Internet‐delivered cognitive behavioural pain management programmes (PMPs) are effective, but less is known about their use outside of research trials. Five years of data from offering the Internet‐delivered cognitive behavioural PMP in an online therapy clinic was examined to assess effectiveness, acceptability and predictors of outcomes.N = 293) were offered a previously validated 8‐week Internet‐delivered cognitive behavioural PMP and administered measures at pre‐treatment, post‐treatment and 3 months.Patients (n = 64 first year to n = 133 fifth year). Moderate‐to‐large improvements on depression  and anxiety , and small‐to‐moderate improvements on disability  were found. Lesson completion and satisfaction were high. Lower pain acceptance, lower pain self‐efficacy and higher pain intensity were associated with lower improvements on depression, anxiety and disability.There was growth in demand for an Internet‐delivered cognitive behavioural PMP over time  offered as routine care in an online therapy clinic. Interest in the service grew over 5 years. Outcomes, engagement and satisfaction were strong. Higher pain acceptance, pain self‐efficacy and lower pain severity were associated with greater post‐treatment improvements on depression, anxiety and disability. Internet‐delivered cognitive behavioural pain management programmes (PMPs) are effective in research trials.Internet‐delivered cognitive behavioural PMPs result in significant improvements in depression, anxiety and disability.This 5‐year observational study shows growth in demand for an Internet‐delivered cognitive behavioural PMP when offered as routine care in an online clinic.Outcomes were strong when an Internet‐delivered cognitive behavioural PMP was delivered in a routine online clinic, and previous clinical trial outcomes were replicated.Higher baseline pain acceptance and pain self‐efficacy, and lower pain severity were associated with greater post‐treatment improvements.1Nearly one in five Canadian adults experience chronic pain at any given time, with about one‐half of those reporting these symptoms for 10 years or more, and one‐third describing their pain as severe , under various conditions, including weekly contact with a therapist, optional contact with a therapist or without therapist contact  and secondary  measures. Predictors of treatment were considered exploratory, given limited past research on the topic.22.1www.onlinetherapyuser.ca) has been funded by the province to provide free Internet‐delivered cognitive behaviour therapy to adult residents of Saskatchewan since 2015 , followed by limited access to a personal computer or Internet (n = 8). Of the 490 individuals deemed suitable, 415 completed a follow‐up telephone interview to further assess programme suitability (75 patients could not be reached). Based on the online and telephone suitability assessment, a total of 311 patients were accepted into the Pain Course, with 293 of those patients starting the intervention.All patients who completed the online suitability assessment for the Pain Course via physicians/medical professionals , other referrals  and other sources .Table Pain Course, prospective patients had to: (1) self‐report chronic pain for >3 months and report past contact with a physician about their pain; (2) self‐report symptoms of low mood or worry ; (3) reside within Saskatchewan for the 8‐week course of treatment; (4) be at least 18 years of age; (5) be willing to provide a medical contact in the event of an emergency; (6) be comfortable using the Internet and (7) not be receiving face‐to‐face therapy more than twice per month. Of note, only a small subset of patients  reported up to two mental health visits per month. Eligible patients were enrolled in the course immediately after the telephone screening and did not receive remuneration for participating.To be suitable for the 2.3Pain Course. In past analyses of Internet‐delivered therapy in routine care, a time frame ranging from 30 months . During the first 2 years of offering the course, if patients did not complete follow‐up measures, an attempt was made to collect primary , but not secondary outcome measures  via telephone or survey link sent via email. Consequently, we have limited secondary measures at 3‐month follow‐up for participants during the first 2 years of the trial.The study received research ethics approval through the University of Regina Research Ethics Board and the trial was registered as an observational trial (ISRCTN15509834) to assess the effectiveness and acceptability of the 2.42.4.1not at all) to 3 (nearly every day). Scores ≥8 can identify probable cases of generalized anxiety disorder with adequate specificity and scores <5 represent minimal symptoms of anxiety  to 3 (nearly every day). A score ≥10 has been used as a cut‐off for identifying individuals who are likely to meet the criteria for major depressive disorder  to 10 (pain as bad as you can imagine). The four BPI pain severity items were combined to create a mean composite score. Cronbach's α in the current study ranged from 0.86 to 0.92 across administrations Cleeland & Ryan, The BPI is a validated measure used to assess the intensity and interference of pain in an individual's daily life. Only the items asking about the intensity of current pain, average pain and least and worst pain in the last 24 h were included in this study. Items are rated from 0  and medication use. Consequently, in this study, we report data for a subsample of patients enrolled from January 2018 onwards, specifically reporting whether patients had seen certain medical professionals or taken prescription medication for pain or mental health in the 8 weeks before completing pre‐treatment and 3‐month follow‐up measures.2.62.6.1As tracked by the website, programme engagement was explored by examining the number of lessons completed, number of messages sent by the patient to the therapist, and total times therapists either emailed the patient and or recorded a phone call to patient.2.6.2At post‐treatment, consistent with past Internet‐delivered cognitive behavioural PMPs . It was licensed for use to the Online Therapy Unit. It consists of five lessons that are released over the span of 8 weeks, with each lesson consisting of a slideshow, downloadable guide and case stories and examples. The five lessons, which patients are encouraged to work on for 1 to 2 weeks each, are intended to help patients understand chronic pain and manage its impacts on their day‐to‐day lives and emotional wellbeing. The Course includes psychoeducation on: (1) the cognitive behavioural model of pain; (2) cognitive restructuring; (3) controlled breathing and pleasant activity scheduling; (4) graded exposure and pacing and (5) relapse prevention and goal setting. Lesson 1 is available immediately after clients are enrolled. Subsequent lessons are released based on elapsed time and the patient having accessed the previous lesson; specifically, lessons 1, 2, 3, 4 and 5 are available at the beginning of weeks 1, 2, 4, 5 and 7. Patients can download additional resources that address topics or concerns that are common among individuals with chronic pain . In addition to emails and telephone calls, patients received weekly standardized automated messages to remind them of upcoming course content.The 2.8n = 24) or email contact (n = 45). If patients selected a preference for email contact, patients were encouraged to write to their therapist during the week. The therapist then responded to all messages on a designated day once per week. Other than differences in the method of offering support, the content and amount of time spent on providing support per patient was the same (e.g. 10 to 15 min). When email support was offered, telephone calls were made only if clinically indicated . Subsequently between January 2018 and February 2020, given the strong patient and therapist preference for email contact, patients were consistently assigned to receive email support (n = 150) with phone calls only made when clinically indicated as described above. All emails were exchanged on the secure messaging system on the Online Therapy Unit platform.The purpose of therapist support was to summarize content, encourage practice of skills, reinforce progress and answer patient questions. Additionally, therapists normalized challenges in learning skills and managing symptoms. The therapists did not introduce any new therapeutic skills. Several different models of providing therapist support were used across the 5‐year time frame, reflecting therapist and patient experiences and preferences. Between May 2015 and January 2017, 74 patients received this support primarily during a telephone call. If therapists could not reach patients by telephone, then therapists sent a brief email containing the same information that would have been relayed in the telephone call. Given that therapists often could not reach and speak to patients by telephone after multiple attempts and were often sending emails, patients accepted between February 2017 and January 2018 were given the choice of telephone (n = 66), two Master’s level registered social workers (n = 37 and 139), one Master's level certified counsellor (n = 52) and one Bachelor’s level registered social worker (n = 16). All clinicians were trained in Internet‐delivered therapy, which included attending a 1‐day workshop. Subsequently, all messages sent to patients were reviewed by a supervisor over the course of several months. After the supervisor approved independent practice, therapists attended regular Online Therapy Unit meetings and received supervision as requested. Previous studies have not found significant differences in acceptability or outcomes when support is offered by either graduate student practitioners or registered healthcare professionals . GEE models estimate changes in a population mean while adjusting for correlated responses within individuals . Of note, completion of secondary measures at 3‐month follow‐up was limited at the beginning of this study but improved over the first 2 years. Imputations controlled for lesson completion, method of support (in the event receiving support primarily via telephone or email impacted outcomes), any observed values of that measure for that patient at pre‐treatment, post‐treatment, or follow‐up and interactions.Missing outcome measures were replaced using predictive mean matching multiple imputation before fitting the GEEs. To specify the imputation models, we examined patterns of data missingness. As in previous studies  and the independent variable used in that model. Consistent with previous research , married or living with their partner , had at least a high school diploma , and were Caucasian . Only 42.0% (n = 123) resided in a large city. A significant number of patients were on short‐term or long‐term disability, with a wide range in the duration of pain symptoms . On average, patients reported 4.45 pain sites (SD = 3.10), with upper back/middle back/lower back pain reported by the largest number of patients . At pre‐treatment, most patients’ scores were in the clinical range for anxiety  and depression , and 52.6% (n = 154) had infrequent use of some form of mental health treatment. Prescription medication and health service use at pre‐treatment for patients enrolled after January 2018 (n = 150) are summarized in Table n = 123) and had seen a GP/nurse/medical specialist in the 8 weeks prior to treatment . A smaller subset had seen a psychiatrist  or a psychologist/counsellor in the 8 weeks prior to treatment .Of the 311 patients accepted into the 3.2Table 3.3n = 203) of patients who completed post‐treatment questionnaires reported that the Pain Course was worth their time and 98.1% (n = 207) that they would feel confident recommending the course to a friend.As seen in Table 3, 96.2%  = 66.2, p < 0.001; GAD‐7: F(2320) = 55.9, p < 0.001; RMDQ: F(2182) = 13.5, p < 0.001). The reductions on the PHQ‐9 and GAD‐7 were moderate at post‐treatment and large at 3‐month follow‐up. Reductions on the RMDQ were moderate both at post‐treatment and at 3‐month follow‐up.Estimated means, standard deviations, percentage reductions and Cohen's Rates of clinically significant improvement and deterioration are presented in Table 3.5F(2180) = 9.2, p < 0.001; CPAQ: F(2234) = 36.4, p < 0.001; PSEQ: F(2246) = 48.0, p < 0.001; TSK: F(2218) = 48.2, p < 0.001). Changes were moderate on the CPAQ‐8, PSEQ and TSK at both post‐treatment and 3‐month follow‐up. Changes on BPI‐Severity were small at both post‐treatment and 3‐month follow‐up.As seen in Table 3.6n = 150), a significant decrease was observed in the proportion of patients who were taking prescription medication for pain or mental health  = 20.83, p < 0.001) and seeing a GP/nurse/medical specialist  between pre‐treatment and 3‐month follow‐up. Changes in the proportion of patients seeing a psychiatrist  =0, p = 1.00) or psychologist/counsellor  =0.11, p = 0.75) were not significant between pre‐treatment and 3‐month follow‐up.Among the subsample of patients enrolled from January 2018 onward  and at 3‐month follow‐up . Significant improvements were also found on secondary measures of pain severity, fear of movement and re‐injury and chronic pain acceptance among the overall sample. Furthermore, fewer patients reported taking medication and visiting a medical professional in the follow‐up period compared to pre‐treatment. High rates of treatment completion (79.5%) and the fact that most patients completed satisfaction measures and regarded the treatment as worth their time  suggest that Internet‐delivered cognitive behavioural PMPs are also an acceptable intervention. The results were comparable to previous controlled studies of the p‐value of 0.1 was used to identify predictors that can provide valuable information for therapists and services. Predictors of treatment outcomes have previously been examined by Dear et al. . In the current study, there was somewhat greater consistency in some measures that predicted outcomes, but the magnitude of the prediction effects was small. In terms of notable patterns, low pain self‐efficacy and pain acceptance and high pain intensity at pre‐treatment were significant predictors of poorer treatment response for depression, anxiety and disability. Also notable was that taking prescription medication was predictive of poorer outcomes on anxiety and disability. While these variables were found to be consistent across our primary outcome measures, the coefficients of discrimination were small and the ability to predict treatment outcomes were weak. Consequently, the results should not be taken to mean that patients with these characteristics will not improve or should not be offered treatment. Instead, it would appear that there is a lower probability of improvement, which could be helpful for clinicians and services to be aware of when delivering these programmes. For example such information could guide clinicians to provide more support to such patients during these programmes, or to take other measures that might enhance the likelihood of positive treatment outcomes, such as coordinating care with patient’s medical practitioners or encouraging use of physical therapists alongside the programme. In general, the findings of this study are consistent with previous research which suggests that pain self‐efficacy plays a role in long‐term disability outcomes  that is reduced by 30% or greater . Consistent with routine care research, patients accessed other services while completing the Pain Course. As with other studies of the Pain Course . The RMDQ was not administered to the last 139 participants, and completion of secondary measures at 3‐month follow‐up was low (44%). There were inconsistencies in questions related to medication and health service use resulting in this data available on a subsample of patients (5Pain Course) when offered as routine care by an online therapy clinic with a large help‐seeking sample. Predictors of poorer outcomes at post‐treatment included lower pain acceptance, lower pain self‐efficacy and higher pain intensity at pre‐treatment across anxiety, depression and disability, which potentially provides beneficial knowledge for clinicians providing Internet‐delivered cognitive behavioural PMPs. Future research that explores whether providing additional therapeutic support to patients who have low pain acceptance, low pain self‐efficacy and higher pain intensity at pre‐treatment could be worthwhile.The current study confirms the generalizability of past research on the acceptability and effectiveness of an Internet‐delivered cognitive behavioural PMP , for people with anxiety, depression and chronic pain.No authors have any conflicts of interest/disclosures to report. Dr. Heather Hadjistavropoulos declares funding as noted above. Dr. Blake Dear and Professor Nickolai Titov are developers of the HDH designed the study, oversaw analysis and interpretation of data, and co‐drafted the article. VP and DT analysed the data and co‐drafted the article. AW and EK worked on analysis and interpretation of data and revising the paper for important intellectual content. MN assisted with design of study, data analysis and revising the paper for important intellectual content. LS, BD and NT assisted with design of the study and revised the paper for important intellectual content. All authors approved the final version of the paper.


In critically ill patients, acute pain occurs frequently, causes sympathetic activation, release of inflammatory mediators, and potential organ dysfunction, with the kidneys potentially sensitive to inflammation-mediated injury. This study aimed to explore the association between acute pain in critically ill patients and the occurrence of acute kidney injury (AKI).Data from a retrospective cohort of adult patients admitted between June 2013 and June 2016 to the Intensive Care Unit (ICU) of a tertiary hospital in São Paulo, Brazil, were analyzed. The main exclusion criteria were ICU length of stay < 48 h, coma, and prior kidney dysfunction. The outcome (AKI) was defined as an elevation in the baseline serum creatinine level of ≥ 0.3 mg/dl and/or > 50% at any time after the first 48 h in the ICU. Multivariable logistic regression and hierarchical cluster analysis were performed.p < 0.01) and mechanical ventilation (MV) ≥ 3 days (OR 5.5 CI 2.3–13.5 p < 0.01) were the variables with positive association with AKI. The hierarchical cluster analysis reinforced the relation between AKI, MV and duration of pain.The isolated incidence of pain was 23.6%, and the incidence of pain duration > 5 days was 10.6%. AKI occurred in 31.7% of the cohort. In multivariable logistic analysis, duration of pain > 5 days (OR 5.25 CI 2.19–12.57 Pain is an especially important issue in critically ill patients and in this exploratory study it appears to be associated with AKI development. The search for more rigorous pain control in ICU is crucial and can influence organ dysfunction. Pain is the most common symptom among critically ill patients in intensive care unit (ICU), and it is poorly controlled in most ICUs throughout the world –4. The IThe literature emphasizes the evidence linking suboptimal pain control to poorer clinical outcomes. Acute pain apparently cause delirium  and prolAlthough it is known that pain can cause metabolic stress, autonomic activation, and the activation of inflammatory cells –15, it rThus, we hypothesized that a painful state might be conceivably associated to distant organ signaling, resulting in predisposition to AKI. Thus, the objective of this study was to explore the relationship between acute pain and AKI in a cohort of critically ill patients.This study was conducted with a retrospective cohort of adult patients admitted to the ICU of Hospital Sírio Libanês, a 480-bed tertiary hospital in São Paulo, Brazil, between 1 June 2013 and 30 June 2016. All the data in the current study were extracted from an integrated electronic medical records of Hospital Sírio Libanês (Epimed® and Philips Tasy® Platforms), with approval of the Ethics Committee of the Institute for Education and Research at Hospital Sírio Libanês (access number 445). All the patients in the database were de-identified for privacy protection, and the need for informed consent was waived because of its observational nature.The study included all adult patients aged > 18 years who were admitted to the general, mixed, 30-beds ICU during the study period and remained there for at least 48 h. The exclusion criteria were any baseline creatinine elevation within the first 48 h of admission, chronic kidney dysfunction comorbidity , transplanted kidney, coma or delirium, or intracranial tumor associated with a diagnosis of intracranial hypertension at admission; admission due to cardiorespiratory arrest; palliative care mandate; and readmission within 24 h.For each patient, we collected information on demographic characteristics, diagnosis, cause of ICU admission, comorbidities, physiological and laboratory findings , organ support during ICU stay , and severity scores for organ dysfunction  from the first day of hospitalization until the outcome (AKI). The SOFA score data was analysed in first 24 h and stratified according to dysfunctions.Pain was evaluated using electronic registry data recorded every two hours by the care teams. Patients who could communicate self-rated their pain using a Numerical Verbal Scale , and those who could not communicate and/or were on mechanical ventilation were evaluated using a categorical Behavioral Pain Scale . We also examined the duration (persistence) of pain with consideration of NVS scores in the presence of any value other than 0 and categorical consideration of BPS scores. Each patient’s need for analgesia  was also evaluated through the grouping of analgesic dosages during ICU stay.The variables of interest had continuous data categorized using the Receiver Operating Characteristic (ROC) curve to determine the best accuracy against the clinical outcome (AKI), with the cutoff score for each variable determined by the highest value of the sum between sensitivity and specificity, corresponding to the point of greatest inflection of the ROC curve, with the following predictors being determined: age > 70 years, MV ≥ 3 days, NVS ≥ 3 or positive pain in BPS, pain duration > 5 days, CRP ≥ 5.2 mg/dl, SOFA ≥ 4 points, SAPS3 ≥ 48 points and absence or presence of use of nephrotoxic drugs, sedatives, vasoactive drugs and use of non-opioid analgesics and strong opioids (yes/no).The primary outcome was AKI (according to adapted AKIN criteria), defined as a ≥ 0.3-mg/dl and/or > 50% increase in the creatinine level only after the first 48 h of ICU stay (in relation to the patient’s creatinine level at admission). The creatinine level after the first 48 h of ICU was considered to make the timeframe association between the independent predictors and AKI plausible.p < 0,05). Then, the division of the cohort was carried out into two groups according to the odds ratios  in the bivariate analysis, forming groups with ORs of < 2.5 [compartment 1 (C1)] and ≥ 2.5 [compartment 2 (C2)]. This OR cutoff value was determined by the ROC curve, and the compartmental model was applied for major performance of the logistic regression, with the variables grouped by similarity. Compartment 1 (C1) included the variables age, gender, stratified SOFA , comorbidities  and use of strong opioids and non-opioid analgesics. Compartment 2 (C2) included in the analysis MV, global and stratified SOFA , CRP-t ≥ 5.2 mg/dl, use of sedatives, nephrotoxic drugs, vasopressors and SAPS3. Both compartments were analysed in multiple logistic regression in association with the predictors of pain: NVS ≥ 3 or positive pain by BPS and pain duration > 5 days.Continuous variables are expressed as mean ± standard deviation or median (interquantile range), as appropriate. Continuous and semi-continuous data were compared with the Gauss curve and determined to be non-parametric by the Kolmogorov–Smirnov test. Given the non-parametric nature of continuous data for the total sample, we compared them using the Mann–Whitney test. Categorical and categorized data were represented as absolute and relative frequencies and analyzed using Pearson’s chi-squared test with bootstrap adjustment for large samples. We then performed multiple (binary) logistic regression, with the variables of minor influence being removed one by one (“step by step”), until the model presents cohesion  and dendrogram 2 (D2)]. The variables were organized by average linkage within groups to elements of a tree, where the leaves represent the variables of patients and the length between nodes represent the distance between them determined by Pearson correlation test, and similar variables are found in the same sub-trees.α ≤ 5% risk for type I error and a β ≤ 20% risk for type II error were considered to be acceptable. Data were analyzed using IBM SPSS® Statistics, version 23.0  and GraphPad Prism, version 5.00 for Windows .In this study, an Data from 3125 patients admitted to the ICU during the study period were included. Figure n = 1470) of patients were aged > 70 years, 9.1% (n = 286) remained on MV for ≥ 3 days, and 32% (n = 1000) of patients had SAPS 3 scores ≥ 48 points. The in-hospital mortality rate was 10%. The incidence of NVS score ≥ 3 or positive BPS finding was 23.6% (n = 739). The incidence of pain duration > 5 days was 10.6% (n = 333). The need for non-opioids analgesics was observed in 27.9% of patients, and strong opioids were used in 16.2% of cases. Elevated levels of C-Reactive Protein (CRP) (≥ 5.2 mg/dl) were found in 72.2% of the cohort. Evidence of AKI development > 48 h after ICU admission was observed in 977 (31.7%) patients  4.4–9.1; p ≤ 0.01; Fig. . For compartment 2 (C2), AKI was associated with pain duration > 5 days , the use of MV for ≥ 3 days , and with the use of nephrotoxic drugs , AKI was associated independently with sex and age , stratified cardiovascular and hematological SOFA scores , pain duration > 5 days and use of strong opioids [OR 10.0 (95% CI 6.4–15.5) and OR 1.8 (95% CI 1.1–3.1), respectively; all In the dendrogram 1 (D1) generated by hierarchical clustering, AKI showed the greatest similarity (clustered) with the duration of pain Fig. . At a siIn the cohort studied, AKI appeared to be associated with pain and its duration, corroborating the likelihood of pathological downstream systemic effects of pain experience in target organs.The 26.6% incidence of pain in our sample is slightly lower than that reported in the literature for hospitalized patients , 21, posk = 0.71 and k = 0.67, respectively) [As the literature overly shows, pain needs to be assessed repeatedly every day, and no single scale is enough for the correct interpretation of pain. In this study, we used the numerical verbal scale (NVS) for patients who were able to report their pain and the BPS for non-communicative patients; both scales are recommended  for clinical and surgical patients , and havctively) . Newer mctively) , 26.The intensity and duration of pain were associated with AKI in this study; these associations have not been explored thoroughly in previous studies. We used a cutoff value of NVS score > 3 when estimating pain intensity in communicative patients, similar to cutoff values reported in the literature . With reThe use of strong opioids was associated with AKI in the multivariate analysis most likely because of it´s a robust surrogate marker of intense pain. Although the use of opioids is the standard option for the control of pain symptoms in critically ill patients and occurred in nearly one-fifth of cases in this study, the many side effects of these drugs, are well known . In our We hypothesize that the downstream effects of the painful state, well acknowledged regarding myocardial infarction risk and thromboembolic complications could as well lead to AKI risk, by the conceivable means of systemic inflammation, sympathic-mediated renal vasoconstriction, just to mention a few potential physiopathological mechanism. Recently, the sedation and pain management in ICU and surgical patients has been received attention, as there might be renal protective profiles based on the use of different treatment approaches –36.Likewise, there are hitherto unanswered questions: which objective measure of pain in patients who are unable to communicate is best ; which sNevertheless, this study has certain limitations. Due to its retrospective design, it is subject to information bias and confounding factors; the precision and completeness of data are relevant issues in studies of this type, although few data were missing for our sample. The study was also conducted in a single ICU, which could have influenced the composition of the sample, and it involved the application of local therapeutic strategies. Furthermore, the global incidence of pain may have been underestimated because of the current regular use of common analgesics and drugs with analgesic potential , such as dexmedetomidine, in the postoperative period and for patients on MV, and because of the presence at the hospital of a specialized pain control group, which was represented well in discussions about analgesia and analgesic protocols. In the postoperative period, many patients depend on multimodal and/or patient-controlled analgesia, which was not examined in this study. We also did not analyze the use of other, less common therapies  applied to critically ill patients, or the incidence of prior chronic pain because of their low levels of representation. In summary, this study provides preliminary data for hypothesis generation of a relationship between the pain and AKI. Whether it is pain or some combination that might be associated with changes in kidney function cannot be completely discerned. Therefore, further studies and more robust analytical studies are strongly encouraged.


Controversies remain regarding the preferred treatment strategy for central introital dyspareunia. The primary goal of this retrospective study was to evaluate the short- and long-term outcomes after operative management of central introital dyspareunia by widening hymenoplasty. In total, 513 patients were included, with a follow-up time of 10 years. We assessed the repair of sexual activities, quality of sexual life, and the prevalence of pregnancies after the procedure. In addition, general health status was assessed using the EuroQol-5D questionnaire. Of the 513 women operated on during the period of January 2009 until December 2019, 380 (74%) agreed to participate by sending a valid response. Eighty-seven percent of the respondents mention no to moderate pain for longer than one week after the procedure, while 9.5% and 4% of patients recalled the procedure as severely or extremely painful, respectively. Seventeen percent of patients recalled a complication; 13.2% reported prolonged healing or postoperative pain, 4.7% reported infection, and 2.4% reported bleeding. Twelve months after surgery, 72% experienced no or only slight pain during penetration. We can conclude that widening plasty of the posterior hymenal rim and vestibulum, performed as an ambulatory care procedure under local anesthesia, resolves more than 70% of the central introital pain problems one year after surgery. Dyspareunia is defined as a complaint of persistent or recurrent pain or discomfort associated with attempted or complete vaginal penetration. In the U.S., it affects 10 to 20% of women [Introital dyspareunia can have several causes. It can be due to identifiable causes, such as a congenitally narrow hymen; congenital malformations, such as a vaginal septum; the presence of vulvovaginal infections , which must be differentiated from the more well-known  vestibulodynia ,6. CID iOur primary endpoint was to assess the short- and long-term functional outcome and general health status after such operative management of CID. Secondly, we identified the clinical and demographic parameters that could influence the outcomes in order to improve treatment strategies and outcomes of CID even further.During the 10-year period from 1 January 2009 until 31 December 2019, 853 patients underwent surgical treatment for CID in the Lower Genital Tract Disease Center of the Department of Gynecology of the Regional Hospital Tienen, Belgium. For 660 of these patients, email addresses or phone numbers could be retrieved from the Tienen administration database regarding operations performed under the term ‘vulvoplasty’ or ‘hymenoplasty’ during that period. CID was defined as pain due to the presence of a painful rim on the posterior vestibulum at 6 o’clock  when touched by a finger moved outward or inward over that area, while providing a gentle downward touch. If the patient admitted feeling pain but could still support it, the pain was scored as ‘+’, whereas if she made painful grimaces, shouted, or automatically withdrew upward on the examination table because of extreme pain, the pain was scored as ‘++’ for ‘palpation pain’. Subsequently, a second finger was introduced (or was attempted to be introduced) to test for distention pain by gently opening both fingers a few millimeters. If this was felt as painful, a score of ‘+’ was given, whereas if it was not possible to introduce a second finger, a score of ‘++’ was given for ‘distention pain’. If the sum of ‘palpation pain’ and ‘distension pain’ was 3+ or 4+, this was diagnostic for severe CID and an indication for surgical widening posterior vestibuloplasty.All these patients were contacted by telephone or email to ask permission to send links by email concerning a commissioned electronic survey. All patients were provided with a written informed consent form for this study, which was required to be signed and sent back before receiving the questionnaire.Apart from the assessment of CID (see above), an extensive clinical examination of the vulvo-vaginal area was performed following the same systematic routine in all patients, as described below.Lateral introital pain was assessed in all patients by gentle touch with a cotton swab on different parts of the introital area of the vulva (Q-tip test) while asking the patient to score the pain they felt from 1 to 10, 1 being touch without pain and 10 being the most severe pain imaginable. This Q-tip touch test was performed at different points of the inner labia minora , and on the posterior commissure (6 o’clock). Women with moderate (scores of 4 to 6) or severe (scores of 7 or above) lateral pain (moderate/severe provoked vestibulodynia) were only excluded if they displayed normal findings upon touch or distention of the posterior commissural area . Therefore, patients with combined lateral and central introital dyspareunia were still allowed to participate in the trial and were kept in the analysis.In addition, as part of the diagnostic workup, all patients’ vaginal fluid was tested with phase-contrast wet mount microscopy to assess lactobacillary grades and the presence of bacterial vaginosis, candida, Trichomonas, atrophy, or aerobic vaginitis ,10. WomeFinally, digital palpation of the levator ani muscles was performed to assess the tension of the pelvic muscles. Women with high muscular tension but without mono-digital central palpation pain were sent to the pelvic physiotherapist for muscle relaxation exercises.Patients younger than 16 were excluded, as well as patients who underwent vestibulectomy, in order to prevent confusion with other pathologies, such as imperforate hymen, pain upon insertion of tampons, or therapy-resistant lateral vestibulodynia without concomitant CID.After receiving the questionnaires, an undefined number of patients noted that they could not complete the questionnaire fully as they were not or were no longer in a sexual relationship. Those who notified us of this were excluded from the analysis of the data related to sexual function and wellbeing. We may not have been aware, however, of the presence of an actual sexual partner for all respondents, as some of them may not have mentioned this explicitly. In addition, we did not inquire about lesbian relationships, although penetration pain may or may not be an issue in the sexual health of these women.The operative approach, which was always performed by the same surgeon (GD), implied a non-excisional widening plasty, typically with local anesthesia. The surgical technique used has been described elsewhere . In shorThe questionnaires were drawn up in Dutch, English, and French and assessed demographic and clinical characteristics, quality of life, surgical experience, and outcomes of the treatment . The queThe demographic variables assessed addressed the following information: age at the time of the surgery; body mass index (BMI); smoking; the presence of debilitating diseases, such as diabetes mellitus and pulmonary disease; and cardiovascular risk factors (CVRFs). To ensure the uniformity of surgical technique, we only included women who underwent surgery performed by the same surgeon using the same surgical procedure during the whole study period.CVRFs were categorized by assessing the following factors: age of 55 years and over, overweight (BMI more than 25), smoking, diabetes mellitus, hypertension, or current cardiovascular diseases.We inquired about the extent of pain the patients experienced during and after the surgery with a score from 1 (not painful) to 5 (extremely painful). Subsequently, the following possible postoperative complications were solicited: operative site infection, delayed or troubled healing, persistent pain, bleeding duration longer than one week, and wound dehiscence. Patients were asked to assess sexual function and wellbeing at 3 months, 6 months, 1 year, 2 years, and more than 2 years after the intervention. The pain was evaluated with a score from 1 to 5 (1 meaning no pain and 5 meaning no penetration was possible because of severe pain).https://euroqol.org/eq-5d-instruments accessed on 28 November 2021). The date of questionnaire completion was defined as the end of follow-up. The EuroQol-5D, Dutch version, was used to assess the functional outcomes in terms of pain and disability.General health issues were tested using the EuroQol-5D questionnaire  and the principles of GCP; in accordance with all applicable regulatory requirements; and with applicable personal data protection and processing of personal data . The protocol was approved by the ethics committee of RZ Tienen .p = 0.14). The CONSORT diagram with the identification/inclusion process is depicted in We did not have recent contact information for 191 of the 853 identified patients who underwent surgery for CID. Furthermore, two patients had died, and 10 refused to participate after telephone contact. Thus, 650 patients were contacted by mail and asked to participate in this retrospective single-center cohort study. Eighty-six of these patients were excluded, as they underwent the intervention at less than a year before (short follow-up) or claimed they had another reason to be operated on other than painful intercourse . Furthermore, 8 patients did not meet the inclusion criteria, 10 answered that they did not remember the operation date, 26 emails bounced back because the e-mail addresses were not correct, and 7 patients refused to participate after receiving the questionnaire. Of the 513 remaining patients who were eligible to fill out the questionnaire, 380 patients (74%) sent back complete and valid responses. There was no difference in age between the responders and non-responders  or extremely painful (score 5), respectively . SeventeAfter 1 month, 41.8% of patients were nearly pain-free during penetration; 64.5% were nearly pain-free after 3 months, and this proportion further increased to 72.1% and 74.2% by 12 and 24 months post-surgery, respectively .A total of 185 (49%) and 89 (23%) patients experienced no pain or slight pain or disability, respectively, during penetration 12 months after surgery . In the r = −0.117, p = 0.02) and anxiety showed a positive correlation with pain during intercourse . None of the other patient characteristics were correlated with pain scores. There was also no significant correlation between coitus frequency and any patient characteristic.The Pearson correlations of the patient characteristics and the pain score and coitus frequency 12 months after surgery are displayed in To our knowledge, we report the largest series analyzing surgical treatment for central introital dyspareunia. The main conclusion of this survey is that the cornerstone of therapy for CID, a frequent and underdiagnosed disorder, seems to be surgery to widen the posterior hymenal area. Two years after the intervention, three of four women who received operations were happy to experience little or no pain upon penetration and could enjoy sex again.Central introital penetration pain is a common disorder that is frequently overlooked and may be misdiagnosed as provoked localized vulvodynia. In a prospective study monitoring the causes of painful introital intercourse for one year, CID comprised 28% of all causes, while lateral vestibulodynia comprised only 18% . In the present study, in one center, 853 patients were diagnosed with and treated for CID for 10 years, which corresponds to around two new cases being referred to our specialized clinic per week. This indicates that CID is rather frequent and should be checked for in all patients presenting with the complaint of painful intercourse.The advantages of this study are the large number of participants and the high response rates. In addition, the use of a stable treatment technique over the full study period is an advantage, as all patients were operated on using the same surgical technique  performeSeventy-four percent of respondents answered the invitation by sending a fully answered questionnaire. While this is a staggering result, one still can wonder why the remaining 26% failed to properly return the completed questionnaire. Among the women who did not comply, some answered they did not recall the exact date of the operation, preventing them from answering the questions. In addition, some of the women no longer remembered the details of the operation after several years, leading them to not respond. Moreover, over this long period of time, a lot of circumstances could have changed, leading to different life conditions, such as being single, fear of resuming sexual intercourse, or being in a lesbian relationship, which we were not able to control for. We knew that non-responders did not differ in age from the responders, but regarding other variables, we did not have information.Compared to different treatment efforts for vestibulodynia , includiThe fact that some women claimed to have only infrequent or no sex after the surgery may have many reasons. First, during the 10-year time span of the study, the drive to have sexual intercourse may have decreased, as it does the general population . FurtherFor the same reason, we were not able to check for potential comorbidities causing painful intercourse. From clinical practice, as well as from our prospective survey, we learned that several causes, such as vaginal atrophy, vulvovaginal infections, increased pelvic floor tension, psychic troubles, and lateral vestibulodynia, often coexist with CID. In this study, we were not able to analyze the frequency or severity of these medical conditions, but we have to keep in mind that the 25% of women still suffering from introital pain after 2 years may have one or more such co-morbidities.In general, the group of patients had good health, with little cardiovascular, pulmonary, and endocrinologic system malfunctioning, and almost all answered that they were self-supportive. However, from the EuroQol-5D questionnaire, it was clear that increased levels of anxiety correlated with more severe pain scores when attempting introital penetration. While increased levels of introital dyspareunia were formerly thought to be caused by automated reflexes of fear for pain and reduced sexual arousal, research has demonstrated that affective associations with sexual stimuli are experienced more negatively in women with dyspareunia than in control women . SmokingWe discovered that widening plasty of the posterior hymenal rim, without resection of any tissue, performed in ambulatory care under local anesthesia resolved 75% of the pain problems, but one must be aware that it can take up to one or two years to achieve the maximal effect and normal sexual activity. We realize that central introital dyspareunia is a frequent problem that needs to be examined and excluded (or treated for) in each patient presenting with introital pain upon penetration attempts during sex. In future studies, this entity, along with existing co-morbidities, must be taken into consideration. For an unclear reason, smoking women recovered better, resulting in less pain during intercourse after the surgical intervention, while anxious women suffered from more pain. This should be taken into account when proposing surgical treatment.


The aim of this study was to identify the effect of different injection times on pain during colonoscopy procedure.In this retrospective study, the data of patients who underwent colonoscopy from June 2020 to September 2020 were assessed to investigate the effect of different injection time of sedative drugs (midazolam and dezocine). The primary endpoint was evaluating the pain intensity of the patients using visual analogue scale (VAS) immediately after colonoscopy .P = 0.22), addition of sedative drugs during procedure , and adequate bowel preparation . However, patients in the 3 Min group had significantly lower VAS than those in the 1 Min group .A total of 152 patients were eligible for this study. Of them, 76 received midazolam and dezocine injection 1 min prior to the colonoscopy procedure (the 1 Min group) and the other 76 patients received the injection 3 min prior to the procedure (the 3 Min group). The vital signs of all patients were stable except for one patient who was diagnosed with inflammatory bowel disease in the 3 Min group. A transient drop in blood pressure for this patient was observed during colonoscopy but returned to normal after general treatment. The two groups had similar rates of cecal intubation (84.21% vs. 90.97%, The timing of drug injection during conscious sedation may affect pain control during colonoscopy, with 3 min prior to the procedure showing lower VAS. Colorectal cancer (CRC) is a global public health issue, with an estimation of 1.93 million new cases and 930,000 deaths worldwide in 2020  and is cColonoscopy often presents as a painful and unpleasant procedure, which is one of its major barriers for willingness among the public . Among pIn this study, we evaluated the safety of sedation with midazolam and dezocine and compared the efficiency of different injection times (1 or 3 min before colonoscopy procedure) using the visual analogue scale (VAS) immediately after colonoscopy.Patients older than 18 years who had undergone colonoscopy were eligible for inclusion, and patients with stage IV colorectal cancer, history of chronic pain, or who had incomplete or missing follow-up data were excluded. The patients were divided into two groups: group 1 (injection of midazolam and dezocine 1 min prior to colonoscopy) and group 2 (injection of midazolam and dezocine 3 min prior to colonoscopy). We retrospectively collected the clinical data of 200 people who underwent colonoscopy between June 2020 and September 2020 at the Six Affiliated Hospital of Sun Yat-sen University . Propensity score matching was used to control selection bias and 152 patients were finally included in this study. The propensity score of being allocated to group 1 and group 2 was calculated using a multivariable logistic regression model with age and sex as covariates. The patients were matched using the nearest-neighbor method in a 1:1 ratio with a caliper width of 0.2 SD of the logit of the propensity score.2)], satisfaction of colonoscopy, and postoperative complications were collected.Demographic data including age, gender, cardiovascular disease history, diagnosis, history of colonoscopy screening, history of previous abdominal surgery, Boston Bowel Preparation Scale (BBPS), addition of sedative drugs during procedure, cecal intubation rate (CIR), resection of polyp, VAS, change in vital signs .2 in To further investigate the safety of the procedure, we have illustrated the changes in arterial blood pressure, pulse, and SPOP = 0.041). Patients’ pain and fear of colonoscopy are among the reasons for reluctance to colonoscopy (P = 0.041). The onset time of a sedative analgesic such as midazolam is relatively slower than propofol. This may be the reason why 3 min injection administration had better pain control effect than 1 min. Further studies are needed to see if lower VAS vary based on time and level of sedation administered.In this study, we found that conscious sedation and analgesia was safe and had a satisfactory level of comfort during the procedure, with a high satisfaction score (approximately 86.84%) and low rate of need for additional pain medication. In addition, intravenous injection of sedative drugs 3 min before the procedure had significantly better pain control than 1 min .Several factors including sedation, adequate bowel preparation (based on BBPS ≥6), previous abdominal surgery, and endoscopists’ experience were identified in previous studies to be associated with pain during procedure , 24. In P = 0.22). However, patients with adequate bowel preparation (BBPS ≥6) had a higher rate of reaching the cecum than other patients (P = 0.001). An adequate bowel preparation could decrease the procedure time and make endoscope insertion easier, thereby having a higher rate of cecal intubation and better procedure tolerance . In addition, patients who underwent polyp resection during colonoscopy had similar median VAS scale with others. It was reported that patients with inflammatory bowel disease favored propofol sedation over conscious sedation (n = 15) presented similar outcomes compared to non-IBD patients (n = 137) in our study (P = 0.75).Except for pain during the procedure, several factors such as previous experience with colonoscopy and appropriate level of sleep were also associated with satisfaction of the procedure . In thisThe limitation of this study was its retrospective nature and single institution data with relatively small sample size. Large prospective large-sample-size and multicenter studies are required to further evaluate the timing of drug injection and outcomes.The timing of drug injection during conscious sedation may affect the pain control during colonoscopy, with 3 min prior to the procedure showing lower VAS.


Precise predictors are lacking for hepatitis B surface antigen (HBsAg) clearance under the combination therapy of nucleos(t)ide analogs (NA) and pegylated interferon-alpha (PEG-IFN-α) in patients with chronic hepatitis B (CHB). This study aimed to determine the quantitative anti-hepatitis B core antibody (qAnti-HBc) and quantitative hepatitis B core-related antigen (qHBcrAg) as predictors for HBsAg clearance in NA-suppressed patients with CHB receiving PEG-IFN-α add-on therapy.Seventy-four CHB patients who achieved HBV DNA suppression (HBV DNA < 20 IU/ml) and quantitative HBsAg (qHBsAg) < 1,500 IU/ml after ≥1 year of NA treatment were enrolled. Fifteen patients continued on NA monotherapy, while 59 patients received PEG-IFN-α add-on therapy. Serum qAnti-HBc and qHBcrAg levels were detected every 12 or 24 weeks for add-on and NA-alone groups, respectively.Serum qAnti-HBc but not qHBcrAg levels at baseline were negatively correlated with the duration of prior NA therapy. After 48-week treatment, both qAnti-HBc and qHBcrAg levels declined further, and 17/59 (28.81%) and 0/15 (0%) achieved HBsAg clearance in add-on and NA groups, respectively. In the add-on group, the rate of HBsAg clearance was significantly higher in patients with baseline qAnti-HBc < 0.1 IU/ml (52.63%). Logistic regression analysis identified baseline qAnti-HBc but not qHBcrAg, which was an independent predictor for HBsAg loss. Receiver operating characteristic curve analysis showed that the combination of qAnti-HBc and qHBsAg had a better predictive value for HBsAg clearance.A combination of qHBsAg and baseline qAnti-HBc levels may be a better prediction strategy for HBsAg clearance in NA-suppressed CHB patients receiving PEG-IFN-α add-on therapy. Approximately 250 million individuals worldwide are chronically infected with hepatitis B virus (HBV) , and 10%The quantitative anti-hepatitis B core antibody (qAnti-HBc) and quantitative hepatitis B core-related antigen (qHBcrAg) are emerging novel markers for patients with CHB. Studies have shown that the qAnti-HBc levels in CHB patients during the immune clearance and reactivation phases are significantly higher than those in the immune tolerance and low replication phases in natural history , 14. TheHowever, it remains unclear whether qAnti-HBc and qHBcrAg levels can predict HBsAg clearance in NA-suppressed CHB patients receiving combination therapy with PEG-IFN-α. This study aimed to investigate the kinetics of serum qAnti-HBc and qHBcrAg levels in CHB patients with qHBsAg < 1,500 IU/ml receiving PEG-IFN–α add-on to ongoing NA therapy, and to evaluate the role of these two biomarkers in predicting HBsAg clearance.The subjects were enrolled from the Fifth Medical Center of Chinese PLA General Hospital. CHB patients aged 18–65 years who had received NA treatment for ≥1 year and achieved serum qHBsAg < 1,500 IU/ml and HBV DNA suppressed were eligible. HBV DNA suppressed is defined as HBV DNA < 20 IU/ml. Patient exclusion criteria were as follows: coinfection with human immunodeficiency virus, hepatitis A virus, hepatitis C virus, hepatitis D virus, or hepatitis E virus; presence of other chronic liver disease or serious systemic diseases; and receiving IFN, glucocorticoids, or other immunomodulatory therapy within 6 months prior to enrollment. A total of 74 patients were enrolled and divided into a continuing NA monotherapy group  and an add-on PEG-IFN-α therapy group  according to their wishes. The NA group received continuous entecavir (ETV) or tenofovir disoproxil fumarate (TDF) for 48 weeks. The add-on group received ETV or TDF combined with PEG-IFN-α-2b (180 μg once a week) for 48 weeks Figure 1ETV was the main type of NA taken before enrollment . If patients received lamivudine, adefovir dipivoxil, or telbivudine before enrollment, they were replaced with ETV or TDF. The baseline characteristics of the patients were comparable between the groups Table 1.10 U/ml. Serum qAnti-HBc and qHBcrAg levels were measured according to the manufacturer’s instructions.Twenty milliliters of peripheral blood samples were collected at study entry and every 24 weeks (NA group), or every 12 weeks (add-on group). Serological and biochemical markers were measured routinely in a central clinical laboratory. Serum HBV DNA levels were tested using the COBAS AmpliPrep/COBAS TaqMan HBV Test ; the lower limit of detection (LLD) of HBV DNA level was 20 IU/ml. Serum HBsAg levels were quantified using Elecsys HBsAg II quant II ; the LLD of qHBsAg was 0.05 IU/ml. Other HBV markers, including HBsAb levels, HBeAg, and HBeAb, were detected using COBAS e602 . Serum qAnti-HBc levels were measured using a double–antigen sandwich immune assay , as reported previously , adjusting for demographic characteristics and baseline indicators associated with HBV infection. A PSM with the nearest-neighbor method using 1:2 matching was performed by R version 4.1.2. Univariate and multivariate logistic regression analyses were used to identify predictors for HBsAg clearance. The discriminatory power of various predictors for HBsAg clearance was tested with the area under the receiver operating characteristic (ROC) curve. All statistical analyses were based on two-tailed hypothesis tests with a significance level of p < 0.05.Serum qHBsAg, qAnti-HBc, and qHBcrAg levels were log-transformed. Statistical analyses were performed using SPSS 25.0 software . Continuous variables were expressed as median (quartiles). The statistical significance of the difference between two groups was determined using the Mann–Whitney The levels of baseline serum qAnti-HBc and qHBcrAg in the NA group were slightly higher than in the add-on group but without significant difference (p > 0.05) Table 1.10IU/ml, p = 0.334; qHBcrAg: 0.23  vs. 0.13  log10U/ml, p = 0.737]  vs. 0.09  logAfter 48-week treatment, 17/59 (28.81%) patients achieved HBsAg clearance in the add-on group, while no patients achieved HBsAg clearance in the NA group Table 1.10IU/ml and 0.26  log10IU/ml, respectively. Dynamic variation of qHBsAg during 48 weeks of add-on therapy showed that the decrease of qHBsAg at weeks 24, 36, and 48 in patients with baseline qAnti-HBc < 0.1 IU/ml was significantly greater than that in patients with baseline qAnti-HBc > 0.1 IU/ml  log.1 IU/ml Figure 410IU/ml at week 12 . Since previous studies found that qAnti-HBc decreased with NA treatment, and the patients had undergone NA therapy for a long time before enrollment, the duration of prior NA therapy was included in the regression analysis, while sex, age, duration of prior NA therapy, early ALT elevation, and baseline HBcrAg levels did not influence HBsAg clearance significantly  remained independent predictors for HBsAg clearance after 48 weeks of add-on therapy , and other predictors included baseline HBsAg levels (<400 IU/ml)  and a decline of qHBsAg > 1 log10IU/ml at week 12; the AUROCs were 0.830 and 0.838, respectively. Furthermore, the combination of baseline qAnti-HBc levels and decline of qHBsAg > 1 log10IU/ml at week 12 had a significantly higher AUROC (0.887). When the three indexes were combined, the AUROC can reach 0.930.Area under the ROC curve (AUROC) was used to compare the predictive effectiveness of these independent predictors for HBsAg clearance , Capital clinical diagnosis and treatment technology research and transformation application project (Z211100002921059), the National Science and Technology Major Project (2017ZX10202201), the National Natural Science Foundation of China , and the Innovation Groups of the National Natural Science Foundation of China (81721002).The authors would like to thank Professor George K.K. Lau for making significant suggestions for the article and are grateful to all the participants.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.


Heart failure (HF) is considered one of the main causes of morbidity and death among chronic diseases worldwide. Patients have increasingly reported chronic pain in long-standing heart failure as a disturbing symptom. Its unknown etiology and mechanism, in addition to its insidious progressive nature, made both the doctor and the patient not notice it until it affects the quality of life (QoL) and general health status. The primary objective of this study is to find the prevalence of pain in chronic heart failure patients and its impact on their QoL. The secondary objective is to determine the predictors of QoL in HF patients.A multicenter cross-sectional design was used. The European Quality of Life scale five dimensions scale and the Brief Pain Inventory were adopted to evaluate QoL and pain, respectively. The Statistical Package for the Social Sciences version 25 was applied to present the data. The Mann-Whitney U, Kruskal-Wallis, and Cronbach alpha tests were used.p = 0.004 and p < 0.001, respectively) and pain interference  were found to significantly associated with both QoL scores; the visual analogue scale (EQ-VAS) and EQ-5D-5L. In multivariate analysis, monthly income was the only variable significantly correlated with EQ-VAS and EQ-5D-5L, along with pain variables.The final study had a total of 142 individuals. The prevalence of pain among HF patients was 84.5%. Knee pain was the main complaint among patients. Our patients' median pain severity score was 18 [5.00–25.00], while the median pain interference score was 39 [24.75–53.00]. They had a median EQ-5D score of 0.34 [0.0–0.6] and an EQ-VAS score of 50 [30–70]. Pain severity (Pain is a common symptom among patients with HF and is significantly associated with their QoL. Low income is also highly associated with poor QoL. Definitive guidelines should be achieved to increase awareness and understanding of the importance of pain management, reaching a higher QoL level, less pain, and good adherence to HF medications. Heart failure (HF) is a group of signs and symptoms caused by a weakened heart, resulting in decreased longevity . TypicalAccording to the International Association for the Study of Pain (IASP), the updated and recent definition of pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage .Quality of life is a term that aims to describe a population's or individual's entire well-being throughout their life at a specific point in time, incorporating both positive and negative aspects. For example, personal health , relationships, education level, work environment, social standing, money, and a sense of security are all important parts of QoL . HoweverHF disease progression is characterized mainly by the decline in daily patient activities and its effect on the QoL . HoweverChronic pain appears to be prevalent, between 23 and 85% among patients . From anRegardless of the nature of pain, the etiology is still vague and controversial. Several factors play a major role in pain severity, including age, comorbidities, mental health status, and even a history of cancer . HoweverHeart failure symptoms were approved to be associated QoL , 17. NevAs a result of a previous review article, the prevalence of pain in HF patients ranges between 23 and 85% . AlthougFurthermore, there is strong evidence that there is a correlation between hidden and unrecognized pain and decreased QoL in HF patients . This stA multicenter cross-sectional design was used, including samples from the cardiology department at Al-Watani Hospital, An-Najah National University Hospital, and the Ministry of Health Clinics in Nablus, Palestine, from November 2020 to March 2021. Due to the coronavirus disease 2019 (COVID-19) crisis, many patients stopped visiting hospitals and clinics as they used to do before, so we visited them at their houses to complete the sample.6th-year medical students carried out data collection via face-to-face interviews. A convenience sample of 142 patients met the criteria and took part in the analysis. Frequent check-ups have been performed to reassure the sampling environment, clear definitions, and criteria correspondence.We included patients 18 years old or more, who had chronic HF for more than 3 months, were stable on the treatment regimen, having a left ventricular ejection fraction of < 40% determined by echocardiography or ventriculography, with the mental and physical capacity to speak with the interviewer and the ability to collect all clinical and demographic data. Those who refused to give their consent, those who were unstable. And patients with documented lacking cognitive ability to respond to the data collection procedures were also excluded. We also excluded patients who had missing items on the BPI scale.Data were obtained through multiple questionnaires. The main variables used were: (i) Sociodemographic data: including age, gender, body mass index (BMI), residency, education status, monthly income, social status, and job status (ii) Clinical data related to HF, including duration of HF disease, comorbid diseases, and chronic medications obtained from the medical record, (iii) HRQoL of HF patients, and (iv) Pain-related data. The data collection form was built based on previous studies' information , 10, 12.p ≤ 0.001 for all dimensions). Moreover, Cronbach’s alpha was 0.75 for the Arabic version of the EQ-5D. The intra-class correlation coefficient for the EQ-VAS was 0.78  for both scores were 18 [5.00–25.00] and 39 [24.75–53.00], respectively. The Cronbach alpha test was utilized to calculate the reliability of pain severity and pain interference scores, and the results were 0.886 and 0.836, respectively.The median EQ-5D score in this cohort of patients was 0.34, with an interquartile range of [0.00–0.65], while the mean ± SD was 0.3 ± 0.36. The reliability of the items tested was 0.75. However, the median EQ-VAS score was 50 [30–70], while the mean ± SD score was 50.8 ± 21.33.p = 0.033) and monthly income (p = 0.001) showed a statistically significant association with EQ-VAS scores. Furthermore, it showed a significant association between the EQ-VAS scores and the severity category (p = 0.026), with the lowest median 30 (20–52.5) for the severe pain group and with the interference category (p < 0.001), the median [Q1–Q3] for low pain interference was 60 (43.75–70) compared to 30 (20–50) for high pain interference.Education level , gender (p = 0.005), social status (p = 0.028), occupation status (p = 0.002), and income (p < 0.001). It also shows a substantial link between EQ-5D-5L and the pain interference (p < 0.001) and pain severity (p = 0.001) categories. Medians [Q1–Q3] of EQ-5D-5L score for pain severity groups were as follows: 0.74 [0.62–0.84] for no pain, 0.36 [0.02–0.55] for mild pain, 0.18 [− 0.05–0.46] for moderate pain, and 0.04 [− 0.17–0.19] for severe pain. In addition, the median was lower for high pain interference 0.04 [− 0.15–0.15] than low pain interference 0.39 [0.04–0.70].The results of the relationships with the EQ-5D-5L are shown in Table The other variables were not significantly related to this score.p = 0.02) in EQ-VAS scores related to monthly income. These findings are detailed in Table p < 0.001) and the pain severity score (p = 0.004) had significant negative associations with the EQ-VAS score.The findings of the linear regression analysis revealed significant positive differences (p = 0.044). We discovered a significant negative relationship between the EQ-5D score and both pain interference (p = 0.001) and pain intensity (p < 0.001)  Table .Table 7AThe current work found a high prevalence (84.5%) of pain among Palestinian HF patients. The important findings were significant and negative correlations between pain interference and QoL on the one hand and between pain severity and QoL on the other. Patients with CHF suffer from many symptoms, such as pain. There is a significant relationship between hidden pain and decreased quality of QoL in CHF patients . SeveralSimilar to a previous study, the prevalence of pain among HF patients was 85%, but the percentage of patients who had severe/very severe pain was 42.5%, which was higher than what we found (18.3%) . HoweverIt was reported that 39.5% of HF patients complained of pain from more than one site . When loThe current work conducted a detailed assessment of QoL in CHF in Palestine. The BPI scale was used to assess chronic pain symptoms, the EQ-5D scale and its EQ-VAS component were used to evaluate QoL. In our analysis, the median scores for EQ-5D and EQ-VAS were 0.34 and 50, respectively. HF patients were documented to have lower QoL compared with other patients with comorbid conditions and the general public . A largeUnemployment and low income were other variables significantly associated with poor QoL. Perhaps this result is because chronic illnesses have many complications, limitations, and acute problems that need a good socioeconomic status to control them . FurtherThe current study will help spread awareness about the importance of pain management in this population in developing countries. Additionally, understanding and managing the effect of chronic pain on the patient's mental health increases the patient's adherence to prescribed HF medications.This study has advantages, including the fact that it applied validated questionnaires to examine the prevalence of pain among HF patients and its influence on QoL in a developing country. Furthermore, face-to-face interviews were used to collect data, which may have enhanced the data's reliability. However, there were certain limitations, such as the spread of COVID-19 and the imposition of quarantine, which reduced the sample size and the doctors' strike in government facilities. Furthermore, elderly patients and patients who cannot walk and reach health facilities to receive their medicines and send a family member to replace them made it difficult to contact them. In addition, the most important limitation lies in the fact that its cross-sectional design makes it impossible to build causal links between exposure and outcome variables. Furthermore, the convenience sampling technique may have lowered the study's generalizability to additional HF patients. Importantly, certain clinical and objective variables, such as ejection fraction and treatment of HF were not collected or analyzed, in addition to lacking of detailed information on comorbidities, which certainly have an impact on the occurrence of pain complaints.Chronic pain was prevalent among a wide range of patients with stable CHF. The subgroups with the lowest QoL are female gender, low education, low income, and unemployed. Additionally, we found that patients with more pain severity and pain interference had significantly lower QoL than others. Our results will provide policymakers and clinicians with reliable information about the impact of chronic pain on QoL, consider changing policies and taking new steps toward pain management, restrict it in current patients, and prevent its progression in future patients. Definitive guidelines should be established to increase awareness and understanding of the importance of pain management, with special guidelines organizing follow-up visits among those patients to reach a higher QoL level, less pain, and good adherence to HF medication.


Background: Pain, sleep disturbances, and mood disorders are considered common symptoms of fibromyalgia (FM). However, the interactions that are established between them and the implication that this has in the disease are not clear. The main objective of this study is to clarify the relationships established between insomnia, pain intensity and anxiety in women with FM. Additionally, the effect that the indicated pathological cycle between pain, insomnia and anxiety may have on the impact of the disease in these patients is explored. Methods: A total of 228 women diagnosed with FM participated in this study . Measurements were conducted at two time points. Initially, the women completed self-report questionnaires about anxiety , sleep problems  and pain intensity , and a week later, they answered questions about the impact of fibromyalgia . For data analysis, models 4 and 6 of the Macro Process for SPSS were used. Results: Insomnia predicts higher levels of pain, which in turn predicts higher levels of anxiety, which in turn predicts a higher impact of fibromyalgia . No significant results were found for the other interactions between the variables. Conclusions: Due to the clinical and scientific relevance of the insomnia–pain–anxiety pathological cycle and given the impact it has on FM, it is especially relevant to develop programs for patients with fibromyalgia based mainly on improving sleep quality. Fibromyalgia (FM) is considered a chronic disease without a well-established etiology, characterized mainly by widespread pain, fatigue, sleep and/or mood disorders . This syAnother frequent comorbidity associated with chronic pain and sleep disorders is mood disorders . It is kA recent case study analyzing the pathological cycle of pain–insomnia–anxiety in FM patients  suggestsThe participants of the present study were 228 women diagnosed with fibromyalgia according to the criteria of the American College of Rheumatology ,21. SeveA total of 268 women with fibromyalgia agreed to participate in the study and met our inclusion criteria. The patients were distributed in groups of 8–10. To facilitate the participation of the patients, the research team (two of its members) traveled to the place where the participants lived. Therefore, the evaluations were carried out at the associations to which the patients belonged. The patients were evaluated twice. The evaluation sessions lasted approximately 30 min. Self-report questionnaires (paper-and-pencil form) were administered to each of them. In the first evaluation, the patients were informed about the research and those who agreed to participate signed the informed consent form. Then, the participants answered the insomnia, severe pain and anxiety questionnaires. In a second evaluation, a week later, the patients were asked about the impact of fibromyalgia (self-report). In order to connect the data in the two stages of the study, a code was assigned to each of the participants. In both assessments, the researchers were present to clarify any question that caused doubts in the completion of the self-report.The final sample comprised a total of 228 patients of the 268 initially interested in participating .The study was carried out between January 2017 and June 2018. This multicenter study was conducted according to the guidelines of the Declaration of Helsinki and approved by the University Ethics Committee of the Universidad Rey Juan Carlos .Insomnia–The Insomnia Severity Index (ISI) was used to assess insomnia [insomnia . The conPain severity–The pain severity scores were obtained by averaging the maximum, minimum and overall pain severity during the last 7 days, together with the pain severity rating at the time of assessment [sessment . All fousessment . Pain sesessment . The intFibromyalgia impact–The Spanish adaptation of the Fibromyalgia Impact Questionnaire—Revised was used to measure the impact of fibromyalgia on functioning [ctioning . The totctioning . The CroAnxiety–The anxiety subscale of the Spanish version of the Hospital Anxiety and Depression Scale (HADS) [e (HADS)  was usedSocio-Demographic and clinical data–An ad hoc questionnaire was used to evaluate age, educational level, employment status, and marital status. Regarding clinical variables, the duration of fibromyalgia was recorded.p value less than 0.05.The SPSS 22 statistical package  was usedp-value of > 0.05, and an approximation of root mean square error of < 0.06 [For the analysis of simple mediation (model 4) and multiple serial mediation , applying two significant mediators, SPSS macro PROCESS was used. As Hayes recommended , the regf < 0.06 . In addif < 0.06 ,34. A toThe mean age of the women was 56.99 years (SD = 10.35). In relation to education, 6% of the women had completed university, 26.6% secondary education, 51.3% primary education and 15.6% knew how to read and write. The majority of the women were married or in a stable relationship (78.1%), 6% were single and 15.9% were divorced or widowed. Seventy-eight percent of the women were housewives. Participants had a fibromyalgia diagnosis for an average of 13.02 years .p > 0.05).p = 0.10) of the predictor on the impact of fibromyalgia. Based on the results of the mediation models, only the effect of model 1 on the impact of fibromyalgia was tested. A significant indirect effect of insomnia on the impact of fibromyalgia was observed through pain severity and anxiety  . That isThe main objective of this study was to elucidate the associations established between insomnia, pain severity and anxiety, thus determining the possible impact of the interaction of these variables on the perception of the disease in women with fibromyalgia. One of the most important findings obtained was verifying that, in line with what is suggested by the latest research ,18, the The exposed mediation model adds that the insomnia–pain–anxiety pathological cycle, in turn, predicts a greater impact of the disease. The literature is consistent in the repercussions that presenting this symptomatology has on the impact of the disease ,35. PrevOn the other hand, in the present study, the simple indirect effect of insomnia on the impact of fibromyalgia through pain was significant. These results are consistent with research using the time series method with daily monitoring in patients with fibromyalgia. The findings of these studies show that after a night of poor sleep, pain intensity increases  and, morCertain limitations of this study should be mentioned. First, the sample is made up only of women with fibromyalgia, which does not allow the results to be generalized to other populations with chronic pain. Second, comorbidity was not controlled, so the results should be taken with caution. In addition, it should also be taken into account that there is no universally accepted definition of poor sleep and there is a wide variety of self-report questionnaires to assess sleep quality, which makes comparison with other studies difficult. Although the questionnaire used in this study was the one used by most of the articles, it is important to standardize the evaluation of sleep.Due to the clinical and scientific relevance of the pathological cycle of insomnia–pain–anxiety and taking into account the findings obtained in this study, it is especially relevant to develop programs for patients with fibromyalgia based mainly on improving sleep quality. The findings presented show that insomnia is related to anxiety only if patients also have pain. Taking into account the fact that pain is one of the central symptoms of fibromyalgia, it is not uncommon for the three components of insomnia–pain–anxiety to appear in most patients diagnosed with the disease.


Cutibacterium acnes, a rare source of de novo intraarticular infection. This case highlights the importance of incorporating patients’ subjective descriptions of illness into differential diagnosis considerations, notably for those caring for patients with sickle cell disease. This case also establishes C. acnes as a rare organism responsible for de novo septic arthritis in the setting of sickle cell disease.Patients with sickle cell disease frequently present to the hospital for pain control secondary to vaso-occlusive crises (VOCs). Diagnostic challenges exist for healthcare providers in distinguishing joint pain secondary to a VOC from an intraarticular infection at initial presentation due to the lack of established clinical markers exclusive to one or the other. We present a 35-year-old female with sickle cell disease and avascular necrosis of bilateral hips and the right shoulder with several previous admissions for VOC pain control complaining of a "different" kind of pain in her shoulder. Treated initially for pain control, our patient was found to be suffering from culture-positive septic arthritis of the shoulder with  Sickle cell disease is a lifelong diagnosis that leaves patients susceptible to many healthcare complications. The most common reason for patients presenting to the hospital are VOCs, also called "pain crises", which cause significant pain for patients as a result of transient focal ischemia . Such inThe clinical pictures of vaso-occlusion and septic arthritis can look similar initially, with patients untreated for a septic joint being in prolonged pain while awaiting an appropriate diagnosis . Our casThis case report was previously presented as a poster abstract at the 2022 Southern Hospital Medicine Meeting on October 13, 2022.The patient is a 35-year-old female with a history of sickle cell disease complicated by bilateral hip avascular necrosis and right shoulder avascular necrosis who presented with two weeks of right shoulder pain. She has had multiple VOCs before but reported the sensation of pain feeling "a bit different" midway through her inpatient stay, described as "in my muscles." She denied any recent viral or bacterial infections and had no history of osteomyelitis or septic arthritis. She denied fever, chills, nausea, vomiting, and trauma and was compliant with her daily hydroxyurea. Due to her frequent hospitalizations, she has a port in her right chest that has been in place for over 10 years. The port is used strictly for hospitalizations. She had not noticed any pain or erythema around the port site. Pertinent labs on admission include a white blood cell (WBC) count of 15.18, hemoglobin of 7.8, reticulocyte count of 7.36, c-reactive protein (CRP) of 19.2, and an erythrocyte sedimentation rate (ESR) of 103. Vital signs were stable, with blood pressure at 101/72, the pulse at 99, the temperature at 99.4 °F, and the respiratory rate at 19 with oxygen saturation at 99% on room air. The physical exam was notable for severe tenderness to palpation on the lateral aspect of the right shoulder joint with no erythema or swelling and limited range of motion due to pain. The right shoulder x-ray did not show an overt fracture. The patient was started on intravenous fluids and an aggressive pain regimen that escalated to a ketamine drip, which provided minimal relief. Due to intractable pain, orthopedic consultants recommended further imaging to rule out joint effusion. A magnetic resonance image (MRI) of the right shoulder showed a large glenohumeral joint effusion . Because the clinical pictures of vaso-occlusion and septic arthritis can initially look similar, patients with pain from septic joints are often left untreated for many days while awaiting aspiration and the results of cultures . As no rOur patient’s glenohumeral joint aspiration contained Cutibacterium acnes. C. acnes is a gram-positive bacillus that commonly makes up human skin flora, especially at the location of the shoulders . Under nAs C. acnes commonly makes up human skin flora at the shoulders, the actual rate of intraarticular infections specifically caused by C. acnes colonization remains debated, as it presumably is only a contaminant in many post-operative or post-aspiration cultures . In thisIn the context of sickle cell disease, the clinical pictures of vaso-occlusion and septic arthritis can appear similar at first, with patients who are untreated for a septic joint experiencing prolonged pain while waiting for an appropriate diagnosis. Our case illustrates that a patient presenting to the hospital with a VOC and a single joint complaint should have septic arthritis as a differential to ensure early diagnosis and treatment, especially in patients with longstanding venous access ports. Moreover, we present a rare case of Cutibacterium acnes septic arthritis, reflecting the variety of bacteria able to manifest joint infection in the setting of sickle cell disease.


Background: Chronic neck pain (CNP) is highly prevalent and complicated, associated with limited movement, and accompanied by shoulder pain and other clinical manifestations such as dizziness, anxiety, and insomnia. Brain structural and functional abnormalities often occur in patients with CNP. However, knowledge of the brain’s functional organization and temporal dynamics in CNP patients is limited. Dynamic functional connectivity density (dFCD) can reflect the ability of brain areas or voxels to integrate information, and could become neuroimaging markers for objectively reflecting pain to a certain extent. Therefore, this study compared the dFCD between CNP patients and healthy controls (HCs) and investigated potential associations of the abnormal density variability in dynamic functional connectivity with pain characteristics in CNP patients.Methods: Resting functional magnetic resonance imaging was performed for 89 CNP patients and 57 HCs. After preprocessing resting-state fMRI images by the Data Processing and Analysis of Brain Imaging toolbox, the sliding window method was applied to investigate dFCD changes in CNP patients and HCs using the DynamicBC toolbox. Then we quantified dFCD variability using their standard deviation. Based on the pain-associated factors collected from the case report form of CNP patients, the mean dFCD variability values of each dFCD from region of interest were extracted to calculate Pearson’s correlation coefficient to study the potential correlation between dFCD abnormal variability and pain.Results: Compared with HCs, the dFCD values of the anterior cingulate cortex, occipital lobe, temporal lobe, and cerebellum were statistically different in patients with CNP. Subsequent correlation analysis showed that the variable dFCD in the related brain region was correlative with the course of the disease and clinical symptoms, such as pain and depression, in patients with CNP.Conclusion: Dynamic functional alterations were observed in the brain regions of CNP patients, and the dFCD of these brain regions could become neuroimaging markers for objectively reflecting pain to a certain extent. This suggests that chronic pain may cause changes in pain processing and emotional feedback and highlights the link between dynamic neural communication in brain regions and disease conditions, deepening our understanding of chronic pain diseases, and guiding clinical practice. Chronic neck pain (CNP), one of the most common chronic pain conditions, is a type of extensive pain characterized as discomfort and stiffness of the neck soft tissue for more than 3 months but no abnormality is observed during imaging or other related examination. It is often associated with limited movement and is accompanied by shoulder pain and other clinical manifestations such as dizziness, anxiety, and insomnia ; lifestyle, social and psychosocial factors. CNP is the result of the comprehensive actions of these factors , which is measured by functional magnetic resonance imaging (fMRI), can be used to investigate the integration of the functional brain network at rest. Resting-state FC has been widely used during neuroimaging studies to examine cerebral functional alterations in various types of pain such as chronic back .The present research conformed to the principles established in the Declaration of Helsinki and was approved by the Sichuan Regional Ethics Review Committee on Traditional Chinese Medicine. Prior to the study, each participant was informed of the experiment process and related matters and signed an informed consent form. Our research has already been registered on Fifty-seven HCs were recruited using advertising and 89 CNP patients were recruited from the acupuncture and orthopedic clinics of the Hospital of Chengdu University of Traditional Chinese Medicine.The criteria for CNP that we used were those compiled by the Orthopedic Section of the American Physical Therapy Association  and the short form 12 (SF-12) questionnaire were used to evaluate the impact of pain intensity and neck pain on daily life. The SDS and SAS were used to assess the emotional status. CNP patients and HCs were matched for age. All participants were provided with information about the research procedure and written informed consent before the experiment.Using a GE 750 3.0-T MRI system with an eight-channel, phased-array head coil , all participants underwent MRI scanning at the Hospital of Chengdu University of Traditional Chinese Medicine. Participants were asked to rest for 15 min before undergoing scanning. Before entering the MR examination room, the participants removed all metal objects  and wore elastic foam earplugs or cotton balls to reduce noise during scanning. In the examination room, participants were placed in the supine position, and a coil and sponge pad were fixed to their heads. The participants were asked to close their eyes, relax their bodies, avoid sleeping, and avoid head movement as much as possible. After the structure image was obtained in the three conventional planes, axial scanning of the structure image was performed using the T1-weighted gradient-echo sequence.The scanning parameters for structure image were as follows: repetition time (TR)/echo time = 2,530 ms/3.4 ms; field of view = 240 mm × 240 mm; matrix size = 512 × 512; turning angle = 12°; layer thickness = 1 mm. The gradient echo sequence of the single-shot planar echo was used for functional imaging. The scanning parameters for function image were as follows: TR/echo time = 2,000 ms/30 ms; matrix = 64 × 64; field of view = 240 mm × 240 mm; turning angle = 90°; slice thickness = 5 mm; continuous scanning without septum; voxel size = 3.75 mm × 3.75 mm × 5 mm. For each participant, 210 volumes were acquired, resulting in a total scan time of 420 s. Scanning was performed for the whole brain, cerebellum, and brainstem.3 were performed; regression of nuisance covariates, including the Friston-24 motion parameters, white matter signals, cerebrospinal fluid signals, and global signal, was performed; spatial smoothing was performed using a Gaussian kernel with full-width at half-maximum of 8 mm; detrending was performed; and temporal bandpass filtering with a frequency band of approximately 0.01–0.08 Hz was performed. No participants exhibited head motions exceeding 3 mm of translation or 3°of rotation in any direction in both groups.The original DICOM format images were transmitted to the workstation, and the integrity of the original data was checked to ensure that all sequence data of the participants included in the statistical study were complete. The quality of the original data was checked by MRIcron software v1.0.20190902The sliding window method was applied to evaluate the dFCD for each participant using the DynamicBC toolboxFirstly, Frison used functional connection in the functional imaging field  Previous studies proposed that the window length is an open, but essential, parameter in sliding window-based resting-state dynamics computation  was used for demographic analyses. The independent sample t-test was performed to assess the group differences in dFCD variability between the CNP and HC groups, with age used as covariates. Multiple comparisons were corrected using the Gaussian random field method (p < 0.05).The dFCD variability value was averaged at each voxel across participants within the CNP and HC groups to obtain the dFCD variability distributions of both groups. A two-sample p < 0.05 was set for all correlation analyses.To further investigate the potential associations of abnormal dFCD variability with pain characteristics of patients with neck pain, the mean dFCD variability values of each dFCD ROI were extracted to calculate Pearson’s correlation coefficient using pain-associated factors of neck pain patients, including scores of VAS, McGill, NDI, SF-12, SDS, and SAS. A statistically significant threshold of p < 0.05) but no significant difference in terms of gender, height, weight, etc. (p > 0.05). Meanwhile, there was a significant difference between the two groups for the score of SF-12, SAS, and SDS  of CNP patients and implied that these areas are important to CNP.The cingulate gyrus has an important role in the limbic system because it is not only the core brain area of the default network but also the main component of the medial pain system. Its anterior part, the anterior cingulate gyrus, is mainly responsible for pain processing. The ACC has the core position in the integration center responsible for pain coding , possibly because the incidence of neck pain occurred in younger individuals as a result of their occupation and lifestyle  experience more pain than men (55.5%). These inequalities were greatest for back/neck pain , data collection or acquisition , statistical analysis (TX and XW), interpretation of results , drafting the manuscript work or revising it critically for important intellectual content , and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (All authors). All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.