepared. The full procedure was executed under a dental operating microscope . Upon exposure of the pulp chamber, the presence of hemorrhage was noticed ; only teeth showing such hemorrhage were included in this trial. Cases with no such hemorrhage were considered non-vital and were debarred from the study, and another patient was assigned. Working length was established using an electronic apex locator  and was set at 0.5 mm short of the “apex” indicator length. Cases in which no apex locator reading was possible were debarred from the evaluation and another suitable tooth/patient was assigned.The instrumentation of root canals was done at this stage using a #15 K-file effectively until reaching the working length to establish a glide path, as per the manufacturer’s directives. For repeated irrigation, pre- and post-instrumentation, a syringe with a 30-G needle  was used with 2 mL of 3% sodium hypochlorite .The XP-endo Shaper (XPS) file was then used to prepare the root canal while in its austenite form, which was induced by body temperature. The XPS file was placed into the root canal in a passive manner to the extent of resistance. Once resistance was hit, the file was then drawn out, and the endomotor  was set in motion. The file was powered at 800 rpm and 1 Ncm torque. The file was utilized with long gentle pecks 4–5 times on the way to attain the working length. Once the working length was accomplished, the file was retracted and cleaned, apical patency was verified with a 15 K-file, the root canal was flooded with 4 mL 3% sodium hypochlorite, and the file was used moreover for an additional 15 pecking strokes up to the working length with intermittent flooding of the root canals with a total of 12 mL (4 mL per 5 strokes).The root canal was flooded with 3% sodium hypochlorite, the XP-endo finisher (XPF) was retrieved from the differentiating plastic cannula, and the rubber reference stopper was specified to working length during this phase. The same endomotor (X-Smart Plus) was used to operate the file at 800 rpm and 1 Ncm. The XPF was inserted to WL, the canal was loaded with 2 mL 3% sodium hypochlorite, and the instrument was driven in the canal for 60 s. Soft 7 to 8 mm in-and-out movements to working length were employed, and subsequent to this, a final flush of 2 mL 3% sodium hypochlorite was achieved.A glide path was prepared using a torque-managed endomotor (X-Smart Plus) according to the manufacturer’s recommendations. The Pre-SAF OS (#40/0.10) was executed as an orifice shaper in the coronal 3 mm of the root canal at 600 rpm and 1.5 Ncm, supplemented by the Pre-SAF 1 (#15/0.02) and Pre-SAF 2 (#20/0.04). Both were applied with a pecking motion using 2–3 gentle movements until the working length was reached. With each instrument, the canals were irrigated with 2 mL sodium hypochlorite using a syringe and a 30-G needle (Neoendo), for a total of 6 mL. A 10 K-file was used to verify the root canal’s patency at the assertion of the glide path preparation, and subsequent to this, a final flush with 2 mL sodium hypochlorite was achieved.To test and verify the glide path, 1.5 mm SAF was manually and gently inserted into the canal up to the working length. Employing a pre-programmed EndoStation (ReDent Nova), the root canal instrumentation was accomplished for four minutes in each canal. It was used at a frequency of 5000 vibrations per minute and an amplitude of 0.4 mm. While the file reached working length, a pecking motion was implemented. With each pecking motion, the outbound component of each stroke was lengthy enough to allow the file to shift its circular location. Irrigation was achieved with 3% sodium hypochlorite, which was delivered along the hollow file by an integrated peristaltic pump (ReDent Nova). With a cumulative irrigant quantity of 16 mL, the flow rate was set at 4 mL/min.Hand instrumentation was executed by the step-back technique with stainless steel K-files. The sequence of instruments was #10/0.02, #15/0.02, #20/0.02, #25/0.02, #30/0.02, and #35/0.02 hand K-files . After initial coronal flaring with Gates-Glidden burs #2 and #3 (Mani), the canal was gradually enlarged to a final apical size of #35. Root canal preparation was brought out using an in-and-out filing motion. The preparation was completed using the step-back technique with recapitulation. Irrigation was performed between instruments using 3 mL 3% sodium hypochlorite, delivered with a syringe and needle, as in the other groups. A total of 18 mL of irrigant was used. The patency of the root canal was confirmed with a 10 K-file at the end of the preparation, followed by a final flush with 4 mL sodium hypochlorite using a syringe and needle.A cumulative of 22 mL of irrigant was used in all the groups to standardize the volume of sodium hypochlorite. Additionally, for effective smear-layer removal, all root canals were irrigated with 3 mL of 17% EDTA solution  through a syringe fitted with a 30-G needle  placed 2 mm short of the WL. This solution was activated ultrasonically  at a minimum power setting (10%), inserted into the canal 1 mm short of the WL. The canals were then finally rinsed with 10 mL of saline solution.The canals were dried by paper points following instrumentation and subsequent irrigation. Teeth were obturated using a resin-based sealer  and a gutta-percha master cone  at the first initial visit. For all groups, accessory cones were added using the lateral compaction technique. Teeth were then sealed with a sterile dry cotton pellet and hydraulic temporary restorative material . Patients were scheduled for a permanent restoration within 10–15 days .Following the endodontic treatment procedure, all patients were instructed to take analgesics (400 mg ibuprofen) at a therapeutic dose of 1 tablet every 6 h if unbearable pain occurred.The principal outcome was post-operative pain severity, appraised using a visual analogue scale (VAS) at 6, 24, 48, and 72 h. All patients were given a VAS (ranging from 0 to 100 mm) to take with them so that they could aid the outcome assessor with pain level assessment while filling out the post-operative questionnaire. The intensity of pain (primary outcome) was classified into four categories: no pain , mild pain , moderate pain , and severe pain . The scale was explained to the patients both before treatment, when assessing the preoperative pain level and again before leaving the clinic. It was done visually, verbally, and numerically to facilitate its use, and the patients were trained on how to fill out the VAS score. They were contacted by the outcome assessor by telephone at a suitable time, approximately 6 h, 24 h, 48 h, and 72 h after the treatment to record VAS scores for post-operative pain.p > 0.05). As the data were normally distributed, parametric tests were implemented. Descriptive statistics were performed to determine the mean VAS scores in all the groups at different time intervals. A paired sample t-test was used to assess the change in VAS score from pre- to post-instrumentation. One-way ANOVA with post hoc Tukey’s test was used to find a significant inter-group comparison of post-instrumentation VAS scores at different time intervals. The reliability between the two independent operators was assessed using the Cohen’s kappa, considering a statistically significant p value of less than 0.05 at 95% confidence intervals.Data obtained were entered and sorted in Microsoft Excel (2017), and statistical analysis was executed using Statistical Package for Social Sciences (SPSS) software 21.0 version. The baseline characteristics of each group  were compared. The normality of the data was checked with the Shapiro–Wilk normal distribution test  years, 30.19 (±8.256) years, and 28.88 (±5.194) years in Group 1, Group 2, and Group 3, respectively . When geThe primary outcome was evaluated using VAS score (0–100 mm) for all three groups. The descriptive statistics were performed for pre-operative and post-operative VAS score following the endodontic instrumentation using a particular file system involved. The mean pre-instrumentation VAS score was almost identical in all three groups .At 6 h post instrumentation, the mean VAS score was found to be the lowest for the SAF group (31.39 ± 7.22 mm), followed by the XPS group (41.75 ± 7.81 mm) and then with HKF (50.55 ± 4.96 mm) .Similarly, at 24 h, 48 h and 72 h post-instrumentation, the mean VAS score in the SAF group was 26.15 (±5.62), 16.17 (±6.42) and 12.57 (±2.64), respectively. For the XPS Group, it was 29.62 (±5.47), 21.3 (±3.59) and 15.82 (±2.47) and for the HKF group was 38.4 (±5.52), 31.15 (±5.17) and 21.95 (±2.70) at 24 h, 48 h and 72 h, respectively .t test, p value = 0.000) in all three groups and showed an overall lesser VAS score with passing time. The intergroup comparison was accomplished using One-way ANOVA and Post hoc Tukey’s test to determine the significant differences between the three groups. There was no significant difference in pre-operative pain between the three groups. At 6 h, there were significant differences in post-operative pain between SAF and XPS, SPS and HKF, and XPS and HKF. Similarly, there were significant differences in post-operative pain at 24 h, 48 h and 72 h . This suggested that the SAF group had the lowest mean VAS score at each time point, followed by the XPS group and then the HKF group . The medication if taken was only in the first 24 h after the treatment. Ibuprofen was used by eight patients in the manual group, four in the XPS group and three patients in SAF group (after the completion of the treatment until 24 h). The Cohen’s kappa coefficient between the two clinicians was 0.85, indicating acceptable operator reliability.There was a non-statistically significant difference in the frequency of analgesic medication intake between the three groups studied  scores for pain. In all groups, the pain decreased following treatment and continued to gradually reduce with time. Similar results of gradually diminishing pain have been noted in various studies ,22,23 asp value = 0.000). Manual instrumentation with K-files resulted in the highest post-operative discomfort. This finding is in agreement with previous studies that have reported that the post-operative pain level was higher when hand files were used compared to the use of multi-file rotary file systems of tapers ranging from 0.04–0.06. Single-file reciprocal systems were also reported to have higher post-operative pain levels than multi-file rotary file systems [In the current analysis, post-instrumentation pain was lower in the full-sequence SAF cluster at all time points compared with the other two groups  cause greater extrusion of debris and (2) result in more post-operative pain when compared to multi-file motorized file systems ,14,19. TThe shape of the tip of the file and its potential to act as a piston are different in the two motorized files used in the current study. The XP-endo Shaper’s circular directing tip may serve as a plunger, thrusting and expelling debris via the apical foramen as it glides in and out of apical portion of the canal. The tip of the SAF, on the other hand, implies a rectangular cross-section of 0.12 × 0.16 mm when adequately squeezed into the circular apical portion of the canal corresponding to a #20 k-file ,29. ThisThe XPS sequence requires periodic manual irrigation (syringe and needle) amid file execution, that is another dividing line betwixt the two file systems. The SAF technique, in contrast, allows for continuous irrigation administered into the root canal via the hollow file for the whole of the procedure. It is indeed realizable that uninterrupted irrigation, which takes debris coronally and out of the canal, benefits in avoiding debris collection, decreasing the likelihood of debris being pushed through the apical foramen . These dPrevious studies have suggested that SAF ,30 and XTo fill all of the imperfections in the root canal system, endodontic sealers should have the ideal flow properties. Insufficient flowability may limit appropriate filling, while increased flow rate may raise the possibility of extrusion. Filling material that flows past the apex may cause more pain or may contact significant anatomical landmarks . For theIt is commonly acknowledged that the success rate and post-obturation pain will depend on the operator’s high level of skill. Law and associates revealed that it was challenging to determine how clinical experience affected post-obturation discomfort . AccordiThe subjective assessment of pain is one of the primary issues in pain research. Any decision to take analgesics will therefore be based on this subjective judgement. Ibuprofen was preferred as the postoperative pain medication in this investigation because nonsteroidal anti-inflammatory drugs have been proposed as first-choice medication for postoperative pain management after endodontic procedures. Furthermore, ibuprofen has been included in several studies examining the effect of various techniques and medications on pain relief following endodontic treatment . The uptIt should be acknowledged that since comparisons were made between three processes in the current study, it was deemed inappropriate and inconsequential to make an effort to level out variables like the quantity of irrigant used, the amount of time needed, or the number of instruments used in any of the groups. Another potential limitation of the study is related to the use of various tooth types. Since discomfort in the apical region of even one root is likely to be mistaken for pain in the treated tooth, a three-rooted molar may be more likely to feel pain after treatment than a single-rooted tooth.The full sequence SAF instrumentation resulted in less post-operative pain than the XP-endo Plus protocol, while manual instrumentation with K-files resulted in the highest post-operative pain.


Individuals attempting to enter the USA from Mexico at non-authorized points along the border fence often sustain injuries requiring medical intervention. We evaluated characteristics of this patient population and their hospital care to better understand patient treatment needs. Given the high-velocity nature of these injuries, we hypothesized that higher pain scores would be associated with longer lengths of hospital stay.In this cross-sectional study, we selected records of all patients from 2013 to 2019 who received care by the Orthopaedic Surgery department following an injury sustained at the California-Baja California border. We evaluated demographics, musculoskeletal injuries, procedures, length of hospital stay (LOS), follow-up, and pain scores via retrospective chart review. We used linear regression, adjusting for age and gender, to evaluate associations between pain scores and hospital LOS. p =  0.08). However, for every surgical procedure performed, hospital LOS was increased by 5.16 ± 0.47 days (p < 0.001).Among all 168 patients, there were 248 total injuries comprised of 46% lower extremity, 15% upper extremity, 17% spine, and 4% pelvic injuries. Average age at injury was 33 ± 10, 74% were male, and 85% identified as Hispanic. Of this patient population, 68% underwent operative interventions, 26% sustained open injuries, and 21% required external fixation for initial injury stabilization. Thirteen percent were seen for follow-up after discharge. Spine (n = 42), pilon (n = 36), and calcaneus fractures (n = 25) were the three most common injury types. Average LOS for all patients was 7.8 ± 8.1 days. Pain scores were not significantly associated with LOS (Many injuries incurred by patients crossing the border were severe, requiring multiple surgical interventions and a prolonged LOS. The higher number of procedures was significantly associated with longer LOS in all operatively treated patients. Future studies are needed to determine how we can optimize care for this unique patient population and facilitate post-discharge care. The southwestern USA shares 1993 miles of border with Mexico , and December 31, 2019. There were 443 patients with “Immigration Health” insurance who were treated by healthcare providers at UC San Diego during this period. Through chart review, we determined that of these 443 patients, 168 were treated by the Orthopaedic Surgery Department and this subset of patients were included for analysis. This study was approved by the University of California, San Diego (UC San Diego), Human Research Protection Program.Demographic, injury, procedure, hospital stay, and pain data were collected for each patient via retrospective chart review. Specifically, we assessed age at the time of injury, gender , ethnicity , race , primary spoken language, injury severity score (ISS), Abbreviated Injury Scale (AIS) , number and type of injury, number and type of surgical procedures, date of admission and discharge, procedure dates, pain scores, and whether patients returned for follow-up.Procedure and injury information were collected from consult notes and operative notes. Type and total number of injuries were identified and categorized by upper extremity  lower extremity [femur and any injury distal to femur], spine , or pelvic  injuries. If there was no bony involvement, injuries were classified as soft tissue injuries. Injuries were also defined as open or closed. Procedures were defined as each surgical intervention per injury and included external fixation application, open reduction internal fixation of the fracture/dislocation, and incision and debridement of wounds/fractures.Length of hospital stay was defined and analyzed as days from admission to surgery and days from surgery to discharge. Pain scores were measured using the visual analogue scale (VAS) with scores from 1 to 10, and collected by a nurse each time vital signs were recorded, when pain medication was administered, and 30 min after intravenous pain medication or 60 min after oral pain medication was given. Pain scores were averaged over the patient’s length of stay and on postoperative day one (POD1) following surgical intervention. Additionally, the chart was reviewed for any postoperative follow-up appointments the patients attended.Descriptive analysis for this population included age, gender, ethnicity, race, language, ISS, AIS, and injury type. Patient characteristics were analyzed overall and by operative and non-operative treatment status. If patients had both operative and non-operative injuries, they were included in the operative treatment group. Patients were further subdivided and analyzed according to location of injury: upper extremity, lower extremity, spine, or pelvis. Patients were included in each category per anatomic location injured. If they had multiple injuries, they were included in the analysis for each.p < 0.05 indicated statistical significance. Analyses were adjusted for age and gender.Linear regression analysis using SPSS (version 27) was used to examine the associations of pain scores, number of procedures, and number of injuries with length of stay where We identified 168 patients assigned “Immigration Health” insurance who sustained a total of 248 musculoskeletal injuries. Characteristics for all patients as well as for patients stratified by operative and non-operative care can be found in Table Table Table Table p = 0.08) or analysis accounting for age and gender (p = 0.11). This is consistent with similar analysis in patients with upper and lower extremity injuries. There was also no association between number of injuries and LOS in any group analyzed. There was a significant association between the number of procedures and LOS in all operatively treated patients (p < 0.001). Adjusted for age and gender, for each procedure performed, patients had an additional 5.16 days longer stay in the hospital (p < 0.001). This association was also significant in the upper and lower extremity sub-analyses and in patients with operative upper extremity injuries. Specifically, adjusted for age and gender, these patients had 7.71 days longer stay in the hospital per procedure performed (p = 0.01).As shown in Table From 2013 to 2019, patients who received care from Orthopaedic Surgery at our institution experienced a variety of musculoskeletal injuries while attempting to cross non-authorized points along the border from Mexico into the USA. Most of the patients were young, Hispanic men. However, the multitude of different primary languages spoken demonstrates diversity within this population. Lower extremity injuries were the most common injury type resulting in the highest number of procedures with highest average pain scores and longest lengths of stay. Thirty-five percent of patients experienced multiple injuries, and approximately one-fifth of all injuries were severe enough to require initial stabilization with external fixators. We found no association between either average pain scores throughout hospitalization or POD1 pain scores with hospital LOS. Instead, we found that the number of operative procedures was significantly associated with a longer hospital length of stay in all operatively treated patients. Despite Orthopaedic Surgery being involved in the care of all patients, only 13% of all patients were seen in clinic for follow-up.Among our patient population, lower extremity injuries were the most common injury type (46%) which is consistent with prior studies conducted at the Texas–Mexico border, and lower extremity injuries occurred 58–60.7% of the time  detention centers, which afforded them the opportunity to return for an examination (US_Immigration_and_Customs_Enforcement Our investigation spans a 7-year period (2013–2019) prior to the change in border wall height that occurred in 2020, so it does not include injuries associated with the higher wall. It includes, however, periods of policy changes, e.g., zero tolerance and metering, affecting individuals seeking asylum at the southwest USA border. Liepert and colleagues observed a surge in injuries and injured persons, even with a taller border wall, in response to Title 42, a COVID-19-related policy stating migrants can be expelled by Customs and Border Protection without asylum screening  video interpreters, there could have been miscommunication in the self-report of pain. Further, we could not account for any other motivations to underreport pain or avoid analgesia, which could have led to lower reported pain scores. Pain reporting and pain management in this patient population warrant further study. Comparisons were made between LOS and pain scores which showed no association; however, this is limited by a small sample size which could have missed a potential association.Strengths of this study include the investigation of care and pain in this patient population, which has not been explored previously. Given that the data were analyzed via direct chart review, we did not rely on procedure coding measures to define patient injuries and we were able to include non-operative injuries in our analysis. Thus, we were able to better capture more subtle aspects of musculoskeletal injuries in this cohort.In conclusion, this patient population consists of mostly young, Hispanic, men who sustained severe, mostly lower extremity injuries requiring a lengthy hospital stay, and frequently, multiple procedures. Longer hospital lengths of stay were significantly associated with higher number of procedures, but not with reported pain scores. Postoperative follow-up care is limited in this patient population and warrants additional research to determine best practices for successful outcomes once discharged.


The introduction of molecular diagnosis into routine clinical practice has substantially improved the diagnosis and management of allergic patients by allowing clinicians to precisely identify the allergenic molecule responsible for immunoglobulin E (IgE)‐mediated allergies. However, it can be challenging to accurately interpret the results of molecular assays, partly due to the limited evidence base. In this context, a panel of experts with extensive experience in interpreting in vitro measures of total and serum specific IgE reviewed the available scientific evidence. After this review, the panel selected a series of representative case studies to demonstrate how determination of specific and total IgE values and the relationship between them  can add value to the diagnostic process by more precisely defining the patient’s sensitization profile. Finally, the experts developed a series of recommendations on the clinical application of ratio analysis to optimize and complement the classical approach to allergy diagnosis. By the year 2025, more than 50% of the European population is expected to manifest some type of allergy.The most important in vitro diagnostic tests are total serum immunoglobulin E (tIgE) and serum specific IgE (sIgE) against the whole extract (we‐sIgE) or allergen molecules (c‐sIgE). IgE antibody levels are compared to the International Reference Preparation for Human IgE, a standard curve developed by the World Health Organization.Ratio 1 (we‐sIgE/tIgE): the analysis of the whole extract serum‐specific IgE/total IgE ratioRatio 2 (c‐sIgE/we‐sIgE): It allows to determine the extent to which a given allergenic component is responsible for sensitization to a whole extract. Ratio 2 is useful in two clinical scenarios: (1) sIgE positive for the whole extract but negative for all major components; this finding suggests that the patient may be sensitized to an untested or unknown component; (2) sIgE negative for the whole extract but positive for a specific component; this finding is commonly observed when a given component  is underrepresented in the whole extract.For these purposes, two ratios have been proposed:For both ratios, the same technique must be used to determine the different IgE values.1.1Allergy diagnosis begins with a detailed medical history and physical examination, the findings of which may strengthen the diagnostic suspicion. In addition to the usual tests  and specific complementary tests for allergy, skin prick tests (SPT) and – less frequently – intradermal tests  are performed. The test results can help with the diagnostic orientation (aetiology) and thus guide selecting the most appropriate in vitro sIgE tests. In some cases, such as allergies to certain drugs or Hymenoptera venom, other tests – such as the basophil activation test (BAT) or measurement of serum tryptase levels – can provide valuable diagnostic information. The final diagnostic step is controlled in vivo challenge testing, the reference standard in the diagnosis of allergy.Although the diagnostic procedure described above applies to most cases, the diagnostic process should be adapted to each case. For example, in cases of anaphylaxis, it is essential to determine the underlying allergy and rule out mast cell activation syndrome (MCAS) by determining serum tryptase levels at baseline and during the acute phase. Other complementary tests may also be necessary. Serum‐sIgE tests are designed to detect and measure the concentration of IgE to a specific allergen.1.2Der p 2 have demonstrated that several different factors  influence the effector cell response.It is essential to collect as much data as possible to establish an accurate diagnosis. However, the individual test results should be considered in the overall context of the entire battery of tests,Another challenge is the difficulty of differentiating between cross‐reactivity and genuine sensitization. In this case, molecular diagnosis, together with the comparative assessment of IgE values, can help determine if sensitization is due to cross‐reactivity and its clinical significance.The present expert consensus statement aimed to compile the available evidence on two ratios – we‐sIgE/tIgE (ratio 1) and c‐sIgE/we‐sIgE (ratio 2) – to elaborate a series of recommendations about the application of these ratios and to discuss their utility in daily clinical practice. These two relations can provide valuable information to optimize the diagnosis of allergic patients, complementing standard diagnostic procedures. In addition, through a series of case studies involving common clinical scenarios, we illustrate how ratio analysis can improve diagnostic accuracy.2In June 2019, an expert panel of clinicians ‐the authors of this manuscript‐ with extensive experience in the management and diagnosis of allergy met to define the scope of this work (see Supporting information). Next, these professionals performed a non‐exhaustive, systematic bibliographic search in PubMed to identify relevant articles published in English and Spanish in the last 10 years. The following search terms were used: (1) specific IgE; (2) total IgE; (3) whole extract; (4) IgE ratio; (5) allergy; (6) in vitro IgE. To identify other relevant studies, the authors reviewed the references of the articles identified through the PubMed search and finally contributed with articles of interest not identified through the aforementioned search process.n = 28) through a two‐round Delphi technique. The external group of specialists was asked to indicate their level of agreement with the proposed recommendations on a four‐point Likert scale ranging from 1 (strongly disagree) to 4 (strongly agree). Recommendations supported by ≥ 70% of respondents (score of 3 and 4) were approved. One recommendation failed to reach the 70% threshold in the first round and was reviewed by the expert panel and modified as necessary based on the suggestions made by the external group specialists. The modified recommendation was re‐evaluated in a second round following the same criteria and process as described above. The approval rate in the first round was 85% (6/7) and 100% (1/1) in the second round.The authors then selected a series of representative case studies to illustrate how ratio analysis can enhance the diagnostic process. After analysis and synthesis of the evidence, the experts drafted and validated a series of recommendations, which were externally validated by an external group of specialists in allergy management and molecular diagnosis  and, potentially, school and work productivity.In cases of severe respiratory disease, the phenotype should be determined during the diagnostic process. This is important because the phenotype can condition the treatment approach  and the prognostic implications.3.1Alternaria alternata or dust mite extracts, di Lorenzo et al. showed that a ratio 1 (we‐sIgE/tIgE) value > 16.2 in monosensitized patients was associated with a better response to AIT. This finding demonstrates the value of assessing this ratio compared to sIgE or tIgE values alone.In some cases, the primary sensitizing allergen molecule may not be included in the AIT for dust mites; consequently, it is essential to determine the main sensitizing component to select the most appropriate AIT composition.Alternaria alternata. In these cases, it is essential to demonstrate sensitization to Alt a 1 and ensure the relevance of that sensitization by evaluating the allergen‐sIgE (Alt a 1) to we‐sIgE  ratio.In clinical practice, many patients test positive for various house dust mite species.Der p 2 and Der f 2 was significantly associated with a favourable clinical response to AIT. Several other factors were significant predictors, including tIgE, tobacco smoke exposure, and family history of atopy.Other ratios have also proven valuable as predictors of response to AIT. Li et al. found that the c‐sIgE/tIgE ratio for A case study is described in Table 3.2A study carried out in patients with cat allergy who received AIT showed that patients with a ratio 1 percentage < 1% were more likely to have lower reactivity on the BAT than those with a ratio 1 > 3%.To identify the main sensitizer, the ratio 2 (c‐sIgE/we‐sIgE) can be assessed. In the case of dog allergy, if the analysis of ratio to Can f 5/whole dog dander extract reveals that the dog sensitization is mainly due to Can f 5, the patients should be advised to avoid the exposure to male dogs, since this protein is originated from the prostate gland.Table 3.3Although the risk factors for asthma exacerbations are not fully understood,As with other allergens, to obtain a broader and more accurate picture of the patient's sensitization profile, it is important to determine the tIgE and the we‐sIgE and perform component‐resolved diagnosis (CRD). A study of monosensitized patients (olive or grass pollen) treated with AIT found that ratio 1 (we‐sIgE/tIgE) values > 16.2 were associated with a better response to treatment. Moreover, analysis of the sIgE to tIgE ratio improved the diagnostic sensitivity and specificity when compared to the same assays considered separately.One studyTable 4In some series, Hymenoptera sting can account for up to 42.8% of all cases of anaphylaxis.Apis, Vespula, and Polistes, even though they have not been stung by all these insects. These findings can be explained by the presence of CCDs, which lead to cross‐reactivity, as well as other components that may also be cross‐reactive.Apis mellifera venom confirmed that ratio 1 for honeybee venom was directly and proportionally correlated with the severity of the reaction. In other words, the ratio was significantly higher in patients with extensive localized reactions vs. those with limited localized reactions and in patients with systemic reactions vs. extensive localized reactions.In this type of allergy, some patients have positive intradermal test and we‐sIgE against Apis mellifera venom that are up to 1000 times higher than the sIgE levels observed in allergic beekeepers; moreover, the number of stings and/or years working as a beekeeper was positively correlated with sIgG4 levels.To our knowledge, the diagnostic utility of ratio 2 (c‐sIgE/we‐sIgE) for Hymenoptera venom allergies has not been studied. However, we recommend evaluating this ratio given that the absence of sIgE against allergen components is not a sufficient condition to exclude sensitization to Hymenoptera venom Table . SeveralA case study is described in Table 5Food allergies affect individuals of all ages. The foods responsible for these allergies differ according to each stage and natural history of the pathology.Ratio 1 (we‐sIgE/tIgE) is useful to assess sensitization to a given food.Ratio 2 (c‐sIgE/we‐sIgE) is useful in foods containing allergens that are underrepresented in the whole extract. For example, Tri a 14 and Tri a 19 are found only in small amounts in whole‐allergen wheat extracts.A/L and a c‐sIgE/tIgE ratio >2.12% were predictive of meat allergy, with a 95% probability.n = 207) reached similar conclusions, finding that serum specific Cor a 14 and Ara h 2 IgE levels were better predictors of allergy severity  than component‐specific to tIgE ratios.Other ratios may also provide valuable data in patients with food allergies. Machinena et al. showed that a tIgE/c‐sIgE ratio ≥3.75 for cow milk protein was a reliable predictor of tolerance, thus potentially eliminating the need for avoidance diets.One study found that the c‐sIgE/sIgG4 ratio for egg components could predict tolerance in allergic patients,Table 6The most recent EAACI guidelinesDiagnosis of food‐related anaphylaxis or Hymenoptera venom allergy should follow the same procedures described in the previous sections. In addition, baseline and acute serum tryptase levels should be determined since patients with severe anaphylaxis (grade IV) have significantly higher levels of tryptase than those with mild to moderate anaphylaxis.A study assessed 171 patients with a history of immediate reactions to β‐lactams compared to 122 healthy controls, finding that a β‐lactam‐sIgE  to tIgE ratio ≥ 0.002 had a positive predictive value of 92.5%, thus enabling the identification of genuinely reactive patients, even among individuals with high tIgE levels (>200 kU/L).As mentioned above , ratio 2 can be useful in patients with anaphylactic reactions due to poorly represented components in the total extracts, such as Tri a 14 and Pru p 7.A case study is provided in Table 7Molecular diagnostics represents a major advance in the management of allergic patients. In routine clinical practice, the optimal use of these diagnostic tools may not always be clear due to the lack of validated protocols, insufficient clinical experience with these tools, and because the test results frequently need to be interpreted indirectly. However, most professionals involved in allergy diagnosis are highly motivated and interested in learning how to apply these techniques to improve the diagnosis and treatment of their patients.Like all techniques, molecular diagnosis has limitations. One significant limitation is that even though numerous different allergens can provoke an allergic reaction, only a limited number can be tested. Another limitation is the diagnostic complexity associated with the molecular diagnosis. While the capacity to detect specific allergenic components is probably the most notable innovation in this field in recent years, and a major improvement in diagnostic efficiency, it has also greatly increased the complexity of the diagnostic process. Moreover, the presence of a given allergenic molecule does not always explain the patient’s whole sensitization profile; in fact, in many cases, the sensitization profile and clinical expression of the allergy are not correlated.In the context described above, it is clear that novel evidence‐based tools are needed to overcome the limitations associated with molecular diagnosis. For all these reasons, we believe that ratio analysis is an essential tool to identify the allergenic components that indeed underlie the clinical manifestations of an allergic reaction. This implies the need to use a two‐pronged approach to diagnosis . This approach would significantly improve diagnostic accuracy and positively impact QoL. Despite the emergence and continuous growth of molecular diagnostics, it is still important to assess we‐sIgE reactivity because molecular findings lose value if not analysed in the context of sensitization to the whole extract and tIgE antibody levels.Expert‐based consensus statements, such as the present document, can be particularly useful when the existing evidence base is limited. Such documents fill a critical knowledge gap, thus helping to improve health care services.It is important to emphasise that no defined cut‐off points have been established for these ratios; that is, there are no clear numerical values to unequivocally indicate that a given whole‐allergen extract, or its components are the main cause of the allergic reaction. Although cut‐off thresholds are not always necessary because the evaluation of the individual test results (sIgE and tIgE) and the relationship between these values (ratios), together with the patient’s clinical history provides important information, future studies to establish cut‐off values would improve diagnostic accuracy.Ratio analysis offers the potential to improve both the diagnosis and management of allergic patients. The clinical applicability of ratios has been supported by the 28 allergy international experts who participated in the Delphi method. With this work we would like to provide allergists with a series of validated recommendations to encourage them to use ratios as a complementary diagnostic tool.Although much progress has been made in recent years, more studies are needed to understand better how to interpret the relationship between sIgE and sIgG4 levels to manage allergic diseases. This is the only way to fully exploit these measurements to determine if they can be used as biomarkers to facilitate allergy diagnosis and treatment.The authors have received consulting fees and financial support from Thermo Fisher Scientific to attend workshops related to the preparation of this article.Olga Luengo Sánchez: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal, Mariona Pascal: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal, C. Moreno: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal, Ignacio Davila: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal, Ana Isabel Tabar: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal, Joan Bartra: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal, Moisés Labrador Horrillo: Conceptualization; Equal, Data curation; Equal, Formal analysis; Equal, Investigation; Equal, Methodology; Equal, Writing‐original draft; Equal, Writing‐review & editing; Equal.Supporting Information S1Click here for additional data file.


Osteoporotic vertebral compression fractures are treated conservatively or in selected cases with percutaneous vertebroplasty (PV). The purpose of this retrospective analysis is to determine predictive factors for a high visual analogue scale (VAS) pain score after conservative, sham or PV and is based on previously published randomized trials.The VERTOS II compared conservative versus PV, and VERTOS IV compared sham versus PV treatment. The conservative group received pain medication. The sham and PV group received subcutaneous lidocaine/bupivacaine. In addition, the PV group received cementation, which was simulated in the sham group. Nineteen different predictors of high (≥ 5) versus low (< 5) VAS pain score at 12 months were investigated.χ2(1) = 15.26, p < 0.0001, OR = 2.57, 95% CI = 1.59 to 4.15). In the subgroup analysis, we detected five predictors for the risk of high pain scores (VAS ≥ 5 after 12 months follow-up), namely: female, baseline VAS > 8, long-term baseline pain, mild/severe Genant and new fractures.20.7% of patients in the PV group demonstrated a VAS ≥ 5 at the 12-month, compared to 40.1% in the conservative or sham group, with a significant difference (Statistically significant more patients had a high pain score at 12 months in the sham and conservative group when compared with the PV group. Five predictors were identified for sustained high local back pain, regardless of the received treatment. Patients with moderate fracture deformity were less likely to have high pain scores at 12 months if they received PV than if they had sham or conservative therapy.The online version contains supplementary material available at 10.1007/s00270-022-03170-7. Osteoporotic vertebral compression fractures (OVCFs) are commonly encountered in the elderly population. In Europe, the incidence of a new OVCF is estimated at age 75–79 years as 2.9% per year in women and 1.4% per year in men , 4.In 2010, VERTOS II  demonstrated that PV resulted in pain reduction, more rapid pain relief, and improved quality of life . VERTOS To examine this observation, we combined the databases from the VERTOS II and VERTOS IV trial, providing data from patients who were treated conservatively, with sham, or with a PV intervention.Both trials specifically looked at (sub)acute OVCFs. The inclusion criteria, the study design and PV technique were the same in both trials. The aim of this article is to determine predictive factors for a high VAS pain score after conservative, sham or PV based on the results of these two RCTs.Both VERTOS II and VERTOS IV were multi-centre randomized trials: one an open-label and the other a blinded trial. Both trials were approved by the Institutional review board as open-label and multi-centre randomized trials performed in community hospitals in the Netherlands and Belgium. The studies obtained ethics approval of all participating hospitals. All patients gave written informed consent before taking part in one of the trials. Both trials were registered at ClinicalTrials.com (VERTOS II NCT00232466 and VERTOS IV NCT01200277). The detailed description of the trials methods can be found online. , 6Inclusion criteria were the same in both trials: age 50 years or more, 1–3 vertebral OVCFs with 15% or more loss of vertebral body height, bone oedema on MRI, T5-L5 focal back pain at the level of fracture, score of 5 or higher on a VAS, and decreased bone density (T-score less than -1). The fracture duration at time of provisional enrolment extended to 6-weeks in VERTOS II and 9-weeks in VERTOS IV, due to slow recruitment.In both trials, all patients were referred by the general practitioner for spinal radiography. Patients with radiographic evidence of fracture were administered a questionnaire. Those patients found to have a crush fracture and reporting pain ≥ 5/10 and pain duration less than 6 weeks (VERTOS II) and 9 weeks (VERTOS IV) were provisionally enrolled pending physician consult and MRI to confirm eligibility. PV occurred later—with a mean delay of 9 days in VERTOS II and a median of 11 days (IQR 7–18 days) in the VERTOS IV trial.Both trials had similar exclusion criteria and included outpatients only.In the VERTOS II trial, the participants were randomly allocated to conservative treatment or PV, i.e. subcutaneous and periosteal infiltration with 1% lidocaine (lignocaine) followed by injection of PMMA under fluoroscopy guidance. In the VERTOS IV trial the participants received local infiltration with 1% lidocaine (lignocaine) and 0.25% bupivacaine, bone biopsy needles against the pedicles and then PV or a sham procedure. The PV procedure consisted of injection of PMMA under fluoroscopic guidance.In VERTOS II trial, 202 patients were recruited and analysed between 2005 and 2008 and randomly allocated to PV (101 patients) or conservative treatment (101 patients). In VERTOS IV trial, 180 patients were recruited and analysed between 2011 and 2014 and randomly allocated to PV (90 patients) or sham procedure 86 patients). The flow diagrams explaining the enrolments and outcomes from the both trials are shown and can be assessed in the original articles. [ patientsIn both trials, VAS ≥ 5 was the main inclusion criterion and considered as a high pain score. Therefore, in the current paper the identical threshold for a high pain score was used, but at 12-monthfollow-up. The analysed groups are: the conservative group (from VERTOS II), the sham group lidocaine/ bupivacaine (from VERTOS IV group) and the PV group (from VERTOS II and IV). The assessed risk factors considered to play a possible role in sustained pain (VAS ≥ 5) at 12-month follow-up were the baseline characteristics: age, gender, days of pain (defined as number of days between pain onset and treatment), a high VAS at baseline ≥ 8), number of fractures at baseline, number of treated fractures, level of treated fractures , type of fracture assessed according to the Genant classification , T-score, number P-values smaller than 0.05 were considered statistically significant. In the subgroup analyses, a Bonferroni correction was applied to adjust the significance level for multiple testing.After merging the VERTOS II and IV datasets, baseline characteristics were calculated separately for the PV, sham and conservative groups. Frequencies and percentages were calculated for categorical baseline characteristics, means and standard deviations for normally distributed characteristics, and the median and interquartile range for non-normally distributed characteristics. The percentage of patients with VAS scores of 5 or higher at the 12-month follow-up were determined for each of the three treatments. A Chi-square test was used to test the null hypothesis that these percentages were independent of treatment. For each treatment and study, logistic regression analyses were used to assess what factors predict patients having a VAS score of 5 or higher at the 12-month follow-up. The resulting estimates were shown in forest plots using the R package metafor (version 2.0). The logistic regression analyses were conducted using the free software R, and all other analyses were conducted using IBM SPSS (version 25). Odds ratios and 95% confidence intervals were computed as effect size in the logistic regression analyses. The baseline characteristics were similar in the three groups, respectively, PV patients from the VERTOS II and VERTOS IV, conservative-treated patients from the VERTOS II and sham patients from the VERTOS IV trial. Both VERTOS II and IV included patients with VAS ≥ 5 at baseline. The average VAS score at baseline was 7.74 (SD = 1.51). The range of fracture duration extended up to 92 days in the VERTOS II trial according to trial manuscript. The median duration of back pain at the time of PV in VERTOS IV was reported as 43 days, which indicates that half the patients had acute fractures (< 6/52 weeks) and half had had sub-acute fractures (6–12/52 weeks) at the time of PV.The difference in baseline characteristics, in terms of back pain duration in days before treatment, between conservative treatment versus sham and PV, can be explained by the fact that conservative treatment was the only treatment in which analgesics were given immediately following randomization during outpatient visits, whereas PV took place a few days later. Randomization in VERTOS IV took place in the angio room a few days after outpatient visit Table .Table 1Sχ2(1) = 0.003, p = 0.960). In VERTOS II, 21.3% of the patients in the PV group showed a VAS ≥ 5, as opposed to 39.4% of the patients who received conservative treatment, with a significant difference (χ2(1) = 7.28, p = 0.007, OR = 2.40, 95% CI = 1.26 to 4.57). Similarly, in VERTOS IV, 18% of the patients in the PV group showed a VAS ≥ 5 at the 12-month follow-up, compared to 41.1% of the patients in the sham group, with a significant difference (χ2(1) = 8.08, p = 0.005, OR = 2.79, 95% CI = 1.36 to 5.73). When combining the data of VERTOS II and IV, 20.7% of the patients in the PV group reported a VAS ≥ 5 at the 12-month follow-up, compared to 40.1% of the patients receiving no PV treatment (conservative or sham), with a significant difference (χ2(1) = 15.26, p < 0.0001, OR = 2.57, 95% CI = 1.59 to 4.15).Table Figure Patients in the PV groups of the VERTOS II and VERTOS IV trials demonstrated significantly less often VAS ≥ 5 at 12 months follow-up compared to the sham and conservative groups. We analysed the characteristics of patients having a VAS ≥ 5 at 12 months.Figure Five characteristics were predictive of VAS ≥ 5 at the 12-month follow-up. Females demonstrated higher odds than males of having a VAS ≥ 5 at the 12-month follow-up . Patients who were in pain > 3 weeks before the intervention showed a higher odds of having a VAS ≥ 5 at 12-month follow-up than patients who experienced pain for a shorter time duration . Patients with a baseline VAS > 8 showed higher odds of having a VAS ≥ 5 at 12-month follow-up compared to those with lower baseline VAS scores . Patients with new OVCFs during the follow-up period showed a higher odds on VAS ≥ 5 at 12 months than patients without new fractures during follow-up . These four effects were pooled across all treatments, because the difference between treatments in these effects did not reach statistical significance.In each dataset and treatment, patients of older age appeared to have a higher odds of having a VAS ≥ 5 at 12-month follow-up. However, these results failed to reach statistical significance . Supplemental Figure S1 presents the odds ratio effects for predictors that were not significantly associated with a VAS ≥ 5 at 12-month follow-up.Z = 2.45, p = 0.014).Patients with a moderate vertebral body fracture showed a lower odds on having a VAS ≥ 5 after PV, than patients with no moderate fracture classification . This effect was not found for either of the control treatments , and the difference between these effects in the two conditions was statistically significant (The results of VERTOS II and VERTOS IV showed that at 12-monthfollow-up patients from the conservative and sham group had more often high pain scores (VAS ≥ 5) than patients who underwent PV. There are four predictors found for the risk of high pain scores (VAS ≥ 5) after 12-monthfollow-up, namely female, baseline VAS > 8, pain > 3 weeks before procedure and new OVCFs. When these four predictors hold true, there is increased risk of high VAS after 12-month follow-up, with no significant pain outcome difference between conservative therapy, sham or PV (no policy difference). However, moderate vertebral body height loss was significantly more predictive of low pain scores at 12 months after PV than after other treatments.OVCFs can cause severe back pain and kyphosis with a negative impact on morbidity and quality of life. The retrospective and sham trials conducted until present showed contradictory results , 6, 9–11In daily practice, clinicians taking care of OVCF patients are faced with the dilemma of whether to treat an individual patient with augmentation or conservative therapy. This paper analysed data and identified factors from two previous published RCTs (VERTOS II and VERTOS IV) that can influence the clinical outcome (pain relief) at 12 months. This may help to identify the patients who most likely benefit from PV.From the combined results of the two VERTOS trials, we found that significantly more patients in the sham and conservative group had a high pain score (VAS ≥ 5) at 12-month follow-up than those in the PV group (40.1 vs 20.7%). When investigating the demographic and clinical characteristics, we identified 5 predictors for sustained high local back pain: female gender, patients with a baseline VAS > 8, pain duration > 3 weeks until treatment, mild or severe fracture classification and new fractures during follow-up. Female gender is more predisposed to osteoporosis and subsequent new fractures. Severe fractures causing kyphosis, heal slower and probably are much more painful. These factors probably combine and result in a high pain score after 12 months. Neither the number of treated levels nor the fracture level were significant predictors of high VAS scores at 12 months.only after PV and not after conservative or sham intervention. The practical implication is that patients with moderate (sub)acute OVCFs are particularly suited to PV and not conservative treatment or sham intervention. Although no definitive recommendation can be made for an individual patient based on these findings, the combined results of these two trials provide additional perspective and further nuance to the VERTOS IV conclusion.Odds ratio effect sizes of two dichotomous predictors can be interpreted inversely . TherefoIn contrast to VERTOS II, VERTOS IV on average did not indicate any added value of PV regarding pain relief compared to sham. However, it may be important to identify individual characteristics of patients for whom PV does result in significant pain reduction. Indeed, we must realize that there seems to be a distinct subgroup of patients with (sub)acute OVCFs and certain baseline characteristics predictive of successful pain relief after PV as opposed to the general conclusion of VERTOS IV.The VAPOUR trial showed clinical success for PV over placebo for patients meeting the inclusion criteria severe pain (VAS ≥ 7) at baseline, OVCFs of less than 6 weeks duration and OVCFs at the thoracolumbar spinal segment as predictors for clinical success . AlthougAlong with the worldwide discussion on PV, this paper discusses the selection of patients for PV. VERTOS IV was the 3rd negative placebo trial of PV in contrast to the VAPOUR trial , which wThese results are based on a large number of subgroup analyses. Based on chance alone, some significant differences are expected. However, we adjusted our significance level for multiple comparisons, minimizing the risk on false positive conclusions. Because of the exploratory nature of these analyses, the findings should be considered as new hypotheses to test in future research. These results are limited to the cohort studied in VERTOS II and VERTOS IV trials. Hospitalized patients were not included, so the findings may not apply to them. It is not clear how many patients had fracture duration < 3 weeks at the time of PV, so findings may not apply to patients with early fractures.The combined treatment results of (sub)acute OVCFs from the VERTOS II and VERTOS IV trials demonstrated that statistically significant more patients had a high pain score at 12 months in the sham and conservative group when compared with the PV group. Five predictors were identified for sustained high local back pain, regardless of the received treatment: new fractures during follow-up, female gender, patients with a baseline VAS score higher than 8, mild or severe fracture classification and more days of pain until treatment. Patients with moderate fracture deformity  were less likely to have high pain scores at 12 months if they received PV than if they had sham or conservative therapy.Supplementary file1 (PDF 12 KB)Below is the link to the electronic supplementary material.


Combination therapies delivered remotely via the internet or mobile devices are increasingly being used to improve and promote the self-management of chronic conditions. However, little is known regarding the long-term effects of these interventions.The aim of this study is to evaluate the effectiveness of a multimodal intervention program that measures associated variables such as catastrophizing, pain acceptance, and quality of life using a mobile device in people with chronic pain in an outpatient setting.web-based psychosocial therapy-type program of activities through a smartphone for 6 weeks. The control group only had access to the Find out more section of the app, which contained audiovisual material for pain management based on a self-help approach. The primary outcome was catastrophizing measured using the Pain Catastrophizing Scale (PCS). Secondary outcomes were pain acceptance measured using the Chronic Pain Acceptance Questionnaire and health-related quality of life measured using the EuroQol Visual Analogue Scale. Assessments were conducted at baseline (T1), after treatment (T2), and at the 3-month follow-up (T3). The variations between the different phases were assessed using the percentage change rescaled with log base 2. The Cohen d was calculated based on the results of the linear mixed model. The investigators of the study who evaluated the results were not involved in patient recruitment and were blinded to the group assignment.A randomized controlled clinical trial was performed using parallel treatment groups. A total of 209 patients with chronic musculoskeletal pain were randomly assigned to one of the two study arms. The intervention group received a standard P<.001) and in helplessness , rumination , acceptance , and quality of life , although no significant changes were found for magnification  and satisfaction with health . Three months after treatment, significant differences were observed in the intervention group for the outcome variable of catastrophizing  and the PCS subscales of helplessness , rumination , and magnification .Positive effects were found in the intervention group (T2–T1) in catastrophizing between the baseline and posttreatment phases (The results of our study suggest that app-based mobile multidimensional treatments for adults with chronic pain improve catastrophizing, quality of life, and psychological flexibility immediately after treatment and that the effects are maintained for the primary outcome of catastrophizing for at least 3 months following treatment. Moreover, they promote self-management and can be used to complement face-to-face pain treatments.ClinicalTrials.gov NCT04509154; https://clinicaltrials.gov/ct2/show/NCT04509154 Pain is estimated to be among the top 10 conditions with the highest burden on health expenditure and health care resources and has a significant impact on patients’ quality of life . Pain isThere is a large body of research on multidisciplinary treatment programs for adults with chronic pain, including reviews of the clinical evidence, effectiveness of pain treatments, and cost-effectiveness of chronic pain programs in outpatient settings ,8. A sysAs chronic pain is a complex and multidimensional problem, it cannot be managed using medical therapies alone. Therefore, multidimensional treatments involving psychological therapies such as acceptance and commitment therapy (ACT), mindfulness, physical exercise, and health assets could play an important role in mitigating catastrophizing, improving pain acceptance, and reducing the use of psychotropic medications ,12-14.The available evidence supports the efficacy of several interventions for the self-management of chronic pain in outpatients. Some of the key components of these interventions are the administration of chronic pain medications according to the type of pain and patient comorbidities ,10,14,15In addition to face-to-face interventions for chronic conditions, interventions are increasingly being delivered via mobile apps or the internet as these technologies have become an essential part of people’s daily lives and are always on call. In a systematic review of the use of information and communication technologies (ICTs) in chronically ill patients, 15.4% of the studies found that ICTs had a positive impact on patient empowerment or self-management, 14% showed an improvement in physical conditions and quality of life, and 5.1% reported greater self-efficacy for managing disease -32. In tThe aim of this study was to evaluate the effectiveness of a multimodal intervention program using a web-based smartphone or mobile device app. The app assesses pain perception by means of associated variables such as catastrophizing, pain acceptance, and quality of life in people with chronic pain.The study was based on the hypothesis that participants assigned to the intervention group will exhibit less catastrophizing and emotional distress, more acceptance of pain, and improved ability to perform activities of daily living according to self-management values. Moreover, they will experience a better quality of life and fewer symptoms, pain intensity, anxiety, and depression. These outcomes will be measured after completion of the intervention period and at the 3-month follow-up and compared with a control group in line with the recommended outcomes in chronic pain research .A randomized controlled clinical trial was performed using parallel treatment groups ,37. BlocTo develop the contents of the multimodal treatment for the mobile device app, a systematic literature review was carried out in a first phase following the Scottish Intercollegiate Guideline Network.As part of a broader research program aimed at improving pain management, we first located articles that described the basic concepts of multi-professional treatments for chronic pain, provided recommendations, and included published evidence for the selected topics of interest. The purpose was to identify the characteristics of pharmacological and nonpharmacological interventions for people affected by chronic pain in different settings by means of a bibliographic search and reading of the literature, a synthesis of the results, and an assessment of the evidence. In the second part of our study, a participatory approach was used to prioritize self-management recommendations for chronic pain selected from the reviewed literature. Specifically, we designed a multimodal intervention protocol combining physical exercise, psychoeducational therapy, health assets, and pharmacological treatment that was delivered using a mobile device. The effectiveness of the intervention was subsequently evaluated by means of a clinical trial .The interventions delivered in the mobile app include ACT and mindfulness exercises to promote greater pain acceptance, reduce the aversive component associated with pain, and help patients dispassionately recognize and observe both pain and related thoughts and emotions. Another group of activities aims to raise awareness of an individual’s own values through a series of activities to recover a meaningful life project ,23,39,40Our research team developed an app called NO+Dolor (NO+Pain) that contains an Android or iOS user interface. The app includes links to several multimedia resources (mainly audios and videos) and was designed based on game dynamics (gamification) to improve users’ concentration, attention, and motivation. Indications on how to use the app and correctly perform the measures are provided in the instructions section of the app. Regarding the technical characteristics of the app, the information technology part required the design of a relational database implemented using MySQL Community Server 5.6. On the server side, a Java 1.8 communications application programming interface was implemented with representational state transfer architecture between the patients’ mobile apps and the database using a client-server pattern. On the client side, hybrid mobile apps were implemented for Android and iOS operating systems. Apache Cordova 9.0 and jQuery Mobile 1.4.5 frameworks were integrated into the app, and HTML5 and CSS3 technologies were used for the presentation layer .The study population comprised residents of municipalities belonging to the Cordoba South Health District of the Andalusian Health Service, Spain, who were registered in the health service user database. Patients were recruited from each of the district’s 11 primary care centers by two collaborators: a nurse and a physician with experience in the follow-up of patients with chronic pain.α error of .05 and a β error of .2  in a 2-tailed test and estimating 15% loss to follow-up, 296 participants were required to detect a statistically significant difference between 2 means at 3 points in our outcome variable with an estimated SD of 12.The sample was drawn from a database using Diraya electronic medical records. The inclusion criterion was being attended by primary care physicians and nurses. The database search was carried out on June 30, 2019, and identified 297 patients diagnosed with chronic musculoskeletal pain, of which 205 (69%) were women and 92 (31%) were men. Accepting an All participants were under pharmacological treatment for chronic musculoskeletal pain  as previously indicated by their primary care physician and were asked to sign an informed consent form. The inclusion and exclusion criteria for the participants in the study are presented in Inclusion criteriaPatients aged ≥18 years with pain in any locationPain with a duration of ≥3 monthsPain with an intensity of ≥4 on the Visual Numerical ScalePresenting one of the following characteristics: continuous pain or intermittent pain ≥5 days a weekAble to use a smartphoneNot participating in another research projectExclusion criteriaCancer-related or postsurgical pain, patients with palliative care, and pediatric populationPatients with acute pain (duration <3 months)History of brain injuryInability to complete the study forms because of mental disability or language barrierThis study was approved by the Cordoba Research Ethics Committee of the Andalusian Public Health System . Informed consent was approved by the Cordoba Research Ethics Committee and completed by the participants. This study is registered at ClinicalTrials.gov (NCT04509154).Block randomization with a block size of 4 was used. The only stratification criterion was the reference health center of the patients. An automated recruitment form hosted on the REDCap  platform of the Maimonides Biomedical Research Institute of Cordoba was used to randomize the patients by simply clicking a button. The data were transferred and recorded in an electronic notebook using the Data Entry Manager system. The statistician (Ipek Guler Caamaño and Juan Antonio Marín Sanz), principal investigator (YM-M), and coinvestigators  of the study who evaluated the results were not involved in patient recruitment and were blinded to the group assignment. A total of 22 recruiters from the 11 primary care health centers of the Cordoba South Health District recruited the patients in 2019. They were also responsible for randomizing the patients (by clicking a button on the automated recruitment form) and were not blinded.Find out more section of the app, which contained audiovisual materials for pain management from a self-help approach, such as information on the origin of chronic pain and advice for pain treatment and relaxation exercises.All patients received a written invitation from their primary care physician or nurse to participate in the study. Two 8-hour face-to-face sessions were held at their reference health center led by a nurse and a primary care physician with experience in the follow-up of patients with chronic pain. At the group meeting, patients who agreed to participate voluntarily in the study were informed that they would receive instructions by email on how to download the mobile app with the treatment contents. The patients were also informed that, if they were selected to participate in the intervention group, the treatment would last from 6 to 8 weeks. The control group would only have access to the The intervention group received the treatment via their smartphones for a period of 6 weeks after completing both face-to-face sessions. Pain intensity was measured daily on an 11-point numerical rating scale when the participants accessed the app.To assess the treatments, self-reported questionnaires were sent to the participants by email and collected at three time points: upon admission to the program (T1), at week 6 of the intervention (T2), and at 3 months after the intervention (T3). The participants completed all 3 questionnaires at home and returned them by email.Consultation section with a contact form where the participants could send any questions or comments. The form was then sent by email to the researchers so that they could respond to the inquiries.The intervention consisted of the implementation of a program of standard, interactive psychosocial therapy activities. The pain management app enables automatic monitoring, skill training, social support, education, goal setting, and achievement of four components: psychological wellness, exercise, pharmacological treatment, and health assets. Each week, the participants received 3 activities for each of the aforementioned components via the NO+Dolor app until completing the 6 weeks of treatment. All the activities were designed to be performed weekly except for the walking challenge, which was performed daily. The first time the participants completed an activity, they were awarded a star. The participants could perform the proposed activity as many times as they liked, but no more rewards were given until the following week. The more activities they completed, the more stars they were awarded, and the higher the percentage of goals reached by the patients each week . The appα=.79), convergent validity and classificatory value, test-retest reliability (intraclass correlation coefficient=0.84), and sensitivity to change in size (effect size>2).The Spanish adaptation ,48 of thnever true) to 6 . The maximum possible score on the CPAQ is 120, with higher scores indicating higher pain acceptance. Initial studies on the acceptance and adaptation of the CPAQ have shown adequate internal consistency and expected correlations with measures of physical functioning and psychological distress. Subsequent studies have evaluated the content and dimensions of the questionnaire and identified two factors: activity engagement (Cronbach α=.82) and pain willingness (Cronbach α=.78) [The Spanish adaptation  of the Ch α=.78) .worst imaginable health state and best imaginable health state, respectively). A third component of the EQ-5D is the social values index obtained for each health state generated by the instrument, which describes respondents’ health state according to five dimensions: mobility, self-management, usual activities, pain or discomfort, and anxiety or depression. Regarding the instrument’s psychometric properties, the test-retest reliability ranges from 0.86 to 0.90, and numerous studies have demonstrated its validity and sensitivity to change [We would like you to indicate on this scale how good or bad your health state is today. Pain intensity was measured using an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The format of this rating was established in the latest Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations on core outcome measures for chronic pain clinical trials [The Spanish adaptation of the EQ-5D  was usedo change . We incll trials .U test, and the Pearson chi-square test was used to compare the qualitative variables and the Fisher-Freeman-Halton descriptive analysis. In addition, the variations between the different phases were assessed using the percentage change rescaled with log base 2. The association between the quantitative variables was determined using bivariate (Pearson linear correlation coefficient or Spearman ρ) and partial correlations controlling for the variables age and sex.A descriptive analysis was performed for the quantitative variables with mean and SD and for the qualitative variables with recounts (n) and proportions (%). Goodness-of-fit to a normal distribution was determined using the Shapiro-Wilk test, and homogeneity of variance was assessed using the Levene test. The quantitative variables of the treatment and control groups were compared using the Mann-Whitney d was calculated based on the results of the linear mixed model. The R project nlme package  was used to estimate all the regression models. The established level of statistical significance was P<.05.A linear mixed effects model ,55 was sA total of 297 participants  were initially invited to participate in the study. Of these 297 participants, 1 (0.3%) was excluded for not meeting the inclusion criteria, 67 (22.6%) were excluded because they did not attend the meeting, and 20 (6.7%) were excluded because they declined to participate. A total of 209 participants were randomized into 1 of the 2 study arms. After randomization, 2.4% (5/209) of the participants were excluded because they declined to participate, dropped out before the intervention, or did not know how to use the technologies. In the intervention group, 15% (15/98) of the patients did not complete the intervention. The analysis was performed on patients who completed all 3 questionnaires at baseline, upon completion of the intervention, and 3 months after the intervention .P=.20), CPAQ (P=.07), and EQ-5D (P=.26) at the beginning of the intervention (baseline), in which participants in both groups did not differ in pain catastrophizing, quality of life, or pain acceptance. No differences were found in sociodemographic variables or use of medications  and the catastrophizing subscales of helplessness , rumination , and magnification . However, at 3 months of follow-up, the mean remained lower , although it was not statistically significant (Immediately following the treatment (T2), statistically significant improvements were observed in the intervention group for catastrophizing  and in the subscales of helplessness  and rumination , although no significant changes were found for magnification . Significant results were also found for catastrophizing at the 3-month follow-up with respect to the baseline  and the subscales of helplessness , rumination , and magnification , all of which improved 3 months after completing treatment  in catastrophizing between the baseline and posttreatment phases (reatment .P=.001), thus indicating a significant decrease in PCS scores over time in the intervention group compared with the control group  or at 3 months following the intervention .With regard to pain acceptance (CPAQ), no significant differences were found between the 2 groups after treatment , although these differences were not maintained after the 3-month follow-up .In terms of quality of life (EQ-5D), the intervention group showed significant improvement at the end of treatment  at the end of treatment, and these differences were maintained over time  registered in the daily records showed significant improvements in the intervention group compared with the control group  and quality of life , but the positive effect on overall satisfaction with health was not maintained .Regarding variations between the different phases, a positive effect was observed immediately following the intervention (T2–T1) in both acceptance , EQ-5D , or overall health state . The exact test results showed that a significantly higher proportion of participants who received the multimodal treatment improved in the mobility subscale (P=.04) and activities of daily living such as going to work, leisure time, and family activities (P=.045) immediately after receiving treatment. These improvements were not significant 3 months after the intervention.We performed a small randomized controlled clinical trial with a sample of mostly women . Randomization of both the sociodemographic characteristics of the study population and the study variables was homogeneous.The results of the study clearly show that the main variable, catastrophizing, had a significant positive effect on the intervention group compared with the control group after the intervention and at the 3-month follow-up. This could be due to changes in cognition or maladaptive behavior that modified erroneous beliefs and decreased catastrophic thoughts. It should be noted that previous research has considered the beneficial effect of multimodal treatments in decreasing catastrophizing and fear. Thus, these results are in accordance with the more pronounced effect found in the intervention group .These results are also in line with the findings of studies on the effects of monotherapies using ACT , mindfulP=.001) reported a better quality of life (P=.002). This is in agreement with other studies that have shown that pain acceptance is a good predictor of a better quality of life [The analysis showed that the intervention group improved in both perceived quality of life and pain acceptance after treatment. This finding indicates that patients who accept pain better exhibit greater psychological flexibility , less psychological distress, and less disability. Moreover, we found that patients with higher pain acceptance . This may suggest that a combination of these interventions promotes skills that result in behavior changes, at least in the medium term.A priori, this relationship could be explained by the additive effect of the combined components of psychoeducational therapy, exercise, pharmacological treatment, and health assets. It may also be explained by the fear avoidance model in that exercise contributes to the reconceptualization of pain and reduces catastrophic thinking and the threat value of pain related to functional limitations . SimilarPhysical activity likely helped the participants in our study learn about activities such as daily walking and low-intensity stretching to improve their physical, mental, and emotional well-being as well as acquire new habits and find alternatives to improve their quality of life . These rACT and mindfulness were also a treatment goal in our study . In the Pain catastrophizing has been identified as a psychosocial factor that predicts adaptation to chronic pain and may contribute to its development and chronicity. In this regard, several studies ,67 have However, another explanation for the effect of our multimodal treatment may be related to patient-treatment matching. Specifically, broader-spectrum multimodal treatments have a greater likelihood of matching at least one treatment component to a patient’s strength or deficit .The overall health state self-reported by the intervention group improved after the intervention, although this effect was not maintained over time. This may be explained by the fact that the participants perceived an improvement in their health state when performing the proposed weekly activities during the treatment period because of the effort and time invested, which is known as the Hawthorne phenomenon . MotivatMoreover, the descriptive analysis of the EQ-5D dimensions showed improvement in at least three of the five core outcome domains  compared with the control group. This finding corroborates the influence of attitudes and beliefs that may affect the development of passive coping mechanisms such as rest and medication versus the ability to adopt active strategies such as physical activity and pain acceptance .This study has several strengths. First, we developed a multimodal program involving a variety of therapeutic activities that could be standardized and used in the future for other patients with chronic pain. An encouraging finding in this line was that the benefits of the treatment were largely maintained at follow-up, which may suggest that these interventions lead to the acquisition of skills that result in behavior change, at least in the medium term. Second, ICTs were used in combination with pharmacological and nonpharmacological therapeutic treatments in the outpatient setting to evaluate their impact on pain catastrophizing, pain acceptance, and quality of life. Third, the fact that the patients did the programmed activities in their natural environment is likely to promote self-efficacy, thus supporting the importance of the self-management component in interventions of this type .One of the most important limitations of our study was the low response rate of the self-reported questionnaires sent via email. It should also be noted that the sample size was small. This may have affected the outcomes of the intervention and could explain the significant differences found between the groups. However, we cannot rule out the beneficial effect of the treatment on catastrophizing in the intervention group as a good prognosis of the disease and that, in the long term, these interventions  are part of multi-professional treatments to achieve the desired effects. Nevertheless, as we used a multimodal therapy, we cannot really know the effect of each individual intervention on the outcomes, and more studies will be needed to determine the effects of specific interventions in patients with chronic pain. Therefore, caution must be exercised when extrapolating our findings to the general population.With regard to treatment adherence ,71, we cAccording to our results and the available evidence, pharmacological treatments are most effective when they are part of an overall multidisciplinary pain management plan that also incorporates psychological, physical, and preventive components ,72-74. CA large number of studies have been conducted on ICT-based interventions to promote self-management in people with chronic pain -77, and In future research, more attention should also be paid to the participants’ gender as this could have affected our findings. It is well-known that gender is strongly related to access to care and treatment response and that, although many patients who experience pain are women, many stigmas are associated with pain in men. Therefore, it is important that we gain a better understanding of the role of gender in health care access as well as gender biases in diagnoses, patient-professional interactions, and treatment.Further lines of research could improve the efficacy of multimodal chronic pain interventions based on new technologies, such as the refinement of treatments, the identification of moderating factors that might influence psychosocial variables, and their association with treatment adherence. To evaluate which groups of patients are more competent to self-manage a technology-based multimodal intervention would have been ideal. In the same vein, it is also worth mentioning that, in our study, we did not specifically assess satisfaction in relation to the use of technologies, and this could be a promising line for future research.In future research, it might be interesting to analyze data not included in this study, such as mobile sensor data using accelerometers, gyrometers, and other sensors to monitor engagement and assess the timing of the activities.The results of our study suggest that multidimensional treatments for adults with chronic pain improve catastrophizing, quality of life, and psychological flexibility immediately after treatment and that the effects are maintained for the primary outcome of catastrophizing for at least 3 months following treatment. This study has also shown that nonpharmacological treatments that include physical and psychoeducational therapy to promote active participation work well in combination with pharmacological strategies and that such interventions improve self-reliance in patients with chronic pain and help them cope constructively with pain.The NO+Dolor app we have developed uses gamification to teach patients distraction methods and divert their attention away from pain as well as mindfulness techniques to improve pain acceptance. It also provides patients with a well-paced program of exercises and information on the proper use of medications to avoid side effects and helps them identify health assets to engage in pleasurable activities or find the resources they need. Moreover, the app-based mobile interventions we have presented here are flexible and self-directed, promote self-management in patients with chronic pain, and can be used to complement face-to-face pain treatments.Preventive interventions for people with chronic pain designed from a salutogenic approach, are essential to promote well-being and prevent further decline in health throughout life.