Intervertebral disc pathology is the most common identifiable cause of chronic lower back pain (CLBP). There are limited conservative alternatives to treat discogenic axial CLBP. Back Rx is a mobile application (app) developed to treat patients with this condition, following the Back Rx exercise program, assisted by a virtual coach.Patients 18 to 65 years of age, with axial CLBP (more than 3 months), and evidence of lumbar disc pathology by magnetic resonance imaging (MRI) were enrolled to the study. Patients’ symptomatology was prospectively evaluated at baseline and after 3 months of using the Back Rx app. The main outcome of the study was back pain evaluated using the visual analog scale (VAS) for pain. Secondary outcomes were the patient's functionality, the weekly pain medication intake, the patients’ adherence to the app, and the patients´ satisfaction rate.P = 0.016). Patients showed a significant decrease in the number of pain medications taken during a week (P = 0.001). Overall compliance with the app was 52%, and 65% of the patients rated the overall experience as good or excellent.Seventy-five patients with CLBP were enrolled in the study. All patients had a statistically significant improvement from baseline to final follow-up in the average VAS scores, and the functionality evaluations. Average VAS scores decreased from 5.17 ± 2.1 at baseline to 3.8 ± 2.6 at final follow-up .The online version contains supplementary material available at 10.1186/s12891-022-05883-9. Chronic low back pain (CLBP), defined as low back pain for > 3 months, is acknowledged as the most common cause of disability worldwide , 2. PatiCurrent treatment guidelines recommend starting with conservative measures to treat patients with CLBP . While sBack Rx app was created to treat discogenic axial CLBP following the Back Rx rehabilitation program. This program was developed in 2004 and has showed great success in preventing and treating patients suffering from this condition , 19. It This prospective clinical trial was conducted at a single institution . Patients from a Physical Medicine and Rehabilitation private practice  were enrolled if they had all the following inclusion criteria: 18 to 65 years of age, axial symptoms of CLBP (> 3 months of duration), low back pain exacerbated by sitting or with lumbar flexion, evidence of lumbar intervertebral disc pathology  on magnetic resonance imaging (MRI), computer literate, and owned a smartphone (iPhone models 5S and later or Android models 2.3 or later). Exclusion criteria included: concurrent pathology that may contribute to the patient’s axial low back symptoms , severe lumbar disc degeneration before beginning the Back Rx exercise program, any peripheral neurological symptom attributed to the intervertebral disc pathology, history of lumbar spine surgery, or history of previous spine trauma. Patients were followed-up for 3 months after starting to use the Back Rx app. The last patient evaluation was performed in September 2016.The study was performed according to Good Clinical Practice guidelines and principles of the Declaration of Helsinki , 21. It Eligible patients were enrolled in a mHealth-based 3-month physical exercise program. Physical exercise has been consistently recommended as one of the first treatment options for patients with CLBP . PatientPatients were instructed to continue their regular pain medications as needed including non-steroidal anti-inflammatory drugs (NSAIDS), dietary supplements, and opiate derivates.The main outcome of the study was back pain evaluated using the visual analog scale (VAS) for pain. Secondary outcomes were the patient's functionality, the weekly pain medication intake, the patients’ adherence to the app, and the patients´satisfaction rate.We evaluated patients’ pain using the VAS for back pain  . PatientYADL is an image-based survey that evaluates a patient’s functional status using images of everyday activities taken from the Western Ontario and McMaster Universities Arthritis Index and Boston Activity Measure for Post-Acute Care , 26. PatMedications of Daily Living is a visual app log used to evaluate “what” and “how many” medications the patient ingested in the last 24 h. A previous study explains both YADL and Medications of Daily Living in more detail .Patients were required to perform the exercises at least three times per week to be considered “active”. At the end of each instructional video, patients confirmed they had watched the whole video and performed the exercises by answering some questions. If patients remained active for the whole 12 weeks, they were considered “compliant”. A patient satisfaction questionnaire was performed at the end of the program.Adverse events related to using the Back Rx app were evaluated throughout the whole follow-up. Patients were instructed to record adverse events they experienced while following the exercise program. In the case a patient presented a severe adverse event (life threatening) or an adverse event that was limiting their daily life, they were instructed to contact the principal investigator right away and stop using the Back Rx app.P values < 0.05 were considered statistically significant. Statistical Analysis was performed using SPSS software version 26 (IBM).All continuous data with a normal distribution were expressed in terms of mean ± SD; the categorical data were expressed as frequencies and percentages. Data with non-normal distribution were expressed in terms of median and variance. Shapiro–Wilk test was performed to assess the normality of continuous variables. All data with normal distribution were compared using the Student t-test for continuous variables and chi-square for categorical variables. Nonparametric tests were used to compare data with non-normal distribution. Pearson's correlation analysis was performed, P = 0.016)   . Overall adherence with the app was 52% (39/75), with 65% (25/39) of the patients rating the overall experience with the program as good or excellent. No adverse events were reported throughout the follow-up.A total of 75 patients with axial discogenic CLBP were enrolled in the study, 11 of which dropped out due to technical problems using the app. Twenty-five patients discontinued using the app before finishing the 3-moth program. A total of 39 patients completed the program and were included in the final analysis. Patients who discontinued using the app had statistically significantly lower body mass index (BMI) compared to patients who completed the follow-up Table , 3 and 416) Fig. , ODI scoThis prospective pilot study evaluating Back Rx as a mHealth instrument for patients with discogenic CLBP showed patients appeared to have significantly less back pain after 3 months of using the app, compared to their baseline pain, according to the VAS for back pain. Patients' functionality significantly improved, and the average amount of pain medications taken daily decreased to half of the baseline medications taken daily. Patients went from having a “moderate disability” according to the average ODI at baseline, to “minimal disability” after 3 months of using the Back Rx app . OverallStudies evaluating exercise programs for CLBP have suggested exercise is effective in reducing and preventing pain, as well as improving function , 9. A reAs mentioned earlier, several mobile apps are being developed addressing chronic musculoskeletal pain, with most apps offering guided exercise programs. , 31–33 APatients’ adherence to exercise programs determines how successful the outcomes are, with patients adhering more to the programs usually obtaining better results . AlthougOur study results show that the Back Rx app can potentially be an effective mHealth tool delivering the Back Rx program to patients with discogenic CLBP and axial symptoms but needs further improvements. Being a more affordable alternative than surgical or minimally invasive procedures, the Back Rx app could help reduce costs related to health care use and productivity loss, as well as avoiding unnecessary risks related to more invasive procedures . By decrA number of limitations need to be noted regarding the present study. First of all, there was no control group to compare with, making it difficult to evaluate the effectiveness of the app. Therefore, a future placebo-controlled or randomized clinical trial is needed. A second limitation is that only 52% of the patients enrolled were analyzed at the final follow-up. This can be due to could be possibly due to a selection bias. Eleven patients of patients dropped out due to technical issues, and 25 patients did not finish the exercise program. However, the latter 25 patients had a lower baseline BMI and may have showed positive outcomes early in the program explaining why they decided to suspend using the app . As suggIn conclusion, the Back Rx app showed improvements related to decrease pain and increase function in patients with discogenic axial CLBP compared to their baseline status. Further measures are needed to increase patients' adherence with the app and the Back Rx program. This app may be an effective conservative alternative to managing patients with CLBP, offering no risks or major economic implications.Additional file 1. The back rx exercises. The Back Rx program was developed to increase flexibility, strength, and endurance with the objective of improving low back pain. It combines physical therapy and rehabilitation, yoga, and Pilates, taking the benefits of all three.


The composition of venom extracts, cross‐reactive carbohydrate determinants (CCD) and the component‐resolved diagnostics (CRD) are important fields of investigation. IgE‐reactivity to CCD complicates the interpretation of IgE to Hymenoptera venoms, especially in patients with multiple‐positivity. We analyzed the clinical importance of CRD and CCD‐inhibition for selection of allergens for venom immunotherapy (VIT).In 71 patients, we measured specific IgE (sIgE) to honeybee venom (HBV), wasp venom (WV), hornet venom (HV), CCD, and recombinant allergens: phospholipase A2 (rApi m 1), hyaluronidase (rApi m 2), icarapin (rApi m 10), antigen 5 (rVes v 5), and phospholipase A1 (Immunoblot). In 29/71 HBV/WV/HV/CCD‐positive patients CCD‐inhibition was performed. According to CRD and CCD‐inhibition, we identified true sensitization and defined groups of multiple‐positive patients who needed CCD‐inhibition before starting VIT.p < 0.001). CCD‐inhibition was helpful in HBV/WV/HV/CCD‐positive patients who were negative to all tested recombinant honeybee allergens. Persistence of HBV‐positivity after CCD‐inhibition requires CRD to other honeybee recombinant allergens.sIgE‐rApi m 1, sIgE‐rApi m 2, and sIgE‐rApi m 10 were detected in 65.7%, 68.4%, and 58%, respectively. In HBV allergic patients, CRD sensitivity was 86.8%. In WV allergic patients, sensitivity of sIgE‐rVes v 5 was 94%. True multiple‐sensitization was found in 44.8% of HBV/WV/HV/CCD‐positive patients after CCD‐inhibition. Patients with multiple venom‐ and CCD‐positivity had more frequent severe allergic reactions (CRD, using a profile of five most important recombinant allergens and CCD, has a high sensitivity for the diagnosis of venom allergy, especially in patients positive to several venom extracts. CRD and CCD‐inhibition are helpful to reveal the clinically relevant, true sensitization and improve the selection of venoms for long‐lasting VIT. Protein‐based and carbohydrate determinants‐based cross‐reactivity are the most frequent causes of multiple‐positivity.Hymenoptera venoms are known to cause life‐threatening and fatal immunoglobulin E (IgE)‐mediated anaphylactic reactions. About 50%–60% of patients with Hymenoptera venom allergy (HVA) have specific IgE (sIgE) reactivity to both insect–species, honeybee , composed of α‐1,3‐fucosylated in vitro diagnostics of HVA.Hymenoptera proteins involved in cross‐reactivity are hyaluronidases (Api m 2 and Ves v 2) and dipeptidyl‐peptidases (Api m 5 and Ves v 3) from honeybee and wasp, respectively.In our previous study, we showed that CCD‐sIgE were more frequently found in honeybee allergic patients.The variability of test systems in allergy diagnostics is due to a lack of international standards for allergens and antibodies. This often leads to different test results and complicates their comparability.This study aimed to analyze the diagnostic importance of CRD for simultaneous determination of five most important recombinant allergens and CCD‐inhibition in patients with HVA. According to the reliable history of insect sting allergy, and the sIgE‐test we intended to identify criteria for true sensitization and to define groups of multiple‐positive patients who needed CCD‐inhibition before starting long‐term VIT.22.1This retrospective, single‐center study included 71 Hymenoptera allergic patients: 46 male (64.8%) and 25 female (35.2%)  with sIgE ≥0.35 kUA/L who have been followed‐up as outpatients or in‐patients from November 2019 to January 2022, at the Clinic of Allergy and Immunology, University Clinical Center of Serbia in Belgrade. A blood sample for analysis was taken from all patients who agreed to participate in the study signing the informed consent. The study has been approved by the Ethics Committee of the Medical Faculty, University of Belgrade, and number 1550/V‐8.Patients who had a documented history of a reliable culprit insect that caused SAR were included in the study. We classified our patients in two groups: CCD‐sIgE positive 29/71) and CCD‐sIgE negative (42/71). Severity of SAR to Hymenoptera stings were classified according to Mueller ranging from I to IV degree (Table  and CCD‐2.2Serum sIgE‐levels to honeybee venom (HBV), wasp venom (WV), hornet venom (HV), and recombinant allergens: rApi m 1, rApi m 2, icarapin (rApi m 10) from HBV, rVes v 5, phospholipase A1 (rVes v 1) from WV, and CCD were measured by Immunoblot . Serum samples of 29/71 multiple‐positive patients were tested in the EUROLINE assay using the anti‐CCD Absorbent (Euroimmun). The absorbent (CCD‐inhibitor) for eliminating CCD‐sIgE was composed of glycoprotein bromelain extracted from pineapple. Serum samples were incubated with anti‐CCD absorbent for 60 min at room temperature according to the manufacturer's instructions. The sera were retested using the same insect venoms profile, as previously mentioned.The cut‐off value for positive sIgE‐test results was 0.35 kUA/L. The sIgE‐reactivity was categorized quantitatively into six classes: Class 1 (≥0.35 to <0.70 kUA/L), Class 2 (≥0.70 to <3.50 kUA/L), Class 3 (≥3.50 to <17.50 kUA/L), Class 4 (≥17.50 to <50.00 kUA/L), Class 5 (≥50.00 to <100.00 kUA/L), and Class 6 (≥100.00 kUA/L).2.3t‐test were used to compare two matched samples. According to a history of insect sting allergy, we calculated sensitivity using the formula: Sensitivity = true‐positive/true‐positive + false‐negative ×  100%.Obtained data were analyzed using IBM SPSS Statistics software for Windows . Mean quantitative variables were used and frequency of qualitative variables were also calculated. Nonparametric Chi‐square and Fisher exact tests were used to evaluate the relationship between variables. The Wilcoxon signed‐rank test and 3A comparison of demographic characteristics of CCD‐sIgE negative 42/71) and CCD‐sIgE positive patients (29/71) is shown in Table  and CCD‐p < 0.001). No significant differences were found in the frequency of severe SAR between female and male patients.The majority of patients (55/71) had severe SAR (III and IV grades of SAR) (77.5%) (p < 0. 001).In the CCD‐sIgE positive group, more patients had severe SAR to Hymenoptera sting 27/29 (93%) than mild SAR 2/29 (6.9%)  patients showed multiple‐positivity, while 30 42.3%) showed single‐positivity: 13 to HBV extract, 15 to WV extract, and 2 to HV extract. Only two (2.8%) patients with a history of SAR after a wasp stings did not show sIgE‐reactivity to venom extracts (Table .3% showeThe majority of patients (65/71) experienced SAR after one insect sting. In all single‐positive patients, a history of insect sting allergy agreed with the finding of sIgE to the corresponding venom extract. Among patients with multiple‐positivity, 19/39 had SAR to the honeybee, 11/39 to wasp, 3/39 to hornet, while 6/39 had two separate SAR to the honeybee and wasp or honeybee and hornet stings.p < 0.001).Among the wasp allergic patients, 31/33 (94%) patients had sIgE‐reactivity to rVes v 5, while 6/31 (19.4%) had sIgE‐reactivity to rVes v 5 and rVes v 1  of them had sIgE‐reactivity to rVes v 5 and rVes v 1. There were no wasp or hornet allergic patients who had an isolated sIgE‐reactivity to rVes v 1  honeybee allergic patients presented HBV‐positivity and all 33 patients had sIgE‐reactivity to at least one tested recombinant honeybee allergen. By analyzing HBV‐positive sera, 13/38 (31.6%) were sIgE‐reactive to all tested recombinant honeybee allergens, 25 (65.7%) to rApi m 1, 26 (68.4%) to rApi m 2, and 22 (57.9%) to rApi m 10 . Seven of 71 (9.9%) patients were negative for all tested recombinant allergens  multiple‐positive patients and in none of the 30 single‐positive patients  after CCD‐inhibition.In the first group of selected patients (7/29) with a history of SAR to honeybee and wasp/hornet stings (except for one patient who experienced SAR due to wasp sting), we found a true multiple‐positivity and a significant decrease of HV‐positivity (The second group (4/29) of patients with a history of SAR due to wasp/hornet sting had sIgE‐reactivity to rApi m 2 and rVes v 5, before and after CCD‐inhibition.p < 0.01) and HV‐positivity (p < 0.05) after CCD‐inhibition. We showed that CCD‐inhibition significantly increased sensitivity for HBV‐single‐positivity from 0% to 77%.In the third group of selected patients (9/29) with a history of SAR to honeybee sting, IgE‐testing confirmed a honeybee allergy due to sIgE‐reactivity to the majority of tested recombinant honeybee allergens and loss of WV‐positivity (In the fourth group of selected patients (3/29) with a history of SAR to honeybee sting, there was no sIgE‐reactivity to all tested recombinant allergens. After CCD‐inhibition, in 2/3 patients we found sIgE‐reactivity to rApi m 1 or rApi m 2.The fifth group of selected patients (6/29) with a history of SAR to wasp/hornet stings, showed initial sIgE‐reactivity only to rVes v 5. After CCD‐inhibition, 2/6 patients showed sIgE‐reactivity to rApi m 1 and rApi m 10 or rApi m 2, in addition to sIgE‐reactivity to rVes v 5.p < 0.01). 22/29 patients retained HBV/WV‐ or HBV/WV/HV‐positivity, but a significant decrease was found in the mean concentration of sIgE to WV and HV extracts  from HBV, and hyaluronidases  from HBV and WV, respectively,α‐1,3‐Linked fucose residue on the p < 0.001). Although, we could not rule out the possibility that patients with mild SAR were less frequently present in our group, it has been previously shown that glycosylation can contribute to epitope availability, immunoreactivity, and enzymatic function of native allergens.Our HBV/WV/HV/CCD‐positive patients (27/29) had more often severe SAR  and significantly interfere with the detection of clinically relevant IgE‐sensitization to protein epitopes.CCD‐sIgE have been reported to be responsible for more than 50% of double‐sensitizations to HBV and WV.in vitro diagnosis of allergy indicates the importance of CCD‐inhibition because it eliminates false‐positive results.In most countries, the accepted clinical standards recommend skin‐testing as the initial method.We demonstrated that CCD‐inhibition should not be performed in all CCD‐sIgE‐positive patients. Based on CRD and CCD‐inhibition, we found the agreement between the results of the IgE‐testing and the history of insect sting allergy.The decision process for VIT is very important for the efficiency of the therapy, and in most cases treatment with only one venom appears to be sufficient. Among the HBV/WV/HV/CCD‐positive patients with wasp/hornet allergy, 5/29 patients after CCD‐inhibition showed sIgE‐reactivity to rApi m 2 and rVes v 5. Although, Api m 2 shows a high percentage of homology with Ves v 2,Interestingly, the sensitivity of HBV‐single‐positivity was significantly increased after CCD‐inhibition from 0% to 77% in our third group of HBV/WV/HV/CCD‐positive honeybee allergic patients. In this group of patients CCD‐inhibition can replace expensive CRD.We demonstrated that CCD‐inhibition is especially helpful in the subgroup of HBV/WV/HV/CCD‐positive patients who were negative for all tested recombinant allergens and in the subgroup of HBV/WV/HV/CCD/rVes v 5‐positive patients. In these patients, HBV‐positivity persisted after CCD‐inhibition. Therefore, these patients require an extended CRD to other recombinant honeybee allergens. Also, the number of patients with sIgE‐reactivity to recombinant honeybee allergens increased after CCD‐inhibition.Having in mind that sIgE‐sensitization can be found incidentally in a patient without a clinical history of SAR, the possibility of an allergic reaction to a future insect sting cannot be completely excluded. Due to the possibility of an adverse effects on a future sting, and according to the latest VIT guidelines of the European Academy of Allergy and Clinical Immunology (EAACI), it is not wrong to perform VIT with two venoms in patients with true double‐positivity according to results of CRD and CCD‐inhibition.In this context, the newly detected sIgE‐reactivity to recombinant honeybee allergens in our four venom‐allergic patients after CCD‐inhibition was very important. It is already known, that sIgE‐levels do not correlate with the severity of the allergic reaction.p < 0.05), and a significant decrease of sIgE‐levels to rVes v 5 (p < 0.01) after CCD‐inhibition in HBV/WV/HV/CCD‐positive patients. The exact reasons for changes of sIgE‐levels to recombinant allergens after CCD‐inhibition are not entirely clear. In fact, this finding may be caused by different structure of native HBV and WV allergens and by difficulties in obtaining purified recombinant allergens. Unfortunately, the recombinant proteins can be modified by posttranslational modifications in Golgi apparatus of eukaryotic cells and may bind different sugars.Surprisingly, we are the first to observe a significant increase of sIgE‐levels to rApi m 1 and rApi m 2  on the mucosal surfaces of the respiratory system, can induce production of certain sIgE‐levels against the CCD epitopes.Our results indicated that CCD‐inhibition can overcome current limitations of some procedures in recombinant technology, especially in Immunoblot which do not display three‐dimensional conformational structure of antigens that hide or change presentation of some IgE epitopes.In this study with a larger number of honeybee allergic patients, the sensitivity of Immunoblot for rApi m 1 was 65.7%. Similarly, we detected solid sensitivity for rApi m 2 and rApi m 10  in honeybee allergic patients. Sensitivity of CRD using simultaneous detection of sIgE for at least one tested recombinant honeybee allergen was 86.8%. So far, 12 HBV allergens have been described until now, and Api m 1 and Api m 4 (melittin) are found in significant amounts in HBV.Importantly, our result identified a very high sensitivity for rVes v 5 in wasp allergic patients (94%) and hornet allergic patients (100%). We also demonstrated no patients with wasp or hornet allergy who had only sIgE‐reactivity to rVes v 1. The minority of patients with wasp and hornet allergy (8/39) had sIgE‐reactivity to rVes v 5 and rVes v 1. The results of several studies have confirmed that rVes v 5 is sufficient in most patients for serological confirmation of wasp or hornet allergy.Since, CRD in our study failed to diagnose (5/38) 13.2% of honeybee allergic patients, and (2/33) 6.1% of wasp allergic patients, it may suggest that additional CRD are needed in these patients. On the other hand, CRD can help identify patients with a history of insect sting allergy without sIgE‐reactivity to venom extracts,Although, sIgE‐levels during successful VIT do not correlate with clinical improvement, changes in IgE‐ and IgG4‐levels are known to indicate VIT‐induced improvements in immune tolerance.Our results demonstrate that the CCD‐inhibition test is useful in patients who tested negative for recombinant honeybee allergens. Our patients, who had persistent HBV‐positivity even after CCD‐inhibition, require CRD to other recombinant honeybee allergens.Molecular diagnostics is a major step toward personalized medicine,In patients with multiple‐positivity, CCD‐inhibition increases sensitivity of CRD and help to define HBV allergic patients who require an extended CRD. CCD‐inhibition and CRD help synergistically to reveal the clinical relevant, true sensitization and improve the selection of allergens for long‐lasting VIT.Dragana Jovanovic: conceptualization ; data curation ; investigation ; methodology ; writing – original draft . Aleksandra Peric‐Popadic: investigation ; validation . Vojislav Djuric: data curation ; writing – review and editing . Maja Stojanovic: data curation ; validation ; writing – review and editing . Branislav Lekic: methodology ; software . Ognjen Milicevic: software . Branka Bonaci‐Nikolic: conceptualization ; investigation ; methodology ; supervision ; writing – review and editing .The authors declare no conflicts of interest.


The purpose of this study is to report the outcomes in patients undergoing arthroscopic tuberoplasty for symptomatic irreparable rotator cuff tear (RCT).This is a retrospective cohort study comparing preoperative and postoperative data of patients undergoing arthroscopic tuberoplasty for symptomatic irreparable RCT. Exclusion criteria included open tuberoplasty, concomitant partial RCT repair, glenohumeral arthritis, concomitant ipsilateral extremity fractures, <12 months follow-up, or pseudoparalysis. Demographics, shoulder range of motion (ROM), RCT morphology, re-operation rates, satisfaction and outcome scores were collected from medical records and questionnaires. Outcome scores included Patient Reported Outcome Measurement Information System Upper Extremity (PROMIS), American Shoulder and Elbow Surgeons score (ASES), Subjective Shoulder Value (SSV), and pain Visual Analog Score (VAS).P = .0029). Pre- and post-operative ROM were unchanged. There were 4 failures requiring revision. The remaining 17 patients reported high satisfaction scores (3.4 ± 0.7) and 15 (88.2%) answered “yes” to getting the procedure again, with 3/4 failures stating they would also undergo arthroscopic tuberoplasty again.Out of 28 patients identified between 2012 and 2019, 20 (21 shoulders) were available for follow-up at a mean of 43.3 ± 20.9 months. Mean age was 64.6 ± 8.8 years. Mean PROMIS was 37.7 ± 7.3, ASES was 82.9 ± 13.8, and SVV was 67.1 ± 19.4. VAS with activity decreased from 5.0 ± 2.9 preoperatively to 2.3 ± 2.6 (Arthroscopic tuberoplasty demonstrates high levels of satisfaction and pain reduction in symptomatic irreparable RCT. In appropriately indicated patients, this treatment should be considered prior to other salvage options. Although classically defined as a tear >5 cm or involving more than two tendons, more recent studies suggest that surgical repair of massive rotator cuff tears should consider several additional factors such as fatty infiltration, tendon length of <15 mm measured on magnetic resonance imaging (MRI), retraction beyond the rim of the glenoid, fixed humeral head subluxation, tear at the infraspinatus muscle-tendon junction, and failure of a prior repair.Despite the number of available options, no consensus on optimal management of massive or symptomatic irreparable rotator cuff tears exists, particularly in elderly patients without pseudoparalysis or evidence of glenohumeral arthritis. While some salvage procedures, such as superior capsular reconstruction or tendon transfer, are better suited for younger patients with high functional demand, others including arthroscopic débridement and subacromial decompression may be sufficient for older patients with low functional demands whose primary complaint is pain. These latter options may be effective for pain relief, but do not halt the progression of arthritis and may not be as durable compared to other treatment options.Alternatively, another previously described surgical option for massive or symptomatic irreparable rotator cuff tears is tuberoplasty. Originally introduced by Fenlin et al, the principle of the tuberoplasty procedure is to relieve subacromial impingement by reshaping the greater tuberosity to create a smooth articulation between the greater tuberosity and the undersurface of the acromion during shoulder abduction.Therefore, the aim of this study is to present our experience with arthroscopic tuberoplasty in patients with massive or symptomatic irreparable rotator cuff tears without pseudoparalysis. We hypothesize that this procedure will show improvement in clinical outcomes and pain with activity.This is a retrospective case series of patients undergoing arthroscopic tuberoplasty for massive or symptomatic irreparable rotator cuff tears without pseudoparalysis with a minimum of 12 months follow-up period. This study was approved by our institutional review board and is in compliance with Health Insurance Portability and Accountability Act protocols.Eligible subjects were identified by chart review of cases performed by the senior author at our institution between September 2012 and November 2019. A total of 28 patients who underwent arthroscopic tuberoplasty were identified. All patients were evaluated preoperatively with an MRI that demonstrated a massive or irreparable rotator cuff tear with retraction to at least the mid humeral head and no signs of advanced osteoarthritis. Preoperatively, all patients demonstrated the ability to actively elevate their arm to at least 120 degrees. Six patients were unable to be contacted for follow-up and two declined to participate leaving a total of 21 shoulders (20 patients) in the final analysis. We excluded subjects who had tuberoplasty by open approach, concomitant partial rotator cuff repair, glenohumeral arthritis, concomitant ipsilateral extremity fractures, follow-up of less than 12 months, or those unwilling to participate.All procedures were performed in the beach chair position under general or brachial plexus anesthesia. Standard posterior, lateral, and anterior arthroscopy portals were used. During arthroscopy, the glenohumeral joint was evaluated and if needed, a partial synovectomy of the glenohumeral joint was performed to débride any inflamed tissue. The rotator cuff tendon tears were evaluated and, in all cases, the tendon was mobilized for possible repair. When the tendon was deemed irreparable despite aggressive mobilization, tuberoplasty was performed . In ordeImmediately after the procedure, all patients were provided with a sling which was to be worn at their discretion only. At one week after the surgery, all patients proceeded with supervised therapy for active and passive motion. At 5-6 weeks, the rehabilitation protocol was advanced to include resistive strength training.Preoperatively, shoulder active range of motion (ROM) was documented, including forward flexion (FF), external rotation at the side (ERs), and internal rotation to the posterior (IRp). Shoulder internal rotation was measured by vertebral segments and converted to the following discrete assignments for statistical evaluation: 0° = 0, hip = 1, buttock = 2, sacrum = 3, L5-L4 = 4, L3-L1 = 5, T12-T8 = 6, T7 or higher = 7.Postoperatively, patients completed questionnaires either in person or over telephone. Functional outcomes included the Patient Reported Outcome Measurement Information System Upper Extremity Computer Adaptive Test (PROMIS UE CAT), American Shoulder and Elbow Surgeons (ASES) score, Subjective Shoulder Value (SSV), and pain VAS. PROMIS Pain Interference and Pain Intensity scores, in addition to PROMIS Global 10 Physical Health and Mental Health, were also completed. PROMIS instruments are scored are on the T-score metric, with the mean of 50 and standard deviation of 10 set to equal the mean of the US general population, and scores ranging from approximately 15-60.,,Follow-up ROM data were collected using subjective patient assessment. If unable to be examined in person, subjects were sent pictorial diagrams and asked to choose the highest level they could reach without assistance in FF, ERs, and IRp. Previous literature has demonstrated suitable reliability of subjective patient ROM assessment using these diagrams.In addition, subjects were asked about level of satisfaction, return to work, and return to sports. Satisfaction was evaluated both by using a scale from 0-4  and a yes/no response to undergoing the surgery again. Clinical failures were defined as any revision surgery in the ipsilateral shoulder after undergoing arthroscopic tuberoplasty.Preoperatively, 11/21 (47.6%) shoulders had available radiographs. The acromiohumeral interval (AHI) was measured in millimeters (mm) and used to calculate the preoperative Hamada classification.P-value below .05 considered statistically significant.Data were evaluated for normality using the Shapiro–Wilk test and those with normal distributions were analyzed using the independent and paired t test. Nonparametric analysis was performed with the Wilcoxon signed rank test to compare data that was not normally distributed. Nonparametric Spearman's rank correlation was used to determine the relation between preoperative variables  and postoperative PROMIS UE, ASES, and VAS pain scores. Statistical analyses were performed using RStudio version 1.2.1335 , with a A total of 21 shoulders from 20 patients were included for the final analysis. The mean age at time of surgery was 64.6 ± 8.8 years with 15 (71.4%) males and 6 (28.6%) females. The mean follow-up period was 43.3 ± 20.9 months. All but seven (66.7%) procedures were on the right shoulder and the dominant side was operated on for 13/21 shoulders (61.9%). One patient underwent bilateral arthroscopic tuberoplasty. Four subjects had a previous history of rotator cuff repair, ranging between 1 and 2 procedures (mean of 1.3 procedures). Average AHI was 7.5 ± 5.7 mm; average Hamada grade was 1.7 (range of 1-3). On preoperative MRI, 4 (19.0%) shoulders demonstrated a tear of only the supraspinatus tendon, 14 (66.7%) had a tear of both supraspinatus and infraspinatus tendons, one (4.7%) had a tear of both supraspinatus and subscapularis, and 2 (9.5%) had tears of all three tendons. Complete demographics are shown in Preoperative and postoperative active range of motion is shown in P = .0029). Mean PROMIS Pain Interference and Pain Intensity was 51.7 ± 9.4 and 42.1 ± 10.3, respectively. Patients' final mean SSV was 67.1 ± 19.4. Complete postoperative clinical outcomes are shown in Postoperatively, the mean PROMIS UE score was 37.7 ± 7.3. PROMIS Global 10 Mental and Physical Health was 52.8 ± 9.4 and 49.6 ± 8.7, respectively. The mean ASES score was 82.9 ± 13.8. To measure pain in the operative shoulder, VAS, PROMIS Pain Interference and PROMIS Pain Intensity were completed. In comparison to preoperative condition, VAS was significantly decreased at the latest follow-up from 5.0 ± 2.9 to 2.3 ± 2.6  were able to return to sport but only one was able to return at the same or higher level. One patient cited pain and weakness in the operative shoulder as the reason for not returning to sport, while the other cited lifestyle changes.Of the 20 subjects, 12 were working prior to the procedure, 5 of which were manual laborers. Ten of these 12 (83.3%) were able to return to work after arthroscopic tuberoplasty. Of note, 3/5 (60.0%) of the manual laborers were also able to return to work. Both patients who did not return to work were manual laborers; one decided to retire and the other cited disability related to his operative shoulder as the reason for not working.Overall, there were 4 (19.0%) clinical failures, defined as the return of pain and weakness of the operative shoulder requiring additional surgery. One of these failures initially reported good clinical outcome, but then fell at 14 months after the procedure and was no longer able to elevate the arm. All patients with failures were treated with a reverse total shoulder arthroplasty (rTSA). For these patients, symptoms began to recur at a mean of 8.8 ± 11.7 months post-tuberoplasty and revision surgery occurred 14.1 ± 13.6 months post-tuberoplasty.In the 17 shoulders without clinical failure, 15 (88.2%) reported being satisfied or extremely satisfied with the procedure, 1 (5.9%) reported being neither satisfied nor dissatisfied, and 1 (5.9%) was extremely unsatisfied. Fifteen patients (88.2%) reported that they would undergo the procedure again if necessary.As expected, the lowest satisfaction scores were reported from the group with clinical failures. Interestingly, 3 of these 4 patients who required revision surgery stated that they would still proceed with the arthroscopic tuberoplasty procedure again in a similar situation, and did not regret their decision despite the failure.Using nonparametric Spearman's rank correlation, there was no statistically significant correlation between any preoperative variable  and postoperative outcomes . In addition, patient outcome parameters, including failure rates, in patients with and without concomitant biceps tenodesis also did not demonstrate any statistically significant differences.This study demonstrates promising clinical outcomes after arthroscopic tuberoplasty for appropriately chosen and counseled patients with massive or symptomatic irreparable rotator cuff tear. Despite no change in shoulder active ROM, pain levels were significantly improved at the latest follow-up. Among those who did not undergo revision surgery, satisfaction was high and most patients in this group agreed to undergo the procedure again if recommended. However, there were 4 clinical failures all requiring rTSA.,,,,,,,,The treatment of massive or symptomatic irreparable rotator cuff tears continues to present a major dilemma for orthopedic surgeons. Numerous salvage procedures have been reported but there is still no single gold-standard procedure to treat this pathology while preserving the native shoulder joint. For elderly patients, subacromial decompression with acromioplasty is an option for pain relief but its efficacy may deteriorate over time as a result of violation of the coracoacromial ligament.,,,Matsen et al describe a similar “smooth and move” procedure, reporting improvements in Simple Shoulder Test scores, abduction and FF at 6 weeks postoperatively.In our cohort, active ROM in all planes did not change significantly after arthroscopic tuberoplasty compared to preoperative values. However, this was not the case in previous studies. Verhelst et al, for example, found that FF and abduction were increased at 38 months post-tuberoplasty. Lee et al also reported significant improvement in FF and ER at 90 degrees of abduction at 40 months postoperatively. Park et al found results more consistent with ours, with only FF showing significant improvement at 98 months. These disparities may be due to ROM being limited by pain and not necessarily the functional ability of the rotator cuff.,,,,Despite a lack of improvement in active range of motion, patients experienced significant relief of pain. In addition, PROMIS Pain Intensity and Pain Interference scores were relatively low. The mean PROMIS Upper Extremity score (which measures only function but not pain) was relatively low, indicating that patients continue to have sub-optimal function. These findings mirror the lack of ROM improvement. However, mean ASES scores were measured to be high. The discrepancy between these two outcome measures may be two-fold; PROMIS UE and ASES measure different combinations of patient health domains and place different weights on each domain in calculating total scores. PROMIS UE measures only upper extremity function, while ASES measures both pain and function and assigns both a weight of 50% for the total score. When calculating a total ASES score, a lower pain subscore will translate into a higher total score, which is the case in our series. These findings are consistent with the previous literature.There were no statistically significant correlations between any preoperative variable  and postoperative outcomes . Overall, in patients without clinical failure, most reported being satisfied or extremely satisfied and that they would undergo the procedure again if recommended. In addition, most of those who were working or playing sports preoperatively were able to return. There were 4 patients (19.0%) who underwent subsequent rTSA.For massive or symptomatic irreparable rotator cuff tears, a number of salvage options have been proposed, including débridement, acromioplasty, biceps tenotomy or tenodesis, balloon implantation, graft interposition, superior capsular reconstruction, tendon transfer as well as rTSA. As each of these procedures has its respective advantages and disadvantages, no consensus exists regarding optimal management. Therefore, despite our relatively high reoperation rates, arthroscopic tuberoplasty is a reasonable option in lower demand patients with massive or symptomatic irreparable rotator cuff tears without pseudoparalysis. While providing relatively high rates of satisfaction, the procedure is minimally invasive with low morbidity and complication rate and a less intensive rehabilitation.This study has several limitations. Like all retrospective reviews, the data may suffer from recall and selection bias. In addition, the cohort is a small number of patients undergoing a relatively uncommon procedure by a single surgeon at our institution. Therefore, the clinical results may not be widely applicable to other patient populations. However, our study design and patient population are similar to those of previous studies reporting outcomes of tuberoplasty. Most importantly, preoperative outcome scores were lacking which prevented demonstration functional improvement associated with the procedure. Future studies should include a longer follow-up period with a control group to mitigate placebo effects in addition to postoperative imaging to assess for superior humeral migration.Arthroscopic tuberoplasty has shown promising results in patients with massive or symptomatic irreparable rotator cuff tears without pseudoparalysis or glenohumeral arthritis, leading to high levels of satisfaction, significant pain reduction, and encouraging rates of return to work. Therefore, for appropriate patients, this treatment should be considered prior to other salvage or prosthesis procedures.Funding: No funding was disclosed by the authors.Conflicts of interest: Young W Kwon: Has consulting relationship with DJO Surgical. The other authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.


This study assessed the relationship between posterior permanent dentition and radiographic changes of the mandibular condyle. This descriptive, cross-sectional study was conducted on 300 panoramic radiographs of patients over 40 years of age . Panoramic radiographs were evaluated for condylar changes such as flattening, subcortical sclerosis, subcortical cyst, erosion, osteophytes, and generalized sclerosis. Presence of muscle pain and temporomandibular joint (TMJ) pain and sounds, and history of TMJ trauma were also assessed. The occlusal scheme of posterior teeth was analyzed according to the Eichner’s index. The frequency of condylar changes was calculated in the right and left sides, and their association with posterior permanent dentition was analyzed by the Chi-square test . The frequency of flattening, muscle pain, TMJ sounds, and erosion was 11.7%, 9.7%, 5.7%, and 3.7% in the right side, respectively. The frequency of flattening, muscle pain, erosion, and subcortical cyst was 12%, 9.3%, 5%, and 5% in the left side, respectively. The frequency of bilateral muscle pain, flattening, TMJ sounds, and TMJ pain was 18%, 16.7%, 11.7%, and 9.3%, respectively. Cases with TMJ trauma, generalized sclerosis, and osteophytes were few. According to the Eichner’s index, most patients with condylar changes had classes A and B, and a smaller percentage had class C. No significant difference was noted between healthy individuals and those with condylar changes regarding dentition patterns. No relationship existed between condylar changes and posterior permanent dentition pattern. The temporomandibular joint (TMJ) is a diarthrosis, better defined as a ginglymoarthrodial joint . It has The mandibular condyle is part of the mandibular bone that also participates in the structure of the TMJ. It also serves as an area for regional adaptive growth while preserving its cartilage ,5. The cIn hard articular tissue, the primary bone is gradually replaced with the secondary bone in response to changes in articular function. In some cases, bone remodeling occurs in the outer surface along with changes in the shape and dimensions of the joint (mainly in the condylar head), which is also detectable on radiographs ,11. CondIn such cases, since patients do not have any clinical symptoms, they do not seek any treatment. Additionally, the condyle has high potential for regeneration, which is helpful in orthodontic and surgical treatments.A correlation has been documented between some clinical problems of the TMJ and radiographic findings . DiagnosAssessment of the correlation of radiographic changes of the condyle and the occlusal scheme is important to find the related factors and strategies to prevent or treat them. Accordingly, this study aimed to assess the relationship between posterior permanent dentition and radiographic changes of the condyle.This descriptive cross-sectional study was conducted on panoramic radiographs of patients over 40 years of age presenting to an oral and maxillofacial radiology clinic. The study protocol was approved by the ethics committee of Qazvin University of Medical Sciences (IR.QUMS.REC.1399.189).The sample size was calculated to be 240 panoramic radiographs according to a study by Nah  assumingThe inclusion criteria were panoramic radiographs of dentate patients with no history of orthodontic treatment, craniofacial deformities, complete oral rehabilitation, trauma, maxillofacial surgery, TMJ ankylosis, or polyarthritis. Additionally, complete clinical information of patients was available in their records. Poor-quality radiographs, and patients with a history of TMJ pathologies, generalized arthritis, or continuous use of steroids or anti-inflammatory drugs as mentioned in patient records were excluded.After obtaining written informed consent from the patients, they were questioned about any problem or pain in mastication, pain in the periauricular area, articular sounds, and mouth opening limitation. The radiographs were evaluated by two oral and maxillofacial radiologists, and radiographic changes of the condyles were evaluated according to the following criteria:Articular surface flattening: Flattening of the round superficial contour of the condyle (flattening of the convexity and concavity in the outer articular borders).Subcortical sclerosis: Increased thickness of cortical plate in areas under loading compared with unloaded adjacent areas.Subcortical cyst: Presence of a cavity (radiolucency) beneath the articular surface which does not follow the normal pattern of the brain.Surface erosion: Absence of integrity in the articular cortex due to resorption of the cortical plate of the articular surface.Osteophytes: Marginal hypertrophy along with sclerotic borders and formation of superficial exophytic bony lesions.Generalized sclerosis: Absence of a specific trabecular direction and inability to differentiate between the cortical plate and trabecular bone that has progressed towards the condylar head.Loose joint body: Presence of specific calcified structures incompatible with the structure of the disc or bony structures of the joint.The frequency of different condylar changes and TMJ disorders, and the pattern of posterior dentition according to the index described by Eichner et al. , were deData were analyzed by SPSS version 25. The correlation between condylar changes and TMJ disorders with different patterns of posterior dentition was analyzed by the Chi-square test. Level of significance was set at 0.05.A total of 300 panoramic radiographs of 112 males (37.7%) and 188 females (62.7%) were evaluated in this study. p > 0.05).No significant difference was noted between male and female patients or different age groups regarding the frequency of radiographic changes of the condyle and pattern of posterior dentition according to the Eichner’s index .The frequency of flattening, muscle pain, TMJ sounds, and erosion was 11.7%, 9.7%, 5.7%, and 3.7% in the right side, respectively. The frequency of flattening, muscle pain, erosion, and subcortical cyst was 12%, 9.3%, 5%, and 5% in the left side, respectively. The frequency of bilateral muscle pain, flattening, TMJ sounds, and TMJ pain was 18%, 16.7%, 11.7%, and 9.3%, respectively. Cases with TMJ trauma, generalized sclerosis, and osteophytes were few. In the present study, no significant difference was noted between male and female patients or different age groups regarding the frequency of skeletal changes of the condyle and pattern of posterior dentition according to the Eichner’s index  and B , and a smaller percentage had class C (no supporting zone in the remaining teeth) . HoweverThe main limitation of this study was using panoramic radiographs instead of CBCT scans. Panoramic radiographs are routinely requested by dental clinicians and since the aim of this study was to assess the correlation of posterior permanent dentition and condylar changes, an adequate number of CBCT scans was required for each dentition group; however, eligible CBCT scans visualizing both condyles and different types of posterior dentition were hard to find. Since selection of an appropriate size of field of view is critical to eliminate unwanted exposure , many avFlattening and muscle pain had the highest frequency in our study population. No relationship was found between condylar changes and permanent posterior dentition pattern. According to the Eichner’s index, most patients with condylar changes had classes A and B. No significant difference was noted between male and female patients or different age groups regarding the frequency of skeletal changes of the condyle and pattern of posterior dentition according to the Eichner’s index.


We investigated the differences in outcomes after total hip arthroplasty (THA) for hip osteoarthritis (HOA) between patients with and without central sensitivity syndromes (CSSs) other than fibromyalgia (FM). After excluding two patients with FM, we compared the clinical data of 41 patients with CSSs and 132 patients without CSSs. Clinical data included scores on the central sensitization inventory, visual analog scale for pain (VAS pain), and Japanese Orthopedic Association Hip Disease Evaluation Questionnaire (JHEQ). VAS pain was significantly higher at 3 and 6 months after THA in patients with CSSs than in those without CSSs . Satisfaction, pain, and mental JHEQ scores were lower in patients with CSSs than in those without CSSs . Multiple regression analyses indicated that one and ≥ 2 CSS diagnoses significantly impacted the satisfaction score . Two or more CSSs were the only factor influencing the pain score . Pain in patients with CSSs reflects central sensitization, which may adversely affect post-operative outcomes. Surgeons should pay attention to patients with a history of CSSs diagnoses who undergo THA for HOA. Demand for the THA procedure is expected to continue to increase worldwide5. However, evidence indicates that despite the absence of post-operative structural complications, approximately 10% of patients with HOA who undergo primary THA report residual pain and dissatisfaction each7. The causes of these post-operative adverse outcomes are not well understood.Total hip arthroplasty (THA) is an effective surgical intervention for patients with persistent painful hip osteoarthritis (HOA), improving not only pain relief, but also the quality of life, gait function, cardiorespiratory function, and patient satisfaction9. A high degree of pre-operative CS has been reported as a risk factor for residual pain at 1-year post-operatively in patients who undergo THA for HOA10. Furthermore, both pre-operatively and post-operatively, CS is resistant to treatment, including traditional physiotherapy and pain medication; however, specific treatments have been found to be effective12. Therefore, identifying the characteristics of patients with HOA with CS components is an important endeavor, as it may influence the selection of treatment for HOA.In the past decade, central sensitization (CS), defined as increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input, has been suggested to contribute to the persistence and extent of pain in HOA and knee osteoarthritis (KOA)13. A lowered threshold for the perception of sensory information, which is a common condition in these disorders, is closely linked to the exacerbation and persistence of pain14. A previous study has reported that approximately 27% of patients with musculoskeletal disorders have at least one CSS15. Furthermore, some studies have described poor post-operative outcomes in patients with musculoskeletal disorders and fibromyalgia (FM), a typical CSS17. Although other CSSs have a similar pathophysiology to FM, post-operative outcomes in patients with CSSs other than FM who undergo THA for HOA remain unclear.Central sensitivity syndrome (CSS) is a generic term for a group of disorders in which CS may be the root etiologyTherefore, we investigated the pre-operative clinical characteristics and post-operative outcomes after THA for HOA, including pain and satisfaction, in patients with and without CSSs, excluding FM.This retrospective study was approved by the institutional review board of our institution. All patients provided informed consent and the study was conducted in accordance with the Declaration of Helsinki. We retrospectively enrolled 235 consecutive patients with HOA due to primary or developmental dysplasia of the hip who underwent THA at a single center between January 2019 and March 2021. All THA procedures were performed under general anesthesia using a minimally invasive anterolateral supine approach. Cementless type implants of both cups and stems were used in all cases. A fully hydroxyapatite-coated stem was mainly used; Zweymüller and modular Wagner-cone types were also used according to the shape of the patient’s medullary cavity. Of the enrolled patients, 29 with missing data and 11 with a previous history of any hip surgery on the same laterality were excluded. Further, ten patients with any peri- or post-operative complications that affect post-operative pain ; four patients who used centrally acting agents, opioids, and/or steroids; patients who underwent contralateral THA during the post-operative course in this study period; and two patients who did not complete the 6-month follow-up after THA were excluded. Finally, 175 patients were included in this study  of patients with specific CSSs was calculated using CSI part B. After excluding patients with FM, we divided the patients into two groups: the patients with one or more CSSs and those without CSSs. In addition, the number of CSSs diagnoses was determined for each patient and patients with CSSs were categorized as having one CSS or ≥ 2 CSSs.The CS inventory (CSI) is a screening tool for identifying the presence of CSSs19. JHEQ has been widely used as a patient-reported outcome measure in Japan to assess the condition of the hip joint. JHEQ consists of items on pain (0–28 points), function (0–28 points), and mental (0–28 points), with 0 and 28 representing the worst and best scores, respectively. Additionally, satisfaction was evaluated using the VAS for satisfaction  included in JHEQ. VAS pain was evaluated 1 month before, and 3 and 6 months post-operatively, and JHEQ scores were evaluated at 6 months post-operatively. HOA was assessed using the Kellgren–Lawrence (KL) classification system20. All patients were categorized as having an advanced or end-stage disease (KL grade 3 or 4). Furthermore, we investigated the correlations between the pre-operative CSI (part A) score and post-operative VAS pain and JHEQ scores in patients with and without CSSs. The differences in post-operative outcomes evaluated by VAS pain and JHEQ scores between the patients with and without CSSs were also investigated.Pain was evaluated using the visual analog scale for pain . Post-operative outcomes were evaluated using the scoring system of the Japanese Orthopedic Association Hip-Disease Evaluation Questionnaire (JHEQ)U test and Pearson's Chi-square test, respectively. The correlations between the pre-operative CSI score and post-operative VAS pain and JHEQ scores in patients with and without CSSs were analyzed using the Spearman’s correlation coefficient. Correlation coefficient was represented by ρ. The effect size of differences in VAS pain and JHEQ scores between the two groups was assessed using Cohen’s d. Multivariate regression analysis was used to identify differences in post-operative JHEQ scores according to the number of CSS diagnoses (one or ≥ 2). All models were adjusted for sex, age, BMI, duration of hip pain, and VAS pain at 1 month pre-operatively. Statistical significance was set at P < 0.05. Statistical analyses were performed using SPSS for Windows .Results are expressed as the mean ± standard error of the mean unless otherwise indicated. In order to eliminate the bias of influences of FM on post-operative outcomes, two patients with FM were excluded from comparisons in pre- and post-operative clinical data between patients with and without CSSs. Age, height, weight, body mass index (BMI), duration of hip pain, CSI score, VAS pain, and JHEQ scores were analyzed as continuous variables; sex, HOA grade (as assessed by the KL classification system), and CSS diagnoses were analyzed as nominal scale variables. Continuous and categorical variables were compared between groups using the Mann–Whitney The number  of patients with CSSs is shown in Table Table Figure Figure Table 22. However, the present study is the first to directly indicate poorer post-operative outcomes, including satisfaction, pain, and mental scores, in patients with CSSs other than FM who underwent THA for HOA than in those without CSSs. These results are important because they indicate that CSSs are one of the factors influencing pain persistence after THA.In the present study, approximately one-quarter of the patients who underwent THA for HOA had at least one CSS, which is consistent with several previous reports on the prevalence of CSSs in patients with musculoskeletal diseases24. As in previous studies, the CSI score correlated with pain, function, mental, and total scores on the JHEQ in patients with HOA without CSSs in this study. In contrast, we did not find significant correlations between the CSI score and all clinical outcomes in patients with CSSs. Patients with CSSs may influence post-operative outcomes regardless of CSI score.We also investigated the correlations between pre-operative CSI scores and post-operative clinical outcomes in HOA patients with and without CSSs. Several studies indicated the associations between pre-operative CSI scores and poor post-operative outcomes in patients with HOA and KOA14. Furthermore, Brummett et al. reported that patients with higher scores on an FM survey, which assessed widespread pain and comorbid symptoms, had poor outcomes 6 months after primary total hip and knee arthroplasty16. Other CSSs may also affect persistent post-operative pain because they have pathophysiological processes similar to FM14.In our result, more persistent pain was observed in patients with CSSs than in those without CSSs at 3 and 6 months after THA. Additionally, patients with CSSs had significantly lower pain scores on JHEQ at 6 months post-operatively than those without CSSs. Previous reports have suggested that CSSs are associated with a lower pain threshold, which is related to CS25. Furthermore, NGF gene expression in the synovium was reported as correlated with pre-operative CSI and pain scores in 50 patients with HOA26. Taken together, the present results and those of previous studies suggest that comorbidities of the pathophysiology of HOA and CSS may be a cause of persistent post-operative pain.CS in osteoarthritis is triggered by an increased expression of various cytokines, including nerve growth factor (NGF), in synovial inflammation27. In the present study, satisfaction and mental scores were also significantly lower in patients with CSSs than in those without CSSs at 6 months after THA. Several factors are closely related to post-operative dissatisfaction30. Baker et al. indicated that persistent pain after total knee arthroplasty (TKA) was the strongest predictor of low satisfaction28. Kim et al. demonstrated that patients with KOA with CS (CSI score ≥ 40) reported severe pain, which was correlated with the satisfaction score, at 3 months after TKA23. Several studies have also suggested that poor mental health status and depression prior to THA or TKA are associated with increased post-operative dissatisfaction scores30. Thus, suffering from CSSs may exacerbate post-operative pain and psychological disorders, affecting satisfaction.In addition to a pain score, JHEQ provides post-operative satisfaction, mental, and functional scores in patients with HOA31. However, to our best knowledge, no study has previously indicated differences in post-operative outcomes according to the number of CSSs morbidities. These previous studies and our results showed that increased CSS morbidities might exacerbate CS and affect persistent post-operative pain and dissatisfaction.The present study also investigated the impact of the number of CSS diagnoses on post-operative JHEQ scores in patients who underwent THA for HOA using multiple regression analyses. Both one and ≥ 2 CSSs diagnoses impacted the satisfaction score. The presence of ≥ 2 CSSs was the only significant factor influencing the pain score on JHEQ. Further, there was near-marginal significance (0.05 < P < 0.18) between one CSS and mental score, both one and ≥ 2 CSSs and total scores on JHEQ, respectively. The relationship between poor post-operative outcomes and the number of CSSs is still controversial. Several studies have reported a correlation between the pre-operative degree of CS and poor outcomes, including persistent pain after THA27. We suspect that JHEQ may be a useful tool in the evaluation of hip joint clinical conditions even in other ethnic patients, but other scales used worldwide might be needed to evaluate together. Third, the assessment of CSS diagnoses was not performed independently at our institution and comprised merely an aggregation of previous diagnoses made at other institutions. Therefore, the present study did not consider the medical conditions and medications for CSSs in individual cases. Despite these limitations, we believe that the present study provides valuable information on the importance of considering CSSs in patients who undergo THA for HOA, as they may be at risk for poor post-operative outcomes.The current study had several limitations. First, the number of patients with CSSs in the current study was relatively small to analyze in the regression analysis. In addition, we could not assess the relationships between the poor post-operative outcomes and each CSS due to the small sample size. Further investigations will be needed. Second, we used only JHEQ to evaluate post-operative outcomes 6 months after THA in this study. JHEQ has been a widely used patient-reported outcome measure in Japan because it includes specific items related to the Japanese lifestyle. Seki et al. reported the reliability and validity of JHEQ to compare the SF-36 questionnaire as a generic quality of life scale and the Oxford hip score as a disease-specific scale used worldwideThe present results indicate poorer post-operative outcomes, including persistent pain and dissatisfaction, after THA for HOA in patients with CSSs, excluding FM, than in those without CSSs. Pain in patients with CSSs reflects CS, which may adversely affect post-operative outcomes. Surgeons should pay close attention to patients who undergo THA for HOA with CSSs, even those without FM.


Hemorrhoidectomy is associated with intense postoperative pain that requires multimodal analgesia. It includes nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and local anesthetics to reach adequate pain control. There are data in literature preemptive analgesia could decrease postoperative pain after hemorrhoidectomy. The aim of this study is to assess the efficacy of preemptive analgesia with ketoprofen 100 mg 2 h before procedure per os with spinal anesthesia to decrease postoperative pain according to visual analog scale and to reduce the opioids and other analgesics consumption.Patients of our clinic who meet the following inclusion criteria are included: hemorrhoids grade III–IV and the planned Milligan-Morgan hemorrhoidectomy. After signing the consent all participants are randomly divided into 2 groups: the first one gets a tablet with 100 mg ketoprofen, the second one gets a tablet containing starch per os 2 h before surgery (72 participants per arm). Patients of both arms receive spinal anesthesia and undergo open hemorrhoidectomy. Following the procedure the primary and secondary outcomes are evaluated: opioid administration intake, the pain at rest and during defecation, duration, and frequency of other analgesics intake, readmission rate, overall quality of life, time from the procedure to returning to work, and the complications rate.Multimodality pain management has been shown to improve pain control and decrease opioid intake in patients after hemorrhoidectomy in several studies. Gabapentin can be considered as an alternative approach to pain control as NSAIDs have limitative adverse effects. Systemic admission of ketorolac with local anesthetics also showed significant efficacy in patients undergoing anorectal surgery. We hope to prove the efficacy of multimodal analgesia including preemptive one for patients undergoing excisional hemorrhoidectomy that will help to hold postoperative pain levels no more than 3–4 points on VAS with minimal consumption of opioid analgesics.ClinicalTrial.govNCT04361695. Registered on April 24, 2020, version 1.0.The online version contains supplementary material available at 10.1186/s13063-022-06107-0. Anorectal diseases are mostly benign and do not affect life expectancy, so currently both patients and clinicians are extremely interested in performing day care surgery. Anorectal surgery itself causes certain discomfort, especially pain, long recovery period, and a decreasing quality of life for several months.The pain appears as a result of endogenous and exogenous factors affecting on the peripheral nerves endings, and also the pathological central nervous system excitation. Any surgical intervention activates nociceptors with various stimuli including mechanical factors as a result of a prick or cut of the tissue, chemical factors as a result of exposure to inflammatory mediators, and thermal factors as a result of heating or cooling the tissue . Thus, aIn anorectal surgery, almost every patient experiences moderate/severe pain in the postoperative period, 12% of patients have severe pain throughout the recovery period, and control of postoperative pain is still problematic in 5% of cases when a severe pain syndrome continues despite standard pain management. It leads to long hospital admission and to an opioid intake increase . ExcisioPreemptive analgesia is aimed to prevent pain after surgery and affects several points of the “pain” cascade . The mosOne of the most commonly prescribed painkillers is non-steroidal anti-inflammatory drugs (NSAIDs), which have an adequate analgesic effect and even in acute pain can reduce the opioid dose by 18.3% . RegardiTherefore adequate postoperative analgesia requires the multimodal approach including opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and local anesthetics. But there is no current standard on preemptive analgesia for adult patients with symptomatic hemorrhoids grade III–IV undergoing Milligan-Morgan hemorrhoidectomy without previous history of anorectal interventions and decompensated somatic diseases, although several studies report some regimens that seem to be effective.The aim is to assess the efficacy of preemptive analgesia with Ketoprofen 100 mg 2 h before procedure per os with spinal anesthesia to decrease postoperative pain according to visual analog scale and to reduce the opioids and other analgesics consumption.This is a prospective, randomized, double-blind, unicenter, superiority, parallel-group 2-arm study with 1:1 allocation ratio conducted in the surgical department of Moscow Research Educational Center of the Lomonosov Moscow State University. It is in the recruitment stage. We are anticipating 144 patients of all genders from 18 to 75 years old in total who come to the clinic. Thus, in this case, a uni-center design can assure sufficient patient recruitment.Symptomatic hemorrhoids grade III–IVPlanned surgery: Milligan-Morgan hemorrhoidectomyEvery patient included in the study must meet the following criteria:Patients who had contraindication or technical inability to perform subarachnoid anesthesia or other somatic diseases  or refused to participate and pregnant women are not included. The written voluntary informed consent to participate , paracetamol (at the maximum dose of 1000 mg per day), and local anesthetics with lidocaine before defecation. Patients are usually discharged on the 4–5th day after surgery when their pain level is below 5 points according to VAS. After discharge, a standard analgesics scheme mentioned above is recommended to all patients. If the pain level reaches 5–6 points according to VAS on the 5th day after the procedure, patients continue inpatient treatment and may receive an opioid analgesic.GenderAgeHemorrhoid stageThe number of enlarged hemorrhoidsHemorrhoid symptomsThe list of the baseline characteristics that we collect to evaluate the population:The trial is conducted to evaluate the primary outcome: the quantity of the opioid administration intake per day during the first week postoperatively that is necessary to hold pain level no more than 3–4 VAS points in every patient. We use tramadol as an opioid analgesic in a single standard dose of 100 mg for patients with persistent severe pain syndrome in our clinic. The study also assesses the following secondary outcomes: (1) the pain severity before and after defecation according to VAS on the 6, 12, and 24 h after the procedure, then 2 times per day up to 7th postoperative day; (2) duration and (3) frequency of other analgesics intake  during the first week postoperatively; (4) readmission rate and (5) overall quality of life on the 7th and 30th days; (6) time from the procedure to return to work; and (7) the complications rate  in the early postoperative period (30 days after procedure). The pain severity, duration and frequency of other analgesics intake during the first week postoperatively will be assessed using “Postoperative protocol for pain management”  to ascertain whether the patient has had any complications and/or adverse events that were treated at another hospital. If the researcher is unsuccessful in contacting the patient, the patient will be considered as lost to follow-up.For the schedule of enrolment, interventions, and assessments, see Table a = 0.05. the statistical power of the study is 80%, the patients are randomized into 2 groups with 1:1 allocation ratio, the noninferiority margin D = 5%, and the required sample size is 144 patients (72 patients in each of the 2 groups).Considering that this is a superiority study, the sample size was calculated using a 1-sided Blackwelder test. According to published data, the incidence of opioid intake after hemorrhoidectomy varies from 20 to 30% . The expAll patients diagnosed with HD II–III stage will be considered for this study.Participants will be randomly assigned to either control or experimental group with a 1:1 allocation ratio using cluster randomization with a computerized random number generator. All subjects will be allocated any interventions. The experimental group receives a tablet with 100 mg ketoprofen, the control one receives a tablet containing starch per os 2 h before surgery (72 participants per arm) . The eCRF should contain results of all the screening procedures, including patient history and demographics, imaging studies, filled-out questionnaires, operation notes, and postoperative rounds during a patient stay in the surgical ward.All data will be collected prospectively using eCRFs designed for this trial. The reasons for withdrawal will be documented. The investigator will attempt to contact each participant at least 3 times during each follow-up window before declaring them lost for observation. The study exit form will be recorded in the eCRF. All prior data will be analyzed within the research.All patients will receive clarifications of all the study procedures and will be able to discuss them with the primary investigator. All patient data will be handled according to the principles of doctor–patient confidentiality; the subjects will be anonymized and analyzed with individual identifier numbers transcribed into eCRF.Data analysis will be performed by one of the researches who is blind to the randomization by using Statistical Product and Service Solutions (SPSS) Statistics for Windows, version 20.0 . Continuous variables will be presented as mean and standard deviation, and categorical variables will be presented as frequency or percentage.The ITT analysis included all randomized patients treated for at least 1 week, who were evaluated for efficacy at baseline and at least once at subsequent evaluation points during the study. The PP-analysis will exclude from the full analysis all the non-compliant patients, patients who received incomplete treatment, and patients who refused further treatment after randomization.t test, providing that its conditions for application are met. Otherwise, the non-parametric Mann-Whitney U test is used. Statistical analysis for categorical variables is performed using the Pearson χ2 test or the Fisher exact test. Specifically, the above methods are used to compare the two groups in terms of baseline characteristics in order to assess whether the randomization has been effective. Ninety-five percent confidence intervals for the ratio will be reported. In all cases, the level of significance will be the usual 5% (α = 0.05).Quantitative variables are described as means with standard deviations, medians, range, or interquartile range as appropriate. Categorical variables are described in absolute numbers and percentages. The statistical analysis of the quantitative variables, with independent groups, is performed with the parametric Student’s This study has a low risk of selection bias due to the use of a computer random number generator. Central allocation and the use of sequentially numbered drug containers of identical appearance allow to achieve a low risk of deviations. Performance bias may be considered as having an average risk due to blinding only participants of the study, the personnel is not blinding. Blinding of outcome assessment is ensured, so detection bias is unlikely. Attrition bias could probably appear because of the difficulty of collecting data from patients outside the hospital or the refusal of future treatment and visiting the doctor during follow-up.There is no data monitoring committee designated for this trial. Any adverse and serious adverse events will be immediately reported to the principal investigator and the primary sponsor. Participants’ names and collected data are subject to medical confidentiality. In cases of withdrawal, collection of data will cease but not be erased. A logistics database with a patient’s complete ID will be used and kept within a separate password-protected system from the results database with all study information. At the end of the trial, the original peri-operative package and database will be archived by the principal investigator, who is responsible for providing data to the trial investigators.This study is conducted in accordance to the principles of the Declaration of Helsinki . The study protocol is approved by the Local Ethics committee of Sechenov University  and improved postoperative analgesia after spinal and abdominal surgery –16. PatiWe hope to prove the efficacy of multimodal analgesia including preemptive one for patients undergoing excisional hemorrhoidectomy that will help to hold postoperative pain levels no more than 3-4 points on VAS with minimal consumption of opioid analgesics.clinicaltrial.gov number ID NCT04361695, date of registration: April 24, 2020, version 1.0. Recruitment began in April 2020 and is expected to be completed by the end of December 2021.Registered at Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.Additional file 2. Postoperative protocol for pain management.Additional file 3. Written form of informed consent of the patient.


Boerhaave syndrome (BS) is a rare gastrointestinal condition related to esophageal rupture that carries a high mortality rate without prompt medical attention. BS is commonly associated with repeated episodes of severe retching, straining, or vomiting. Diabetic ketoacidosis (DKA), a serious acute complication of diabetes, is characterized in part by laboratory findings of profound hyperglycemia and ketoacidosis. Clinically, nausea and vomiting are seen commonly in DKA patients, which can often include repeated forceful retching, but rarely associated with esophageal rupture. In this article, we will describe a case of BS secondary to repeated episodes of emesis in the setting of DKA. Boerhaave syndrome (BS) can be characterized by full-thickness esophageal perforation induced by barogenic trauma . The mecBS in the setting of diabetic ketoacidosis (DKA) has been previously reported in the medical literature, albeit exceedingly rare. Upon review of available literature, two prior case reports describe such a situation. In one of these, a 2013 report by Alkuja et al., an iatrogenic etiology of esophageal rupture could not be ruled out ,7.An otherwise healthy 22-year-old male presented to the emergency department due to nausea, vomiting, abdominal pain, and chest pain for the previous four days with associated fatigue and polyuria. Emesis was noted to be non-bilious, non-bloody but seemingly constant. The patient reported that he could not tolerate anything by mouth during this time. The chest pain was described as substernal, non-radiating, constant, progressively worsening, and provoked by eating. The abdominal pain was described as diffuse, non-radiating, constant, stabbing in nature, and provoked by eating.2. Venous blood gas (VBG) revealed a pH of 7.149, pCO2 of 26 mmHg, and bicarbonate of 8.7 mmol/L, consistent with metabolic acidosis. Urinalysis (UA) showed 3+ glucose and 2+ ketones. Beta-hydroxybutyrate was over 8 mmol/L. Combined results of the VBG, UA, and comprehensive blood profile indicated that the patient was in DKA  of the chest, abdomen, and pelvis with contrast was ordered due to concern for non-specific pain and demonstrated anterior and posterior pneumomediastinum with diffuse thickening of the distal esophagus, confirming esophageal perforation consistent with BS Figures , 2. The BS remains a feared complication secondary to sudden increased intra-esophageal pressure from retching with subsequent esophageal perforation. BS has an incidence rate of 3.1 per million and is fatal if left untreated . BS typiBS usually occurs in patients without underlying esophageal disease. However, a subset of patients has esophageal rupture secondary to peptic ulcers, Barrett esophagus, eosinophilic esophagitis, pill esophagitis, and other causes of esophageal inflammation ,3,8. DKASigns of BS vary widely based on the anatomical location of the rupture. Most commonly, patients present with refractory, unremitting chest pain, crepitus on palpation, fever, dyspnea, tachycardia, tachypnea, cyanosis, and hypotension . More prBS is usually diagnosed incidentally in patients being evaluated for chest pain. It should be suspected in patients who complain of severe neck, chest, or upper abdominal pain after an episode of severe retching and vomiting. Other causes of increased intrathoracic pressure such as intubation, pneumothorax, and pleural effusions may also result in BS. Subcutaneous emphysema may be noted on physical examination and the diagnosis is established by CT scan with oral contrast. Delay in diagnosis is often associated with a higher risk of mortality and complications . Myocardial infarction, pancreatitis, aortic aneurysm, peptic ulcer disease, pneumonia, or spontaneous pneumothorax can also cause acute-onset chest or upper abdominal pain. History, electrocardiogram, laboratory evaluation , diagnostic imaging , and physical examination are important to distinguish these etiologies from esophageal perforation. In addition, patients with Mallory-Weiss syndrome may have similar, albeit less severe presentation; however, there will be no evidence of subcutaneous, mediastinal, or peritoneal air on radiography or extravasation of esophageal contrast .Perforations diagnosed within 12-24 hours have the best outcomes. There are three common treatment options including conservative, endoscopic, and surgical. Intensive care unit admission is recommended not only for patients with hemodynamic instability but also for patients with multiple comorbid conditions [Endoscopic management of esophageal perforation should be considered in patients who are not surgical candidates or with extensive underlying comorbidities -15. A muThe prognosis usually depends on the timing of diagnosis and treatment. Delayed diagnosis and treatment are usually associated with poor outcomes. Those who undergo diagnosis and surgery within 24 hours carry a survival rate of approximately 75%, but this can drop to 50% if the diagnosis and treatment are delayed after 24 hours and approximately 10% after 48 hours .BS related to DKA has rarely been described in medical literature in the past. With this rare association in mind, clinicians should add BS to the differential when faced with patients experiencing extreme chest pain in DKA. The severe retching seen in DKA typically manifests with Mallory-Weiss tears in the extremis, but BS has also been identified as a possible, albeit rare, complication discussed in the above case. This case was unique in the sense that many patients have severe retching during DKA but do not develop BS. Our patient also did not fit the typical demographic that develops BS other than being male, as he was not middle-aged or using alcohol.In this case, we highlight the importance of radiologic imaging acquisition in a timely manner to provide a diagnosis for extreme chest pain in the setting of DKA. Also highlighted is the benefit of using CT chest and abdomen in DKA cases that present with chest pain and abdominal pain to rule in BS. Prompt CT will allow for appropriate surgical or endoscopic care quickly to prevent high morbidity and mortality associated with delay. We hope this case provides awareness to clinicians of BS as part of the differential diagnosis in patients with severe chest and abdominal pain after retching.


KiOil has evidenced structural modifications in the subcomponents of the formulation. Clinical treatment with ketoprofen showed an average NRS of 7.77 ± 2.25 before and an average NRS of 2.45 ± 2.38 after MF treatment. There was a statistically significant reduction in NRS (p = 0.003) and in SF-36 (p < 0.005). Patients treated with KiOil showed an average NRS of 7.59 ± 2.49 before treatment and an average NRS of 1.90 ± 2.26 after treatment (p < 0.005). SF-36 showed statistical significance for all items except limitations due to emotional problems. A high-intensity pulsed magnetic field is an adjunct to topical treatment in patients with localized pain, and the effect of MF does not evidence significant effects on the molecules.High-intensity, low-frequency magnetic fields (MFs) have been widely used in the treatment of diseases and in drug delivery, even though they could induce structural changes in pharmacological molecules. Morphological changes in ketoprofen and KiOil were investigated through Fourier-transform infrared spectroscopy (FT-IR). Unsupervised principal component analysis was carried out for data clustering. Clinical validation on 22 patients with lower back pain was managed using diamagnetic therapy plus topical ketoprofen or KiOil. The Numerical Rating Scale (NRS) and Short-Form Health Survey 36 (SF-36) were used to evaluate clinical and functional response. Ketoprofen showed clear clustering among samples exposed to MF (4000–650 cm Needleless intradermal drug delivery represents a valid alternative to classic intracutaneous techniques in the treatment of various pathologies ,2. To da+ and Ca2+ voltage channels . PC. PC−1, aS evaluates clustering patterns among the samples and represent the variance on sample direction; L detects the variables that evidence the highest importance for the observed pattern on the scores and represent the variance on wavenumber direction; R points out eventual errors. PCA is useful to reduce dataset dimension in a small number of principal components (PCs) that cover most of the spectral data variance. The first PC represents the most part of data variance, followed by the second orthogonal PC, etc. .We conducted a pilot single-center open-label randomized clinical study between 1 June 2021, and 30 March 2022 in patients with lumbar pain referred to our ambulatory of Pain Medicine of the Operative Unit of Pharmacology and Pharmacovigilance of the University of Catanzaro. The study, approved by the Ethics Committee of Calabria Centro (number 15/2022), was carried out according to the Good Clinical Practice guidelines and with the ethical principles of the Declaration of Helsinki. Before the beginning of the study, all participants signed written informed consent.0), and 2 months later (T1: end of treatment), the physician blinded to the group of the study evaluated the NRS  in each treatment session and evaluated patients’ functionality through the Short Form Health Survey 36 (SF-36) questionnaire. Student’s paired t-test was performed with GraphPad. Diamagnetic therapy protocols used, according to the diamagnetic equipment  manual, are summarized in Patients with a clinical and instrumental (Magnetic Resonance imaging) diagnosis were enrolled and randomized to receive a topical treatment with topical NSAIDs (ketoprofen) (Group 1) or fixed compound (KiOil) (Group 2). Patients enrolled were male or female above the age of 18 with a diagnosis of chronic back pain (>3 months). Excluded patients included those who with pacemakers, prothesis or other implanted metallic devices, and with a diagnosis of cancer. At the time of enrollment (TInfrared spectra of wet and dried samples (at 50 °C under nitrogen flow for 2 min), were firstly analyzed. In −1 and 3000 cm−1 which is due to excipients, such as water. Previous investigations performed on biological samples evidenced how a proper removal of these components does not cause statistically significant differences among samples [−1). Dehydrated samples can be further analyzed to investigate the chemical/physical state of the drug in the considered formulation. The literature evidenced how pure ketoprofen is characterized by two absorption peaks at about 1655 cm−1 and 1697 cm−1, which are mainly due to C=O stretching in the dimeric carboxyl acid and ketonic group [−1 in the wet sample, shifted up to1588 cm−1 in the dry sample). Thus, the overall spectra can be heterogeneous and multiple interference can cause the onset of new absorption bands. The same analysis performed on KiOil which is a nutraceutical product evidenced a much lower contribution to the shadowing effect by interfering molecules. In this case, the absence of water inside the formulation is beneficial for FT-IR analysis. Comprising a mixture of different components , FT-IR spectra results were composed of related absorption bands. For example, arnica is characterized by strong adsorption bands around 1740 cm−1 and 1160 cm−1 caused Carbonyl stretching. Green tea is characterized by a strong absorption band around 1640 cm−1 (carboxylate), and other lower peaks in the bands from 1200 down to 800 cm−1, whereas pure Devil’s claw spectra evidenced absorption bands correlated to ether linkages , and phenolic OH groups (around 3000 cm−1) present in the Harpagoside [−1), more in particular down to 800/1000 cm−1. The gel is based on ketoprofen lysine salt and other excipients . The wet components of the formulation provide undesirable effect on the spectrum, creating a shadowing of molecular specific absorption bands.  samples ,23. Moreic group . The conic group ,39. The pagoside ,42. The −1 for ketoprofen lysine salt and 1800–600 cm−1 for KiOil). In −1) which contains specific features of the ketoprofen together with lysine salt (as showed in −1), evidencing that structural modifications in the nutraceutical product affect the formulation also in the fingerprint region . Hypertension and mild cardiovascular affections; osteoporosis/osteopenia, dysthyroidism and hyperlipidaemia were the most frequent comorbidities. All patients were previously treated with at least one pain controlling drug. The totality of the group (eleven patients) received NSAIDs .p = 0.003, < 0.05). SF-36 questionnaire data are available in A mean of 7.77 ± 3.09 sessions with PMFs were performed. During this period, nine patients (81.8%) consumed pain drugs. In total, six patients (54.6%) continued NSAID consumption during the diamagnetic therapy period: this choice was autonomous since we tried to reduce NSAID consumption. Interestingly, in their last session, six patients (54.6%) were still consuming a drug, evidencing a reduction compared with the beginning of the treatment. The Medium Numerical Rating Scale before treatment was 7.77 ± 2.25, whereas it was 2.45 ± 2.38 after treatment. This was statistically significant . SF-36 questionnaire data are available in Patients age was 58.63 ± 14.71. Females represented the majority of this group . Hypertension, hyperlipidemia, gastroenterologic pathologies, obesity, and other cardiovascular illnesses were the most frequent comorbidities. Ten (90.90%) patients were previously treated with at least one pain-controlling drug. A medium number of 7.27 ± 1.48 sessions with PEMFs therapy was performed. During this period, ten patients (90.90%) consumed pain drugs, according to our team, or on their own . In theiA standardized protocol has been defined to ensure reproducibility of data during single or multiple repeated analytical sessions. PCA is one of the most popular machine learning techniques for unsupervised clustering. Since our work data frame has a small sample size, PCA results are useful for exploratory analysis, evincing two subgroups covering the most part of variance. The used framework applied for preprocessing and clustering represents an initial step. Further studies aim to increase population size in order to apply a supervised classification and validate the diamagnetic therapy effects. Results obtained through an unsupervised classification technique evidenced not significant structural changes in the ketoprofen respect to KiOil. However, this cannot be suddenly considered as a negative effect since, in some cases, literature evidenced magnetic field have enhancing pharmacological effect. In any case, it is necessary to provide clinical evidence if these changes have beneficial effects or not.Diamagnetic therapy is based on PEMFs. In a randomised pilot trial by Vicenzino et al., PEMFs were used to transdermally deliver glucosamine, chondroitin and hyaluronic acid in a court of 114 male individuals with knee injuries. The effect of this therapy was compared with NSAID gel application alone. The PEMF group had superior results in pain control . As repoIn other pathologies, a RCT by Osti et al., showed short term benefits on shoulder pain (after rotator cuff repair) in a 66 patients court repair. However, these effects in pain control and functionality disappeared at a two-year follow-up . The triFew information is available on ankle pain. All of these sets of data allow us to highlight an important consideration: pulsed magnetic-field therapy effects may also weaken as time goes by, and functionality improvements are not visible in all subjects. However, parameters, device, and time of treatment varied greatly in all these studies. On the other hand, given the characteristics of diamagnethotherapy of selective interaction with biological tissues, it is important to consider this therapy as a drug finding the proper dosage for each patient and the right protocol basis for the single pathology . 1.8 and NaV1.9, down-regulated in painful conditions, were re-regulated after PEMF treatment [The efficacy of this therapy may be due to many different mechanisms. Modulation on neuropathic pain component. An animal model by Coksun et al. showed that low-frequency PEMFs are capable to modulate ionic channels in rats. Sodium channels NaVreatment . In an ireatment . Moreover, PEMFs modulate several ligand binding and receptor activity. They act as antagonist of A2A and A3 adenosin receptors, reducing the release of pro-inflammatory cytokines, the expression of NFκB and of prostaglandin E2 (PGE2). Furthermore, they seem to modulate bone formation . AnotherTopical treatment in addition to diamagnetic therapy seems to be a safe approach in reducing drug adverse events. Despite the possibility of local reactions and a small number of systemic reactions, topical analgesics are sharply safer .SF-36 questionnaire items showed important results. Significant improvements of all items were registered in ketoprofen group. In KiOil group all the items, except energy/fatigue, limitations due to emotional problems and social functioning. This fact should be related to patients baseline high capacity in social and emotional sphere.Finally, confounding factors may have affected SF-36 results: one patient have rheumatologic comorbidities, since pain level is also influenced by the control of this pathology . OtherwiIn this study, we presented a technique for drug analysis of molecules exposed to pulsed high-intensity low-frequency magnetic field using FT-IR ATR and multivariate classification algorithm. The first part of the work was focused on the standardization of a protocol for the analysis of drug molecules of pharmacological interest exposed to MF. Diamagnetic therapy is a useful add-on therapy to manage chronic and acute pain. Millions of patients suffer from pain. Pain is a real syndrome capable of affecting physical and psychological components of individuals. Although PEMFs have been well known for a long time, the absence of specific guidelines, of large RCT and the lack of homogeneity in devices are still important limits that did not allow us to use this therapeutic option in a rigorous way. Our study showed that this therapy is capable to reduce pain and improve physical functioning in certain patients, in addition to pharmacologic treatment. In particular, our analysis on 22 patients with chronic lower back pain showed an important improvement on pain control and functionality. These subjects benefited from the concomitant transdermal administration of topical substances, vehiculated by diamagnetic therapy. Ketoprofen and KiOil are only two of the possible products that may be administered in this clinical context. Diamagnetic therapy may offer a safe approach to manage several chronic pain conditions including shoulder, low back, knee, cervical, and ankle pain of different causes and origins. This approach has a key advantage: the possibility of reducing the number and the dosage of drugs of used for pain management. In fact, these compounds are characterized often by several adverse events and the necessity of chronic consumption. However, our study has an important limitation in the number of patients examined. This study may be the basis for larger RCT dedicated to specific pathologies, and scenarios have been used to assess real-life effectiveness, the most responsive patients, and long-term effects.