CYP2D6 PGx testing to inform chronic pain medication management for poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Future efforts to implement PGx testing in chronic pain management, however, must address patient concerns about genetic test result access and genetic discrimination. Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study  are open to pharmacogenetic testing, and most  believe that genetic testing has the potential to improve their medical care. Our results further support the potential for  The Camden Opioid Research Initiative (CORI) is a multi-armed research study  consistiIn theory, pharmacogenetics has the potential to improve medication management by increasing medication efficacy and decreasing adverse drug reactions ,6,7,8,9.CYP2D6 plays an important role in the metabolism of several commonly prescribed opioid pain medications, including oxycodone [CYP2D6 gene, CYP2D6, is the primary enzyme that metabolizes each of these medications into the active metabolites that provide the majority of analgesia [There is strong evidence that xycodone ,12,13,14xycodone , tramadoxycodone ,14,16, axycodone ,18. The nalgesia , codeinenalgesia , tramadonalgesia , and hydCYP2D6 and opioids [CYP2D6 and codeine, tramadol, and hydrocodone [CYP2D6 [The Clinical Pharmacogenetics Implementation Consortium (CPIC) supports the implementation of PGx testing in clinical care. CPIC guidelines for  opioids  categori opioids ; each of opioids  and each opioids . CPIC furocodone , althoug [CYP2D6 . CYP2D6 pharmacogenetic testing in chronic pain management [CYP2D6-guided treatment and usual care patients with chronic pain. Importantly, the authors found a significant pain reduction in CYP2D6-guided care patients (n = 51) relative to usual care patients (n = 19) in the subset that was IM and PM that was prescribed hydrocodone, tramadol, or codeine at baseline. One recent study in Florida assessed the potential clinical utility of nagement . Smith enagement  comparedOPRM1 gene (rs1799971) potentially reduces the response to buprenorphine [CYP3A4 variant rs2740574 T allele  may increase the rate of buprenorphine metabolism and thereby increase the rate of withdrawal as well as decrease its overall efficacy [With respect to OUD treatment, the Center for Healing at Cooper University Health Care routinely treats with buprenorphine. Buprenorphine is a partial, high-affinity mu-receptor agonist shown to be an effective treatment for persons with opioid use disorder . While tnorphine ,21, and efficacy , this evOPRM1 and CYP3A4 variation.Given the established role of CYP2D6 in the metabolism of many opioids used in pain management, the encouraging chronic pain management PGx results  and the GOALS and OPTIN are prospective, observational studies that include the collection of self-reported demographic and perception survey data at enrollment. In addition, participants are asked to grant access to their electronic health records for up to five years prior to baseline enrollment and up to 12 months after baseline enrollment [CORI study enrollment criteria consist of an age of at least 18 years, English language proficiency, written informed consent, willingness to provide a saliva sample for DNA analysis, and either in-treatment status for chronic pain at Cooper University Health Care clinic (OPTIN) or in-treatment status for opioid use disorder at the Center for Healing at Cooper University Health Care as defined by DSM-5 (GOALS) [The study was conducted according to the guidelines of the Declaration of Helsinki. The study protocol was reviewed and approved by Western IRB (IRB study # 1251380 for GOALS and # 20190132 for OPTIN), as well as by the IRBs of Cooper University Health Care (IRB study # 19-025 for GOALS and # 19-030 for OPTIN) and Coriell Institute for Medical Research (Study #R164 for GOALS and #R165 for OPTIN). Written informed consent was obtained from all subjects involved in the study after an in person review with study staff and after all questions were answered. Participants could choose not to participate in the study without any penalty or loss of benefits. In addition, participants could choose to withdraw from the study at any time without any penalty or loss of benefits.CYP2D6, OPRM1 and CYP3A4. In total, 119 participants enrolled in OPTIN, and 125 participants enrolled in GOALS. All of the GOALS and OPTIN participants answered demographic questions and completed a baseline genetic perception survey  run on a QuantStudio TM Flex 6 Real-Time PCR system , and copy number was calculated using CopyCaller ® Software .Of the 125 GOALS and 119 OPTIN participants, 118 GOALS and 114 OPTIN successful DNA extractions were sent for low pass sequencing, and the subset of 113 GOALS and 109 OPTIN WGS data passed Gencove quality checks for minimum coverage of total bases sequenced and variants covered with at least one read. Given the the 4x coverage data, we were unable to infer the CYP2D6 genetic variation and corresponding CYP2D6 metabolizer status in a previous study [All genetic data collection included a sample (n = 197) of DNAs previously collected and assayed for us study  to assesAll genetic data collected for this study were for research purposes only. No clinical PGx testing was performed, and no clinical PGx results were returned to clinicians or patients. All study results presented below consist of data collected at baseline.In total, participant baseline perception data from 119 participants enrolled in OPTIN and 125 participants enrolled in GOALS were retained for analysis. In total, genetic data from 113 OPTIN participants passed all of the quality control checks listed above and were retained for baseline medication management analysis. In total, genetic data from 102 GOALS participants being treated with sublingual buprenorphine passed all of the quality control checks listed above and were retained for baseline medication management analysis. All data analysis was performed using standard R functions (Version 3.6.3) , includiIn total, data from 244 participants are included in the current study: 125 participants enrolled in GOALS, and 119 participants enrolled in OPTIN. As displayed in p-values > 0.05) with the answer to this survey question . One patient strongly disagreed with this statement and reported concerns about genetic discrimination and about who would have access to their genetic test results. Out of 12 people that disagreed with the statement, five (45%) were concerned about who would have access to their genetic test results, and one (9%) was concerned about genetic discrimination.p-value > 0.05) between metabolizer status categories  for any of the medication categories ; however, we note that according to the electronic health records, none of the four PMs were exclusively taking opioid pain medications that required CYP2D6 for metabolism at baseline. One of them was only being treated with non-opioid pain medications at baseline; one was being treated with a combination of opioid pain medication that requires CYP2D6 for metabolism as well as non-opioid pain medications at baseline; and the other two were being treated with a combination of opioid pain medication that requires CYP2D6 for metabolism, opioid pain medications that do not require CYP2D6 for metabolism, and non-opioid pain medications at baseline. We additionally note a visual trend for UMs to be treated with a larger number of non-opioid pain medications; however, this trend was not statistically significant .OPRM1 gene playing a role in buprenorphine [p-value > 0.05). Finally, we explored the relationship between CYP3A4 variation, particularly rs2740574, which defines the *1b allele [p-value > 0.05). CYP2D6 does not play a role in metabolizing buprenorphine, the primary medication used for opioid use disorder treatment at the Center for Healing at Cooper University Health Care; however, given the moderate CPIC cited evidence for variation in the norphine ,20,25, wWhile pharmacogenetics has the potential to improve medication management ,5,6,7,8,We first considered evidence for a PGx role in medication management in each clinical setting. For chronic pain management with opioids that require CYP2D6 activity for analgesic benefit  agree or strongly agree with the statement, “Genetics have the potential to improve my medical care”. This result is consistent with results from the Mayo Clinic RIGHT protocol  study that found the majority of participants (87%) agreed with the statements regarding pharmacogenomic results having the potential to improve medication choice and dosing . In respOPRM1 gene (rs1799971) potentially reduces the response to buprenorphine [CYP3A4 gene impacts buprenorphine response. One or two copies of the rs2740574 T allele  may increase the rate of buprenorphine metabolism and thereby increase the rate of withdrawal and decrease overall medication efficacy [Published evidence for a potential PGx role in OUD medication management is less clear. Variation in the norphine ,21, and norphine . Similarefficacy . We did Perception survey results for the GOALS cohort  were similar to the OPTIN cohort. The majority of the GOALS cohort (69%) agree or strongly agree with the statement, “Genetics have the potential to improve my medical care”, and in response to “If there was a genetic test that would advise your doctor on which of the three opioid use disorder medication-assisted treatments  would work best for you, how much would you want to get tested?”, a similar majority (66%) chose extremely or considerably . A non-tA general patient PGx perception study conducted in Spain has shown a higher proportion (99%) of patients agreeing that pharmacogenetic testing is beneficial . StudiesTo our knowledge, this is the first report of patient perceptions of pharmacogenetic testing in the context of chronic pain management and OUD treatment, and the majority of patients were open to PGx testing in both of these clinical settings. Patient concerns about genetic test result access and genetic discrimination, however, should be seriously considered and weighed against the potential benefits of clinical PGx testing in clinician discussions with their patients prior to clinical PGx testing. Concerns about PGx test result access and discrimination were previously documented in two general studies of pharmacogenetics ,32.Limitations of our study include the modest sample size recruited from a single clinical center, particularly the modest sample size of CYP2D6 poor metabolizers (N = 4) and ultra-rapid metabolizers (N = 5), which limit the statistical power we had to detect statistically significant differences in opioid and non-opioid pain medication management. In addition, we used cross-sectional, baseline electronic health record medication data, which did not include information about whether OPTIN and GOALS patients had reached stable dosing and treatment targets.CYP2D6 PGx testing to inform chronic pain medication management for PMs and UMs. To realize the potential benefits, however, future efforts to implement CYP2D6 PGx testing in chronic pain management must address patient concerns about genetic test result access and genetic discrimination. Our study of chronic pain and opioid use disorder patients treated at Cooper University Health Care in Camden City, NJ demonstrates that most patients in both arms of the study are open to pharmacogenetic testing and believe that genetic testing has the potential to improve their medical care. Our results further support the potential for


Resilience and coping ability were less affected by the rehabilitative treatment. Our attempt of mind-body technique telerehabilitation has shown good results in the improvement of painful symptoms and quality of life for the FM patients but showed fewer positive impacts for the resilience and coping abilities aspects.Fibromyalgia (FM) syndrome is characterized by the close correlation of chronic widespread pain and other non-pain related symptoms. Aim of this study was to investigate whether telerehabilitation that provides physical and psychological support services of the mind-body techniques can affect the clinical profile and pain relief of FM patients. The study included twenty-eight female FM patients, mean aged 56.61 ± 8.56 years. All patients underwent a rehabilitation treatment  through Zoom platform, with the following principles of rehabilitation treatment: Anchoring to a positive emotion; listen and perceive your “own” body; conscious breathing; improve interoceptive awareness; relax. All patients then underwent clinical assessment of the physical distress and fear of movement for the Numeric Rating Scale (NRS); the Fatigue Assessment Scale (FAS); the Fear Avoidance Belief Questionnaire (FABQ); with measures of physical and mental disability for the Fibromyalgia Impact Questionnaire (FIQ); the 12-Items Short Form Survey; the Resilience Scale for Adults and the Coping Strategies Questionnaire-Revised. The evaluations were performed at T0 (baseline), T1 (after 8 weeks of treatment), and T2 (after 1 month of follow-up). The main finding was that telerehabilitation reduced physical and mental distress, fear, and disability ( Fibromyalgia syndrome (FM) is characterized by the close correlation of chronic widespread pain and other non-pain related symptoms, such as fatigue, poor sleep, and cognitive disturbances, which are variable during the disease. Surely, the physical and psychological distress have a continuous distribution in the FM characterizing the clinical profile of each fibromyalgia patient . It occuAlthough the etiology of this condition is unknown, its onset and maintenance appear to be explained by a complex interplay between genetic/biological and psychosocial factors, which negatively affect the course of the disease and the quality of life .It has been suggested that a multidimensional approach is the best option for the care and cure of FM patients that include pain management, pharmacological therapies, patient education, rehabilitative approach and psychological interventions are recommended. Since evidence suggests that only a small portion of FM patients continue to follow their doctors’ prescriptions for pharmacotherapy over time due to diminished effectiveness, side effects, and costs, non-pharmacological intervention, as rehabilitative exercise and mind-body technique, has recently gained attention. For example, low to moderate aerobic and muscle strengthening exercises represent an effective way of reducing pain in FM patients. .The relevant role of pain management, also psychological factors should be taken into account, as psychological factors significantly contribute to both symptomatology and functioning in the treatment response in chronic pain patients.Fear of movement, in fact, is associated with worse physical functioning and higher levels of pain intensity, while protective factors such as higher resilience and functional coping skills are associated with lower symptom burden and better adjustments . Thus, aAlso mind body interventions , that arFor example, guided imagery relaxation therapy could be incorporated as part of FM treatment with breathing technique to improvement in physiological reactivity to a standard laboratory stressor .Patients with FM should be monitored in terms of psychological distress, especially during the pandemic period . The COVAlso, during the pandemic period of the SARS-CoV-2, the provision of face-to-face rehabilitation therapies was, often, not possible for lockdown and restrictions to prevent the spread of COVID-19 and reduce the infection risk .The, telerehabilitation architecture, with separate units for delivery of therapeutic protocols, recording of performance, and providing of feedback and monitoring progress could be an important resource .stress, resilience, and coping) in order not only to verify the effectiveness of the therapy, but to understand which are the patient’s weak points on which to intervene , or other causes of chronic pain; other diseases that prevented physical loading; surgery of the spine; vertebral fractures; sciatic pain; tumors; and enrollment in another type of physical therapy program. Patients were excluded if they had comorbidities, such as cardiovascular risk factors, previous myocardial infarction, lower extremity arterial disease, major neurological problems, diabetes, gastrointestinal disease, chronic respiratory disease, kidney disease, and severe poor vision.All patients were given explanations about the study by the referring psychologist and by the physician speacialized in physical medicine and rehabilitation through an on-line one-to-one interview.Self-report questionnaires were administered to analyze the evolution of physical and psychological conditions in patients during the study. The different measures were divided into four groups: 1) Physical distress and fear of movement, 2) physical and mental disability, 3) resilience and 4) coping ability. The evaluations were performed before treatment (T0 = baseline), at the end of the rehabilitative treatment , and after 1 months of follow-up (T2).Numeric Rating Scale (NRS) for pain. This scale consists of one specific item, which measures the level of pain suffered by the patients. Score is from 0 (no pain) to 10 (maximum pain) and the higher the score is the higher the level of pain . This scale consists of ten items with a 5 points Likert scale. The higher the score, the higher level of fatigue or distress felt by the patient. The scale is divided into two subscales, each with 5 items: the Physical FAS (P-FAS) which measures physical fatigues and the Mental FAS (M-FAS) which measures cognitive fatigue ( fatigue .Fear Avoidance Belief Questionnaire (FABQ). A self-report questionnaire that consists of 16 items with a 6-point Likert scale. The total score ranges from a minimum of 0 to a maximum of 96. The higher the score, the higher is a patient’s fear and tendency to avoid movement . This scale consists of 20 items with a 5 points Likert scale. The higher the score, the higher the level of disability by the patient. This scale also includes a subscale for measuring the level of anxiety experienced along with the disability (Anxiety-FIQ or A-FIQ) (r A-FIQ) .12-Item Short Form Survey (SF-12). This scale is a self-reported outcome measure assessing the impact of health on an individual’s everyday life. The lower the score, the higher the level of disability experienced by the patients. The scale includes two types of disability scores: A physical (PSF-12) and a mental score (MSF-12) ((MSF-12) .Resilience Scale for Adults. This scale examines intrapersonal and interpersonal protective factors presumed to facilitate adaptation to psychosocial adversities and consists of 33 items with a 7 points Likert scale. The higher the score, the higher the patience’s resilience. The scale includes six subscales for intrapersonal and interpersonal factors of resilience. The intrapersonal factor subscales are: Perception of Self (RSA-PS) which evaluates the individual’s confidence in her/his abilities; Planned Future (RSA-PF) which assesses the individual’s ability to make plans for future; Social Competence (RSA-SC) which assesses the individual’s ability to socialize with others and Structured Style (RSA-SS) which evaluates the individual’s ability to organize her/his activities. The interpersonal factor subscales are: Family Cohesion (RSA-FC) which evaluates the support received by the individual from her/his family and Social Resources (RSA-SR) which evaluates the support received by the individual from her/his friends or others (Patients’ resilience was measured with the r others .Coping Strategies Questionnaire-Revised (CSQR) that consists of 27 items with a 6 points Likert scale  were present at the session, with the camera turned off or on as desired.The rehabilitation therapies were performed using the Zoom platform in collaboration with the Italian Association of Fibromyalgia Syndrome (AISF), Abruzzo Section, L’Aquila, Italy and through the google-moodle platform the above mentioned scales were made available. All patients made a synchronous connection by creating a virtual class of participants: the rehabilitation session was performed by the physiotherapist who showed all the phases of the exercises in sync with the patients. Together with the physiotherapist, the physiatrist and the psychologist of the IAFS  anchoring to a positive emotion through the choice of a color; 2) “here and now”: listen and perceive your “own” body in motion; 3) conscious breathing; 4) “close your eyes”: improve interoceptive awareness during exercise; 5) relaxation: Breathe, moving slowly and without pain .At the beginning of each session, the physiotherapist reminded the patients of the importance of having comfortable clothing, bare feet or wear non-slip socks, a comfortable and peaceful environment (those who wished could insert a background music of their choice). Patients were asked to have the camera on and the microphone off. Each patient could, in case of need, turn on the microphone to ask any question when switching exercise.1) Proposal of the color associated with the session. Request to the patient to visualize a scene, in an external environment, natural with pleasant memory. Maintain these positive emotions and feelings associated with the memory during the session. At the patient’s choice, metaphorically paint a part of the body with the reference color. We used 8 color stimuli: Red, orange, yellow, green, blue, purple, pink, and brown.i) About 5–15 min of warm-up, with a light walk on the spot, then adding the movement of the arms, alternately and rhythmically.ii) Patient in the supine position, knees bent, become aware with the phases of the breath. Then, work on conscious breathing, with eyes closed and alternate normal breathing with diaphragmatic breathing exercises.iii)Exercises of active mobilization, with phases of isometric maintenance of posture at the end of the sequence. The patient began the exercises in a supine position, then on the side, followed by a quadrupedal position and, finally, in an upright position. All movements were proposed to the patient with open eyes and then with closed eyes, rhythmic speed with the slow rhythm of breathing and recognizing and perceiving the movement and position of the body in space. The physiotherapist, in the first sessions explained the exercises and illustrated them, then guided movement with her voice in every aspect. In the following sessions, the therapist guided with her voice and simultaneously performed the exercise together with the patients.i) exercises for active joint mobilization of the lower and upper limbs ;ii) self-mobilization exercises of the spine;;iii) “bridge” and “cat” exerciseiv) lower and upper limb coordination exercise in quadrupedal position and standing positionv) exercise to maintain balance in single stance;; When the patient performed the movement with his eyes closed, he was asked to imagine it before performing it (motor imagery task). The sequence used was: eyes open - eyes closed - eyes open (5 repetitions) at a time.vi) exercise of maintaining balance in mono-podalic support with hip abductionvii) exercises of active global stretching, on the mat in the first 4 sessions and, also, in standing position in the last 4 sessions.Each movement was repeated 5–10 times, with rest breaks of at least 1–2 min between the execution of one repetition and the next:All patients were always asked to stop if they experienced pain. The physiotherapist adapted and controlled all the exercises to avoid any adverse event and to ensure patients’ safety. See A multivariate analysis was performed on different measures of physical and psychological characteristics of FM patients under telerehabilitation. The aim of these analysis was double: firstly, we analyzed the temporal evolution of physical and psychological characteristics during the three periods of evaluation time ; subsequently with multidimensional scaling applied to all physical and psychological measures, we identified the latent dimensions by which it should be possible to categorize FM patients under telerehabilitation to allow the implementation of specific intervening strategies and rehabilitative care profiling FM patients.Subsequently, multidimensional scaling showed to be a valid method of analysis in defining rehabilitative care, profiling FM patients’ under treatment or medical intervention . More inA descriptive statistic was provided for demographic and biometric data: Mean, standard deviation, standard error, skewness, and kurtosis. Skewness and kurtosis values between −2 and 2 indicate good distribution of the data .We analyzed the trend of the rehabilitation effects on the measures of physical distress and fear, physical and mental disability, resilience, and coping ability using the regression analysis with orthogonal polynomial coefficients was used. The polynomial coefficients for the linear trend were −1, 0, and 1, and the coefficients for the quadratic trend were −1, 2, and 1. Test was applied to determine whether the linear or quadratic trend was significant. Positive (negative) t values for the linear trend indicated a constant increasing (decreasing) effect from T0 to T2 and a maximum (minimum) effect in the middle (T1) of the time series . We alsoMultidimensional scaling (MDS) was applied to define the latent dimension of patients under telerehabilitation. To define the number of latent we followed the procedure of Oganian and colleagues .r, because it is a more reliable values of the connection between variable  strongly significant, indicating evidence of telerehabilitation efficacy.The root mean square of coefficients of determination and the mean of correlations among all variables for T0, T1, and T2 were reported in the Our hypothesis was that a telerehabilitation program based on body awareness exercises in movement and muscle stretching, linked to mindfulness “Here and Now” strategies, could improve the main FM symptoms during the period of mobility restrictions imposed by the COVID-19 pandemic. Moreover, the various forms of social support by technology and a positive life approach appear to be protective with respect to the emotional and psychological distress caused by the pandemic . ConsideHowever, resilience and coping ability, measured by RSA and CSQR subscales, are less or none affected by telerehabilitation on our sample. This could indicate that resilience and coping ability are individual characteristics probably more connected to the personality and psychological attitudes of patients, more than to the rehabilitative process. Or, from another point of view, it could be a limitation of the rehabilitation proposals not face to face with the physiotherapist and physiatrist .Therefore, rehabilitation has a strong positive impact on patients’ quality of life, but their psychological reaction to their physical conditions is partially affected by a remote rehabilitative therapeutic process.Considering the limitations of the retrospective observational studies, however, our results are encouraging, as in fact two important issues were shown: firstly, telerehabilitation improve FM patients’ conditions, because there was significant reduction of the levels of pain, fear of movement and disability. Secondly, the reduction of patients’ physical and mental distress  during the study highlights the improvement in the quality of life in patients due to the applied telerehabilitation.The latent factor of stress includes all the negative physical and psychological aspects of rehabilitation that are, above all, the disability, sufferance and fatigue that afflict the patients. The latent factor of coping includes all the measures connected to the patient’s ability to cope or manage the stressful events during the rehabilitation, the ability to tolerate pain, continue activity and cope with the fear of therapy. In particular, FM patients showed a notable lack of self-forgiveness as problem (distress and catastrophizing) with a negative emotional status, also alexithymia related, that reduces and limits coping strategies .However, our rehabilitation protocol was mainly based on the awareness of movement, using “color” as a positive emotional anchor to induce chosen low intensity movement. An approach oriented to mind-body techniques, proposed with benefit in fibromyalgia patients and spine chronic pain . This inFor example, the therapy is not very effective because the patient has a low tolerance to pain and suffering, is not very resilient, or because she does not have the coping resources necessary to deal with the discomforts and difficulties: the evaluation of these important aspects by the rehabilitation team  would give the possibility to really adapt the rehabilitation path according to the needs of the individual patient.It should be noted that FM share several clinical manifestations  with other diseases as temporomandibular disorders (TMD) . A potenDuring the COVID-19 pandemic emergency, telemedicine, which includes telerehabilitation, enabled us to closely monitor FM patients over time, provide feedback, and our presented telerehabilitation tool can even offer future opportunities for cognitive-motor assessment. This important therapeutic resource should be maintained and used in parallel to traditional therapeutic pathways to more optimally serve and challenge in chronic diseases both physically and cognitively over time in future lockdowns, to provide long-term remote training and feedback .We are aware that this study is not free from limitations: first, the lack of the control group (for example in the waiting list), which given the contextual need for care to be provided and the lockdown period it was not possible to enroll; second, the short follow-up of re-evaluation, linked to the fact that some patients would soon have started other treatments (for example yoga courses online); third, the study design that does not define a cause and effect relationship.Also, we did not use measurement tools  or expert evaluations that could indicate the usefulness to implement the tool for a clinical setting. For future studies, it would be interesting to measure the feedback of the patients, but also of the caregivers on the applied telerehabilitation therapy, also using the chat unit that was manned by physiotherapist/physiatrist/psychologist during the sessions.The literature points out that telerehabilitation has shown to provide comparable results to outpatient physical therapy and to face-to-face home rehabilitation, while reducing costs . FurtherIn addition, the organized architecture at the base of telerehabilitation would make it possible to deliver rehabilitation care asynchronously, and to reach the patient at any time of the day .Also, it would be interesting to investigate if and how the body and mind telerehabilitation approach could be of benefit to other chronic non-communicable diseases above all in elderly patients or in psychologic confidence-lacking patients. As reported by In conclusion, the FM remains a complex pathology with an interconnection between psychological and physical factors that might lead patients to suffer a chronic and disabling pain syndrome. Indeed, it should be taken into consideration that the mind and body could play a key role in the pathogenetic mechanism of the clinical manifestations of FM, including: Generalized chronic widespread pain, fatigue, sleep disturbances, psychological distress and cognitive alterations, joint rigidity with muscle stiffness, and tenderness.By the present study, our attempt of mind-body technique telerehabilitation has shown good results in the improvement of painful symptoms and quality of life in the FM patient, not the same for the psychological aspects. Future studies are desirable to confirm these data in a larger sample according to the RCT model. Further developments, to re-propose more in depth, the rehabilitation protocol could provide for the support of artificial intelligence interfaces to analyze the patient’s mood and participation in the therapy with facial expressions.


Knee osteoarthritis (KOA) is ubiquitous. However, effective pain managements for patients with grades 3 or 4 KOA for whom conservative treatments are unsuccessful, but for whom surgery is not an option, remain lacking. This case series presented two motor-sparing interventional pain treatment modalities for five such patients. Three of the patients with a mean total WOMAC score of 41 underwent thermal radiofrequency (RF) ablation using a modified motor-sparing approach. One-week and four-week post-RF, the total score dropped to 27 (by 34%) and 19 (dropped 53.7%), respectively. Two other similar patients with a mean total WOMAC score 96 underwent chemical neurolysis using a motor-sparing approach with modified landmarks. The WOMAC score dropped to 58.5 (by 39.1%) and 49 (dropped by 49.0%), one-week and four-week postchemical neurolysis, respectively. A narrative review of the currently available approaches is also provided, with the conclusion that neural ablation using the modified landmarks approach may achieve better pain control and preserve the motor functions for patients with severe KOA for whom conservative treatment was unsuccessful and who are not candidates for surgery. Knee osteoarthrosis (KOA) is a very common joint disease, with a prevalence ranging from 4.2% to 15.5% and gradually increasing with age . Pain anThis case series describes and evaluates the outcomes of alcohol neurolysis and thermal RF ablation of the articular branches of the knee in KOA. Patients with KOA pain who underwent knee articular branch denervation via chemical neurolysis or RF ablation between April 2021 and Jan 2022 were included in this report. Institutional approval was sought from the New Territories West Cluster (NTWC) Research and Ethics Committee, Hospital Authority, Hong Kong (Reference no: NTWC/REC/21090).2 supplementation or assisted ventilation, (4) previous ipsilateral total knee arthroplasty or denervation, (5) concomitant lumbar spinal stenosis with lower limb radicular pain, (6) concomitant chronic hip and low back pain, (7) presence of significant psychiatric illness, or (8) significant coagulopathy . Written informed consent for both the procedures and potential publications was obtained before all neuroablative procedures.Patients with severe KOA pain in public hospitals are usually referred to pain services for nonsurgical management when they are inoperable. Inoperability was defined as (1) unacceptably high risk associated with anesthesia as assessed by an anesthesiologist, (2) unacceptably high risk associated with surgery as assessed by a surgeon, or (3) patient refusal of surgery. Another reason for referral was the prolonged waiting time for total joint replacement. Between Apr 2021 and Jan 2022, all such patients presenting to the pain service of the public hospital were evaluated for knee joint denervation. The treatment modality was based on our institutional experience with satisfactory pain control with knee denervation. To be eligible for the denervation, patients had to fulfill the following criteria : (1) radiographic confirmation of KOA of grade 3 or higher unresponsive to conservative treatments, (2) moderate-to-severe pain according to the patient or their caregiver, and (3) a positive diagnostic block (defined as an improvement of Western Ontario and McMaster Osteoarthritis (WOMAC) score ≥ 50%). The following exclusion criteria for knee denervation were also applied: (1) inability to assume a recumbent or semirecumbent position, (2) significant cardiac morbidity with hemodynamic instability, (3) respiratory failure requiring >50% OAt our institution, the motor-sparing neural ablation of the knee is accomplished using either alcohol neurolysis or thermal RF ablation. The anatomical basis for such neural ablation procedures was based on the recent cadaver studies by Tran et al. and by Fonkoue et al. –12. The For the medial or lateral branches of NVI, a high-frequency linear transducer was first placed longitudinally along the femoral shaft to look for the junction between the femoral shaft and its medial epicondyle. The accompanying superomedial or superolateral genicular artery should be identified as a guide to target the nerve. The transducer was then turned 90 degrees to provide a transverse view perpendicular to the femoral shaft. Using an in-plane approach, the RF needle was advanced percutaneously toward the area connecting the femoral shaft to the medial or lateral epicondyle (epiphysis/diaphysis junction) at the middle of the measured anteroposterior depth of the femoral shaft. The periosteum appeared as an echoic line running along the cortical bone. The RF needle was further advanced until the needle tip reached the fascial plane immediately above the periosteum. A supplementary coronal view allowed checking of the position of the needle tip close to the nerve and the vessel . The RF The next target for RF was the adductor tubercle which was the true target for the SMGN. The transducer was placed in a coronal orientation over the medial femoral epicondyle and then slide proximally to the adductor tubercle. The target for RF was the bony cortex 1 cm anterior to the peak of the adductor tubercle, using an in-plane approach. This was often accompanied by the superomedial genicular artery. After denervating the SMGN, the needle could be further advanced beyond the adductor tubercle, and another denervation could be done 0.5–1 cm posterior to the peak of adductor tubercle. This was often accompanied by the saphenous branch of descending genicular artery .At the superolateral side of the femur, two needle targets were needed to cover the relevant nerves. The first target was the junction between the femur shaft and the lateral epicondyle as the superomedial side. It covered the lateral branches of NVI . A supplTo target the IMGN, the transducer was placed in a coronal plane over the medial femorotibial joint line and a long-axis linear slide distally to visualize the tibial enthesis of the medial collateral ligament. Once the nerve and its accompanying inferomedial genicular artery were identified, the transducer was then turned 90 degrees transverse to the axial orientation. Using an in-plane approach, the needle was advanced from anterior to posterior to fit at the midpoint of the tibial width, close to the periosteum. A supplementary coronal view allowed checking of the needle tip beneath the medial collateral ligament, close to the nerve and the vessel .Posteriorly, using a curved probe, PNP could be ablated by putting an RF needle from lateral to medial in a supine position with the knee flexed at around 90 degrees. Three stacked radiofrequency lesions were created in the subcutaneous interspace between the popliteal artery and posterior knee capsule along the line joining the superior aspect of the two femoral condyles. If the chemical approach was adopted, the needle trajectory was modified such that the needle advancement was maintained underneath the lateral head of gastrocnemius and plantaris while the final needle position was the same .For quality assurance purposes, we assessed and documented each patient's pain scores and functional status before and after the intervention. The WOMAC is a common tool used to assess these impacts on patients with KOA. It has three domains  and contains a total of 24 questions. Each question is rated between 0 and 4 depending on the severity.The primary outcome measure was the total joint WOMAC pain score at 1-week and 1-month postintervention compared to that before the pain intervention. The secondary outcomes were the total WOMAC score, the total knee stiffness score in the WOMAC, the total functional score in the WOMAC, and the overall WOMAC score across the same time points. Adverse events were defined as unfavorable and/or unintended findings  or symptoms associated with the study procedure, for instance, prolonged postprocedural pain and hematoma. All the postprocedural follow-ups were conducted by pain nurses in the pain clinic.The COVID-19 pandemic substantially disturbed the provision of elective pain service to chronic pain patients, leading to a small patient load during the current study period. Five patients fulfilled all requirements and were thus evaluated. Two patients underwent alcohol neurolysis while the other three underwent thermal radiofrequency ablation. The patient demographics are listed in The exact WOMAC scores of the patients are shown in Regarding the overall preintervention status, the mean total WOMAC score of all the five patients undergoing the modified motor-sparing neural ablative therapy was 63/96. One week after the neurolytic procedure, the total WOMAC score had reduced to 39.6/96 (drop by 37.1%) and further reduced to 31/96 (dropped by 50.8%) at 1-month postintervention. The overall mean pain score reduced from 15.6/20 before the procedure to 7.8/20 (dropped by 50%) and 5.8/20 (dropped by 62.8%) at 1-week and 1-month postintervention, respectively. The overall mean stiffness score had improved from 5/8 preoperatively to 2.4/8 (reduced by 52%) and 1.6/8 (reduced by 68%) measured at 1-week and 1-month postoperatively. The overall function score had improved from 42.4/68 preoperatively to 29.4/68 (improved by 30.6%) and 21.6/68 (improved by 49.1%) at 1-week and 1-month postintervention, respectively .Clinical neurological examination of the lower limb was routinely performed after the denervation procedure. Neither motor nor sensory deficit was elicited in any recruited patient. On subsequent follow-ups, no wound infection was detected by the pain nurse in any recruited patient.Innervation of the knee joint follows Hilton's law, which states that the nerves supplying a joint also supply the muscles moving the joint and the skin over the joint . The innSensory input for the anterior knee joint capsule  is carriSensory input for the posterior knee joint capsule originates from the posterior division of the obturator nerve (PON), the sciatic nerve (SCN), the CFN, and the TN . These bPericapsular denervation techniques for the major joints have opened new horizons for interventional pain physicians involved in the management of advanced osteoarthritis of the major joints. While regenerative injection therapy is proven to be useful in reducing pain and improving function in KOA –17, its We extrapolated our experience with alcohol neurolysis and thermal radiofrequency ablation in hip fractures or inoperable osteoarthritis of the hip to the management of advanced inoperable KOA –21. The Interestingly, the functional score was improved to a relatively smaller extent for both treatment modalities. This can be explained by the KOA severity. The patient who underwent alcohol neurolysis was often nonambulatory, and the resultant lower limb muscle wasting could be anticipated, thus a lesser impact on the functional score improvement. In patients who underwent thermal RF, the mean functional score was not high initially and, thus, was difficult to improve significantly. Moreover, a variety of other factors affect overall functional performance, such as altered biotensegrity secondary to joint deformity and chronic intracapsular inflammation.In our patients, the overall benefit of alcohol neurolysis appeared to be noninferior to the traditional denervation by thermal radiofrequency ablation. No transient neuritis or an initial pain flare-up was detected in any of these patients 1-week postintervention.Motor-sparing denervation/neuromodulation techniques for the knee joint are basically categorized into four main approaches. The earliest approach is to target the saphenous nerve or its infrapatellar branch. Pulsed radiofrequency is the usual neuromodulation technique applied, while thermal radiofrequency ablation or neurolysis are not used for this purpose. Cryoablation has also been described in this context. The most popular approach is to target the genicular nerves. However, recent cadaver studies revealed that articular innervation is far more complex , 10. DesNeuralgia of the infrapatellar branch of the saphenous nerve is a pain generator in many patients with osteoarthritic knee pain , 32. IdeCryoablation has also been used in this context , 34. It α, IL-1, and MMP-3 [The rationale is to deliver an electrical field effect to the C fibers and, as a consequence, modulate the pain via the needle electrode positioned intra-articularly in the knee joint . The paind MMP-3 . Gupta end MMP-3 .Aly et al. suggested that a specific technique and regimen of IA pRF consists of targeting the superolateral joint space by placing a linear probe on the upper outer border of the patella in the transverse axis . A 5 cm Gulec et al. compared unipolar and bipolar IA pRF and found that bipolar IA pRF was more advantageous in reducing pain and improving function than the unipolar pRF 3 months after the intervention . The tecThere are 10 nerves that carry sensory input from the anterior knee capsule, and 4 nerves carry sensory input from the posterior knee capsule,Early studies targeting the articular branches of the knee essentially tackled the genicular branches only, namely, the SMGN, IMGN, and SLGN. The ILGN is usually spared in view of its proximity to the fibular nerve around the fibula. These older studies used fluoroscopy as the only guidance, whereas the newer studies used either ultrasound guidance or combined ultrasound and fluoroscopy (CUF) guidance.The initial technique of fluoroscopy-guided approach, as described by Choi et al., targets the SMGN, SLGN, and IMGN by looking for the periosteal junction between the shaft and the epicondyle of the corresponding long bone . This isHuang et al. reviewed eight publications including a total of 256 patients in their meta-analysis . The autIn view of our recent understanding of the innervations of the anterior and posterior knee capsules, only targeting the SMGN, IMGN, and SLGN in denervation may be an oversimplified approach nowadays. In fact, the original landmarks for SMGN and SLGN only cover a few branches of these two nerves, and they actually mainly cover the medial and lateral branches of NVI . The truSensory stimulation indicative of intraarticular numbness or aching may be applied to improve the accuracy while motor stimulation can be considered to rule out any local muscle fasciculation and patellar twitching. However, this is not mandatory. The use of multitined expandable RF needles or cooled RF technique can maximize the lesion size. Stacked lesions can be created to improve nerve coverage, especially the PNP. Fluoroscopy in the true anteroposterior and lateral views can confirm the final needle position before denervation.There was a theoretical concern that denervation at the adductor tubercle would lead to significant and prolonged flare-up because of the chemical/thermal injury to the tendon insertion of adductor magnus at the adductor tubercle. This could create iatrogenic tendinitis-like pain. However, such flare-ups were not observed in these five patients at 1-week postintervention. This might be explained by routine prescriptions of oxycodone and etoricoxib as the postintervention analgesics. When these analgesics are contraindicated, a short course of oral steroid is an alternative. Adjustment of the denervation target slightly proximal to the adductor tubercle so that the denervation process would be less likely to involve the tendon insertion can also be considered. However, further studies are needed to confirm this.Chemical neurolysis of the genicular nerves is also an option when radiofrequency facilities are unavailable, when the procedure is contraindicated, or when is a financial concern as reported by two patients who experienced satisfactory pain relief 6 weeks after the neurolytic procedure . A mixtuBy extrapolating our experience in chemical hip neurolysis in inoperable hip fracture, 10 minutes of waiting time would be sufficient for evaluation of diagnostic knee articular branch blocks . InjectiOne of the biggest myths regarding knee denervation is the lack of optimal approaches. Given the 14 nerves involved in the knee joint innervation, it remains debatable whether partial denervation would be noninferior to complete denervation. It is also unclear how many and what nerves need must be denervated to provide adequate pain relief. We believe a modified, tailor-made approach would better fit individual needs.This case series has some limitations, including its small sample size, nonrandomization of the denervation modalities, the absence of the control group, unblinded assessment, and the lack of postprocedure radiographic and electrophysiological assessments. The long-term effects of this modified motor-sparing neural ablation for knee pain are yet to be concluded. Further randomized controlled trials are warranted to validate the techniques more thoroughly.Our case series suggested a modified approach of motor-sparing denervation for knee pain control in patients with KOA for whom other conservative treatments failed but who were not candidates for knee replacement. Our observations provided important insights to permit the suggestion of a modified motor-sparing denervation approach, by either a chemical or neuroablative way that hopefully optimizes the success rate and facilitates pain physicians to develop a tailor-made interventional algorithm in Kellgren-Lawrence classification grade 3 and 4 KOA management. Further randomized controlled trials are needed to validate the techniques described here more thoroughly.


Musical Integration and Cognitive Agency. Musical Integration refers to the degree to which the music can provide an immersive and absorbing experience. Cognitive Agency refers to having an increased feeling of control. At the group level, participants reported a preference for low energy music, and reported that they found high energy music more irritating. However, is it important to note that individual people had different music preferences. Thematic synthesis of patient responses highlighted how these processes mediate the analgesic benefits of music listening from the perspective of chronic pain patients, and highlighted the wide range of music used by participants for chronic pain management including electronic dance music, heavy metal and Beethoven. These findings demonstrate that chronic pain patients use specific attentional strategies when using music for pain management, and these strategies align with the cognitive vitality model.Music interventions for pain are more successful when patients choose the music themselves. But little is known about the attentional strategies used by chronic pain patients when choosing or using music for pain management, and the degree to which these attentional strategies align with the cognitive mechanisms outlines in the cognitive vitality model . To investigate this question, we used a sequential explanatory mixed method approach, which included a survey, online music listening experiment, and qualitative data collection, with chronic pain patients (n=70). First, we asked chronic pain patients to name a piece of music that they would use to manage their chronic pain, and answer 19 questions about why they chose that particular piece of music using a questionnaire based on the CVM. Next, we asked chronic pain patients to listen to high energy and low energy pieces of music, to understand aesthetic music preferences and emotional responses at the group level. Finally, participants were asked to qualitatively tell us how they used music to manage their pain. Factor Analysis was completed on the survey data, and identified a five-factor structure in participant responses that was consistent with five mechanisms identified in the CVM. Regression analysis indicated that chronic pain patients choose music for pain management if they think it will facilitate  The World Health Organization recommends arts-based interventions including music interventions as part of routine clinical care . This isThis use of music in interventions in routine pain management settings is supported by the results of several meta-analyses which indicate that music interventions reduce self-rated chronic pain , and canAutomated Attention orientates the individual’s attention to the music and provides a lower-level distraction from pain. (2) Cognitive Agency is the way in which the person actively feels in control of the music, and uses self-directed music-listening strategies to actively engage with the music (3) Meaning-Making and Enjoyment is required to elicit personal reflection or aesthetic appreciation to deepen the level of engagement with the music, which motivates the person to keep listening and reduces the perceived effort involved in active listening. Meaning-making is key to emotional regulation processes as people can use the perceived meaning of music to reappraise their own thoughts and feelings, or because the person may have strong personal associations or memories with the music  that lead to a range of emotional responses. Eventually, after continued, uninterrupted engagement with the music (4) Musical Integration can occur, which means that the music is absorbed fully into the individual’s conscious experience on a cognitive, and emotional level. When musical integration occurs, the individual tends to lose track of time or feel like they have escaped, zoned out, or been transported to another place. Full absorption into the musical experience prevents the formation of competing constructions of reality that include the pain experience. Finally the person feels an enhanced sense of (5) Cognitive Vitality and cognitive energy which facilitates adaptive coping, an enhanced locus of control and a strengthened sense of self. Together these five mechanisms describe different states of cognitive engagement with music where people transition from lower level attention through to full absorption, and posits that higher levels of absorption in musical experiences elicit stronger wellbeing benefits. As indicated in Self-chosen music is the greatest predictor of effective music-listening interventions for pain , and peoEmpirical support for the CVM has been partly established in experimental studies . ParticiAlthough the CVM provides a framework for understanding the cognitive mechanisms that mediate the wellness benefits of music engagement, it is important to examine the external validity of the model. In the current study, we specifically focus on the perspective of chronic pain patients. This is particularly important because the psychological experience of chronic pain is different from the psychological experience of acute pain, because there is no sense of certainty that it will dissipate completely . In ordeanalgesic potential of music selected by the patient. The analgesic potential of the music is the degree to which patients estimate that their music selection will be helpful with their pain management. Understanding the factors that contribute to the analgesic potential of music is important because self-selected music is the best predictor of a successful music intervention  is also an important factor to consider in music interventions. In line with current theories of emotional engagement with music  the authThe present study examined the nature of patient choice in music-listening interventions using an online survey and experimental design. The main aim of this study was to examine the external validity of the CVM. A questionnaire based on the mechanisms identified in the CVM was used to identify the degree to which patients’ motivations for choosing music for pain management aligned with the CVM. Additionally, a qualitative thematic analysis was used to gain a deeper understanding of patients’ experience of music listening for pain management. A secondary aim of this study was to assess chronic pain patients’ preference for different musical features, which was assessed using by asking chronic pain patients to provide aesthetic and emotional ratings for different music samples.These aims were addressed with the following research questions:RQ1a: Can the analgesic potential of patients’ self-chosen music be predicted by components of the CVM?RQ1b: Do patient descriptions of music listening for pain correspond with the CVM?RQ2: Do patients with chronic pain report any preferences in terms of the type of music that they find most beneficial for pain management?This study used an online survey and experimental design accessible by smart phone, tablet or home personal computer. A sequential explanatory mixed method approach was used to address the main research question  which inPatients with chronic pain were invited to participate in the study through pain management clinics in St. Vincent’s University Hospital, Dublin, and online through social media, using twitter and Facebook. The primary researcher attended weekly clinics and provided information leaflets for the study to 400 patients over 6 weeks. Patients named their diagnosis, which was then classified by the primary researcher according to the International Classification of Diseases 11 (ICD-11) definitions for chronic pain .Participants rated their pain intensity and pain unpleasantness on mixed Numeric Rating Scales (NRS) using a pointer, before listening to the music. The 100-point intensity scale had three anchor points ‘no pain’ (0), ‘moderate pain’ (50), and ‘worst pain imaginable’ (100). The 100-point unpleasantness scale ranged from ‘not unpleasant’ (0) to ‘extremely unpleasant’ (100). Numeric rating scales (NRS) are considered the gold standard for measuring patient’s subjective feeling of pain intensity and pain unpleasantness, because they are more sensitive than other self-report measures that treat pain as a unidimensional construct .Patients were asked to estimate how much their chosen music piece would help to reduce their pain on a continuous Likert scale ranging from 0 ‘it would not help at all’ to 100 ‘It would help a lot’.The CASP-19 Quality of Life Scale was used to measure wellbeing based on four domains; Control, Autonomy, Self-realization, and Pleasure . The CASP-19 includes 19 items which are scored on a 4-point Likert scale ranging from 0 ‘never’ to 3 ‘often’. Scores range from 0 to 57 with higher scores indicating a higher quality of life.Twenty-one items were created for the Cognitive Vitality Questionnaire based on the CVM . The iniNineteen items were included in the original cognitive vitality questionnaire. *items did not load onto the factor structure of the questionnaire so data from these questions were not included in the final analysis, and should not be used.Participants completed the short version of the Geneva Emotional Musical Scale GEMS-9;  to evaluHigh Energy, and music with low levels of energy, danceability, energy, and tempo was labeled as Low Energy. All songs that were commercially available without lyrics had a mean familiarity rating of 3 or lower. This resulted in three Low-Energy music pieces: Sleeping Music by Deep Sleep Music Collective, This Isn’t You by Kyle Dixon, and Danger of Hell by Thomas Newman; and three High-Energy music pieces: Solero by Sons of Maria, Lighthearted by Deep Chills, and The Balance by Moses Boyd.A pilot study was used to select 6 pieces of music which were used in a previous lab-based experiment , and theParticipants completed the online survey at a time and location that was convenient for them. Each participant listened to six pieces of music which were presented in counterbalanced order. For each piece, participants completed the GEMS-9;  and rateExploratory factor analysis was conducted on participants responses to the cognitive vitality questionnaire to examine the factor structure of the responses. Regression analysis was then used to examine if scores for each factor could predict ratings for how effective the participants thought the self-chosen song would be for pain management. This allowed us to examine which factors were most important in mediating the analgesic benefits of music listening from chronic pain patients perspective. The qualitative analysis was used to explore the quantitative results in more detail.via social media. The entire sample of 70 patients had an age range of 18–70 , and was comprised of 56 females, 13 males, and 1 transgender person. The sample consisted of 26 (37.1%) patients with primary chronic pain, 17 (24.3%) patients with chronic musculoskeletal pain, 7 (10.0%) patients with neuropathic pain, 6 (8.6%) patients with multiple independent diagnoses, 6 (8.6%) patients with chronic visceral pain, 4 (5.7%) patients with chronic postsurgical and posttraumatic pain, 3 (4.3%) patients with chronic headache and orofacial pain, and 1 (1.4%) patient with chronic cancer pain. Pain intensity scores ranged from 0 to 10 with a mean of 5.43 (SD = 1.98). Pain unpleasantness scores ranged from 0 to 9 with a mean of 5.20 (SD = 1.99). Wellbeing scores measured using the CASP-19 ranged from 7 to 54 and patients reported a mean wellbeing score of 28.31 (SD = 9.48).Seventy patients with chronic pain completed the study. Nine participants were recruited from pain management clinics in St. Vincent’s University Hospital, Dublin. Additionally, 61 participants were recruited to participate The main research question was examined using a sequential explanatory mixed methods approach. This approach allows us to conduct a quantitative analysis followed by a qualitative analysis in order to gain a greater understanding of the quantitative findings .analgesic potential of music selected by the patient. In order to achieve this the quantitative analysis was conducted in two parts. First, an exploratory factor analysis was conducted to examine the factor structure of the questionnaire and quantify how patient responses corresponded with the cognitive mechanisms identified in the CVM. Second, a regression analysis was conducted to examine how patient scores for each factor of the cognitive vitality questionnaire predicted the analgesic potential of the patients chosen song.The goal of the quantitative phase was to identify the degree to which the mechanisms outlined in the CVM relate to the χ2(171) = 561.69 p < 0.001]. On examination of the scree plot, and the eigenvalues, a five-factor solution was determined as the most appropriate to fit the model. This decision eliminated one factor that had an eigenvalue greater than one; however, this factor only included two negatively worded items, that were not otherwise related, and it appeared to the research team that it was more likely that it was the wording of the item that was causing people to rate them similarly rather than an underlying construct. Instead, the remaining five factors were considered to represent the latent constructs outlined in the CVM, and a common factor analysis was completed. Principal axis factoring, with a Promax rotation with Kaiser Normalization was used to account for the fact that the data was negatively skewed  and the small sample size . The Kaiser-Meyer-Olkin measure of sampling adequacy was 0.75, which indicated that we achieved sampling adequacy . Bartletple size . This meple size . Items wThe five-factor solution was examined for adequacy. Each factor was loaded by a minimum of two items  = 0.682, p < 0.001, Automated Attention and sEnjoyment r(69) = 0.530, p < 0.001, and sCognitive Agency r(69) = 0.492, p < 0.001. Weak positive correlations were found between the Benefit for Pain rating and Motivation sr(68) = 0.317, p < 0.01 and sMeaning-Making r(68) = 0.318, p < 0.01. The strength of the correlations was used to select which factors to include in a regression analysis. The three factors  that were moderately correlated with the analgesic potential rating were then entered into a linear regression analysis to predict the outcome variable of analgesic potential. The regression model was significant, F = 39.85, p < 0.001, R2 = 0.559. The analgesic potential was significantly predicted by Musical Integration, ß = 0.67, t(63) = 6.69, p < 0.001; SE = 0.10, 95% CI , and Cognitive Agency, ß = 0.24, t(63) = 2.96, p < 0.01; SE = 0.08, 95% CI . This indicates that Musical Integration was the best predictor as it had the highest beta co-efficient of 0.67, followed by Cognitive Agency, with a beta co-efficient of 0.24. This means that for every 1-unit increase in Musical Integration scores for a chosen song, the analgesic potential of that song increased by 0.67. For every 1-unit increase in Cognitive Agency scores for a chosen song, the analgesic potential increased by 0.24. This suggests that Chronic pain patients think that the degree to which a song will elicit Musical Integration is the most important factor leading to subsequent analgesic benefits, but they also think that their specific music choices are an important component in achieving music analgesia  = 3.57, p < 0.001 95% CI  with a significantly higher analgesic potential; t(69) = 5.16, p < 0.001 95% CI  and significantly less irritating t(69) = 4.86, p < 0.001 95% CI  compared to music with high levels of energy . However, while these results demonstrate that patients rated low-energy music as more enjoyable, more helpful for reducing pain, and less irritating compared to high-energy music, overall it is important to note that the wide confidence intervals here indicate a high degree of variation between individual patients. No difference was found in ratings of boredom between high-energy music and low-energy music. Additionally, we compared patients’ emotional responses between the two types of music. Low-energy music was rated as inducing significantly higher levels of Wonder, Transcendence, Tenderness, Peacefulness, Sadness, and Nostalgia responses compared to high-energy music  as significantly more enjoyable; usic See . High-enusic See . These rsr(69) = 0.497, p < 0.001. Subsequently, a linear regression was calculated and identified that self-rated enjoyment was a significant predictor of how helpful people thought their chosen song was for pain management, F = 11.57, p < 0.001, 2R = 0.147. This indicates that while enjoyment is a significant predictor of the likelihood of pain reduction, on its own it only accounts for 14.7% of the variance.Although different levels of enjoyment were identified between the two different types of music, we also wanted to investigate the role of enjoyment overall and examine how it relates to the analgesic potential in patients’ chosen music. To account for the marginal skewness in the data a non-parametric Spearman’s rho correlation was calculated. A moderate positive correlation was found between patient ratings of enjoyment and patient ratings for the analgesic potential of their chosen song, Musical Integration and Cognitive Agency as the most strongly linked to the analgesic potential of their chosen song. This means that different pieces of music are being used by people with chronic pain to facilitate cognitive strategies that correspond with cognitive agency and musical absorption. This result was based on a quantitative analysis that was conducted in two parts. First, an exploratory factor analysis was conducted to examine the factor structure of the questionnaire and quantify how patient responses corresponded with the cognitive mechanisms identified in the CVM. The factor analysis demonstrated that the pattern of patient responses corresponded with five factors that represented the five cognitive mechanisms outlined by the CVM. This suggests that chronic pain patients are largely in agreement with the cognitive mechanisms outlined in the CVM. While patients may differ in the specific music that they choose for pain management, it seems that there is relatively strong agreement in terms of why patients are choosing the music. Second, a regression analysis was conducted to examine how patient scores for each factor of the cognitive vitality questionnaire predicted the analgesic potential of the patient’s chosen song. The regression analysis demonstrated that the analgesic potential of the music was most strongly predicted by the factors of Musical Integration and Cognitive Agency. This result is in line with the CVM which emphasizes the importance of Musical Integration and Cognitive Agency in facilitating an enhanced sense of self and subsequent vitality as a result of music listening for pain management. Patients’ tendency to acknowledge the relationship between the cognitive mechanisms of Cognitive Agency and Musical Integration and the music’s analgesic potential suggests that patients have a conscious awareness of these two mechanisms. In this instance, patients recognized that their music choice was motivated by specific reasons, which gives participants a chance to exert their individual autonomy and subsequently enhance their internal locus of control. Additionally, patients’ interpretation of Musical Integration on the questionnaire was tightly related to a strengthened sense of self and mental energy. This suggests that the mechanism of musical integration is not readily separable from the mechanism of cognitive vitality from the chronic pain patient’s perspective and may be more tightly interwoven than initially outlined by the model. Similarly, chronic pain patients were more likely to consider enjoyment as a component of attention rather than meaning-making as proposed by the initial model.Until now, the degree to which the CVM corresponds with chronic pain patients’ experience of music listening as a pain management strategy, was untested. The main aim of this study was to explore the degree to which the analgesic potential of patients’ self-chosen music can be predicted by components of the CVM. Overall, the findings demonstrate that patients rated the factors of These discrepancies between the initial proposed model, and chronic pain patients’ ratings, need to be considered in further detail, both methodologically and theoretically. Factor 4, Personal Meaning, is intended to reflect meaning--making processes related to emotion regulation . Given tPatient descriptions of the benefits of music listening were used to explore the questionnaire responses in more detail using qualitative analysis. This helped to gain a greater understanding of the quantitative results, and to provide more insight into the specific reasons patients have for using music for pain management. The specific reasons for music listening are an important component of music-listening interventions , since tMusical Integration outlined that music absorption can help to provide an escape from the reality of pain. Specifically, patients reported that music could be used to transport them out of their current experience and helped them to stop thinking about their or problems and to focus on something else. These descriptions from patients correspond with the idea that music helps to reduce pain because it is absorbing on a cognitive and emotional level . Chronic pain patients reported that the degree to which a song will elicit Musical Integration is the most important factor leading to subsequent analgesic benefits, but they also think that their specific music choices are an important component in achieving music analgesia. The role of motivation, and optimal arousal, was identified by participants as additional factors that need to be explored further. Qualitative responses from patients highlighted that Cognitive Agency was important because active engagement and individuality can help patients to strengthen their sense of self. This is particularly important for chronic pain management where people often experience low self-esteem and low self-efficacy due to diminished capacity, and pain management strategies that enhance the patient’s internal locus of control have been shown to be the most effective . AdditioThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by St. Vincent’s Hospital Research Ethics Board. Anonymous electronic informed consent for participation was provided by all of the participants who took part in the study in accordance with the national legislation and the institutional requirements.All authors CH, RW, PD, and BR contributed to the initial research design and write-up of the final manuscript. CH and RW were responsible for data collection. CH and BR were responsible for data analysis and interpretation. All authors contributed to the article and approved the submitted version.This project was supported by a research grant from the Irish Research Council (grant number GOIPG/2017/1006). The funding agency did not have any influence on the results or findings of the study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background and Objectives: Elderly patients affected by acute heart failure (AHF) often show different patterns of comorbidities. In this paper, we aimed to evaluate how chronic comorbidities cluster and which pattern of comorbidities is more strongly related to in-hospital death in AHF. Materials and Methods: All patients admitted for AHF to an Internal Medicine Department (01/2015–01/2019) were retrospectively evaluated; the main outcome of this study was in-hospital death during an admission for AHF; age, sex, the Charlson comorbidity index (CCI), and 17 different chronic pathologies were investigated; the association between the comorbidities was studied with Pearson’s bivariate test, considering a level of p ≤ 0.10 significant, and considering p < 0.05 strongly significant. Thus, we identified the clusters of comorbidities associated with the main outcome and tested the CCI and each cluster against in-hospital death with logistic regression analysis, assessing the accuracy of the prediction with ROC curve analysis. Results: A total of 459 consecutive patients . A total of 55 (12%) subjects reached the main outcome; the CCI and 16 clusters of comorbidities emerged as being associated with in-hospital death from AHF. Of these, CCI and six clusters showed an accurate prediction of in-hospital death. Conclusions: Both the CCI and specific clusters of comorbidities are associated with in-hospital death from AHF among elderly patients. Specific phenotypes show a greater association with a worse short-term prognosis than a more generic scale, such as the CCI. Heart failure (HF) is a global epidemic, often affecting elderly subjects afflicted by several comorbidities ,2. The iAge is a major determinant of complexity , and it A reduced exercise capacity can be observed in chronic obstructive lung disease (COPD), which often exacerbates AHF and represents an independent risk factor for death and hospitalization for HF . SubjectIncreased serum creatinine levels and electrolyte imbalances are common in chronic kidney disease (CKD), which often affects elderly, diabetic patients with HF , being aNon-valvular atrial fibrillation (NVAF) worsens cardiac hemodynamics by reducing LV performances and is associated with an increased risk of death, hospitalization, and a worse quality of life, particularly in subjects with reduced ejection fraction (EF) ,13.Chronic anemia (CA) has been identified as an independent risk factor for mortality in AHF ,15. PatiCardiac comorbidities are common among patients affected by myelodysplastic syndromes (MDS) . AHF assAHF can be associated, especially in the elderly, with severe concurring clinical events, such as, for example, ACS or the Takotsubo syndrome , but alsThe role of generic comorbidity scores, such as the Charlson comorbidity index (CCI), has already been studied in HF. CCI has been associated with an increased mortality in the first year after the first AHF episode ,23, whilIn this work, we aimed to evaluate whether the different clusters of comorbidities can predict short-term prognosis in a population of elderly patients admitted for AHF, considering both de novo AHF (first AHF episodes) and acutely decompensated heart failure (ADHF). We also evaluated CCI performance in predicting in-hospital death from AHF and compared the performance of CCI with the phenotypes of comorbidities observed in our population. We retrospectively enrolled all the consecutive patients admitted to the Internal Medicine Department of INRCA-IRCSS of Osimo (Ancona) from the Emergency Department of the same hospital for AHF over 4 years (from 01/2015 to 01/2019), aged ≥65 years. The AHF diagnosis was made by the attending physician, according to the guidelines relevant at the moment of study . We investigated age, sex, BNP at admission, BNP at discharge, echocardiography-assessed cardiac EF at admission, the number of comorbidities, the number of drugs taken before admission, the days of hospitalization, and the presence of 17 different comorbidities. For each subject, we calculated CCI according to its original definition . The maiThe ethics committee reviewed the protocol and approved the study . All the participants and/or caregivers gave their written informed consent. All the subjects were treated according to the Declaration of Helsinki. The data that support the findings of this study are available from the corresponding author upon reasonable request.COPD was defined by a clinical history supported by previous suggestive spirometric findings; obstructive sleep apnea syndrome (OSAS) was established by the presence of a previous diagnosis supported by polysomnographic data interpreted by an expert neurologist; CA was ascertained if the hemoglobin levels were lower than 13 g/dl for men or 12 g/dl for women for at least 6 months before admission without clinical or instrumental findings of bleeding; the presence of dementia (DEM) was evaluated according to the patient’s clinical history in the presence of a previous neuropsychologic evaluation. An acute deterioration of cognitive function was not considered. Hypertension (HYP) was appraised in the subject’s clinical history and by the chronic use of anti-hypertensive medications given for this specific application. An in-hospital finding of increased blood pressure levels was not considered. Dyslipidemia (DYS) was defined by the patient’s history or lipid-lowering-agents use for this specific purpose. CKD was defined as the persistence of kidney function abnormalities for at least 3 months of clinical stability before hospital admission . ModeratAll subjects aged 65 years old or older with AHF and admitted from the ED in the Internal Medicine Department were enrolled. We excluded (a) subjects younger than 65 years old and (b) all patients admitted for AHF among whom we observed a second acute related or unrelated condition that could have significantly modified the prognosis. Per protocol, we excluded patients admitted for AHF when it was associated with (i) acute coronary syndromes (ACS) or other acute coronaric diseases, such as the Takotsubo syndrome, (ii) acute valvular diseases, (iii) acute infective events, including pneumonia, sepsis, or septic shock, (iv) terminal conditions in palliative care, and (v) end-stage renal disease requiring dialysis. We also excluded patients with an incomplete medical history, whose electronic medical records did not allow us to calculate CCI, with incomplete follow-up, or subjects admitted from departments other than the ED.All the enrolled patients were subdivided, according to their clinical history, into de novo AHF  and acutely decompensated heart failure .In-hospital mortality, sex, and comorbidities were synthesized as dichotomous variables. Age, admission BNP, number of drugs used at admission, and days of hospitalization were collected as continuous variables. CCI was calculated according to its original definition  and collp ≤ 0.10. From the results of Pearson’s bivariate test, we selected “groups” of ≥2 significantly associated comorbidities or “clusters”.To identify the clusters of chronic pathologies in this cohort, we adopted two-tailed Pearson’s bivariate test. We considered two disorders as being associated when Pearson’s statistic emerged as significant at a level of p ≤ 0.10.The covariate selection for the multivariate models  was performed with Pearson’s bivariate test, selecting the features associated with the main outcome variable at a level of significance of To evaluate the association between CCI and the main outcome in this sample, we prepared a binary logistic regression model considering in-hospital mortality as the dependent variable, CCI as the main predictor, and the covariates selected with Pearson’s test. Age was not included as a covariate in this model, since it was already considered in CCI. The individual predicted probabilities of this model were saved at the end of the binary logistic regression procedure and used to generate the ROC curve.p ≤ 0.05 and whose uncorrected ROC curve had an AUC ≥ 0.65. The selected phenotypes were used to generate the complete models, which considered in-hospital mortality as the main outcome, the associated pathologies, and the covariates selected with Pearson’s test, including age. The individual predicted probabilities of each model were saved at the end of the binary logistic regression procedure and used to generate the ROC curves. We compared the performance of the ROC curve of each cluster with the other clusters and with the ROC curve derived from the CCI model, adopting the DeLong method.We considered for further assessments only the clusters whose binary logistic regression analysis model emerged as significant at a level of Lastly, we ran a Cox proportional hazards model considering the main outcome as the dependent variable, days of admission as the time variable, the four CCI quartiles as the main independent variables, and the covariates selected with Pearson’s test, excluding age, since it was already considered in the CCI. From an initial sample of 512 patients, we excluded 15 subjects due to ACS, 36 due to concurrence of acute infective events, and 2 due to acute valvular diseases, obtaining a final sample of 459 consecutive subjects. The baseline characteristics of the cohort are synthesized in p = 0.0001) in the uncorrected model, which increased in the corrected model, adjusting for sex, number of drugs used, admission BNP, and days of hospitalization , phenotype 6 , phenotype 9 , phenotype 10 , phenotype 11 , phenotype 12 , and phenotype 14 . We did not observe a statistically significant difference between the ROC curves of the six selected clusters, while the CCI showed significantly lower performances than the selected clusters, particularly when compared with phenotypes 6, 9, 11, and 12, as shown in In the Cox regression model, considering sex, number of drugs, and BNP at admission as covariates, we observed a significantly increased risk of in-hospital death from the first to the fourth CCI quartile, as shown in Patients admitted for AHF represent a markedly heterogeneous group who differ by the etiology, severity of clinical presentation, and associated diseases. Our cohort was characterized by elderly patients burdened by several associated pathologies and treated with several drugs before admission, confirming the association between HF, significant morbidity, and polypharmacy observed in previous studies ,29. Non-Even the presence of a single comorbidity complicates the clinical course of AHF. Patients with COPD can be more difficult to diagnose and treat due to the presence of respiratory insufficiency, while patients with CKD often face lower response rates to diuretics, and decongestion is often complicated by a worsening of the renal function, which reduces the use of ACE-I, ARB, and MRA . When coIn our study, we observed a mean of four comorbidities and a median of seven drugs, suggesting a high clinical complexity of this typology of subjects. AHF in the elderly represents a diagnostic and therapeutic challenge, especially when associated with multiple comorbidities and a subsequent state of polypharmacy. In this population, survival is also affected by age and pathology–pathology interactions. Drug–pathology and drug–drug interactions must also be considered when treating this specific group of patients.In our cohort, we were able to identify six different phenotypes characterized by the clustering of chronic pathologies and to evaluate their association with short-term AHF prognosis. This analysis allowed us to underline which associations of pathologies, or phenotypes, were significantly associated with the main outcome. We observed that vascular, chest, and metabolic diseases often cluster in the same individual to generate a state of high clinical complexity and a worse short-term outcome. Two of the phenotypes identified with our methods were characterized by metabolic (phenotype 6), vascular (phenotype 10), and metabolic–vascular (phenotype 12) diseases, while the other remaining clusters were depicted by the association of NVAF and dementia in connection with metabolic (phenotype 4), ischemic (phenotype 9), and neoplastic (phenotype 14) diseases. Of note, NVAF is highly prevalent and correlated to a worse prognosis in several phenotypes of this critical illness, as already observed in other studies . The assWe also evaluated the role of a more generic score, the Charlson comorbidity index, in the setting of AHF and compared its performance with the AUC resulting from the analysis of each specific cluster. CCI represents a validated assessment of the patient’s comorbidity status and has a definite role in predicting long-term mortality ,39. SeveSeveral predictive models, such as the EHMRG score, have been suggested to assess short-term AHF prognosis since the patient’s arrival in the ED. These models are largely validated and should be preferred to stratify the 7-day mortality risk over other approaches, even in a geriatric patient ,44. HoweIn our study, we also confirm the prognostic role of CCI in AHF short-term mortality, lower quartiles of CCI being associated with a lower risk of in-hospital death. However, when comparing specific clusters of chronic diseases with a more generic but validated score, we observed that six specific phenotypes were able to outperform the CCI in the prognostic evaluation of elderly patients affected by AHF. These observations lead to some considerations that can be useful for the physician. First, the CCI should be evaluated at admission of elderly subjects with AHF to weigh rapidly the individual complexity and to stratify the subject’s short- and long-term prognosis. CCI is largely used in the evaluation of geriatric patients; moreover, it is a validated and extensive score that gives the physician several hints as to the patient’s status. Second, our results suggest that an accurate investigation on the patient’s history, focused mainly on vascular and metabolic comorbidities and their interaction, is useful to identify the subjects at the highest risk of clinical deterioration, underlining the importance of applying a good clinical method. The major limitations of this work are mainly related to its monocentric and retrospective design. For this reason, this must be considered as a pilot study, and the results must be considered as preliminary, requiring validation in larger prospective cohorts.