Background: Multimodal analgesia techniques, including regional analgesia, have been shown to provide effective analgesia and minimize opioid consumption after liver resection surgery. While thoracic epidural analgesia (TEA) is considered the gold standard, its role in the current era of enhanced recovery after surgery (ERAS) has been questioned. Erector spinae plane blocks (ESPBs) have the potential to provide effective postoperative analgesia without the risks associated with epidural analgesia. The primary aim of this quality improvement project was to evaluate the analgesic efficacy of ultrasound-guided ESPB in comparison with TEA in patients undergoing open liver resection.Methods: Fifty patients who underwent open liver resection and received TEA (n=25) or ESPB (n=25) as part of an ERAS pathway were retrospectively identified. The primary outcome measure was cumulative postoperative opioid consumption at 24 hours. Secondary outcomes included opioid consumption, pain scores, the incidence of nausea and vomiting requiring antiemetics, lower extremity muscle weakness, and occurrence of hypotension requiring treatment on arrival to the post-anesthesia care unit and at 2, 6, 12, 24 hours, and daily through postoperative day 7. Results: Opioid requirements were significantly lower in the TEA group compared to the ESPB group. Postoperative pain scores at rest and with deep inspiration were significantly lower in the TEA group through postoperative day 5. There were no differences in other outcome measures.Conclusions: These findings suggest that compared with ESPB, TEA provides superior pain relief after open liver resection. Adequate pain control improves postoperative outcomes and is imperative for enhanced recovery after surgery (ERAS) -3. Open The erector spinae plane block (ESPB) provides both visceral and somatic analgesia and has been shown to provide effective postoperative pain control over a wide spectrum of surgical procedures including thoracic, breast, abdominal, and spinal surgeries -11. ESPBThis quality improvement project was performed at Parkland Health and Hospital Systems, Dallas, Texas. A waiver of documentation for informed consent was obtained from the Institutional Review Board of the University of Texas Southwestern Medical Center, Dallas, Texas (STU-2021-1059). Patients scheduled to undergo elective liver resections under general anesthesia between January 2019 and September 2021 who received either TEA or right-sided ESPB with catheter placement as part of a multimodal opioid-sparing pain management pathway were included. Exclusion criteria included age <18 years, American Society of Anesthesiologists (ASA) physical status of 4 or greater, non-elective surgery, chronic pain conditions or chronic opioid use, contraindications to TEA or ESPB placement, coagulation abnormalities, or allergy to local anesthetic. The choice of epidural or ESPB placement was at the discretion of the faculty anesthesiologist and faculty surgeon. Both TEA and ESPB catheters were placed preoperatively on the day of surgery by an attending anesthesiologist. TEA placement occurred at the T7/8 interspace using a sterile technique. Subcutaneous lidocaine 1% was used at the point of entry. A 17-gauge Tuohy needle was introduced and advanced to the appropriate depth using the loss of resistance technique. The epidural catheter was advanced to a depth of 4 cm beyond the tip of the needle, and a test dose consisting of 3 mL lidocaine 1.5% and epinephrine 1:200,000 was injected to assess for intravascular placement of the catheter. The catheter was secured with adhesive wound closure strips and a clear occlusive dressing. Right-sided ESPB catheter placement occurred at the T7/T8 level with the patient in a sitting position. After aseptic preparation, the ultrasound transducer was placed approximately 2 cm lateral to the T7/T8 spinous processes in a parasagittal orientation. External landmarks and ultrasound imaging in real-time were used to identify the transverse process. An 18 G × 8.5 cm E-catheter  was introduced in-plane to the ultrasound beam, cephalad to caudad, through the paraspinous muscles until reaching the transverse process. Visualizing the catheter and needle tip under the erector spinae muscle and contacting the top of the transverse process, 20 mL of ropivacaine 0.5% was intermittently administered in 5 mL increments. The local anesthetic spread was observed in the erector spinae plane, raising the erector spinae muscle fascia off the transverse process. The needle was withdrawn, leaving the catheter in place. The catheter was then affixed to the patient’s back using a clear occlusive dressing. Approximately 2 hours prior to the procedure, gabapentin  was administered. Midazolam was avoided when possible, except in cases of extreme anxiety. A standardized general anesthetic technique was used for all patients as part of the liver resection surgery enhanced recovery pathway. Fentanyl , propofol , and rocuronium  were used for induction of general anesthesia, and a 50% mixture of oxygen/nitrous oxide and sevoflurane or desflurane  was used for maintenance. The patient’s hemodynamics  were maintained within 20% of the patient’s baseline values. Fentanyl was limited to less than or about 1 mcg/kg, IV, IBW/h, excluding the induction dose. Postoperative nausea and vomiting (PONV) prophylaxis included dexamethasone 8 mg, IV, and ondansetron 4 mg, IV, administered intraoperatively. In addition, patients at high risk for PONV received a scopolamine patch prior to surgery. Hydromorphone 5-10 mcg/kg, IV, IBW was given approximately 20 minutes prior to procedure end. Upon completion of the surgery, ropivacaine 0.2% plus 2 mcg/mL of fentanyl infusion was initiated through the epidural catheter or ropivacaine 0.2% infusion through ESPB catheter and continued postoperatively at 6 mL/hour.In the post-anesthesia care unit (PACU), patients complaining of pain received hydromorphone 0.1-0.2 mg, IV, until they were comfortable. Scheduled acetaminophen 1 g orally and cyclobenzaprine 10 mg orally were included as part of the patient’s postoperative regimen. Rescue analgesics included 0.2-0.5 mg, IV, hydromorphone every 4 hours as needed for severe pain and 5-10 mg oral oxycodone immediate release every 8 hours as needed for moderate pain. Post-operative rescue antiemetics included ondansetron 4 mg, IV, or 8 mg orally disintegrating tablet and/or 0.625 mg, IV, promethazine.Co-authors (MS and JK) not involved in block placement extracted data from the electronic medical record, including patient demographics , anesthesia and operative time, systolic and diastolic blood pressure, estimated blood loss (EBL), duration of PACU stay, time to catheter discontinuation, hospital duration, opioid prescription prior to surgery, and if the patient underwent a major hepatic resection or not. In addition, pain intensity using a 0-10 numeric rating scale (NRS) and opioid consumption  were recorded. Opioid doses were converted to oral morphine equivalents (OME) for normalization , and cumThe primary outcome measure was cumulative postoperative opioid consumption (in OME) at 24 hours. Secondary outcomes included interval opioid consumption, NRS pain scores at rest and during deep breathing, the incidence of PONV, use of rescue antiemetics, and episodes of hypotension on arrival to the PACU at 2, 6, 12, 24 hours, and daily through postoperative day 7. Patients discharged before day 7 were contacted via telephone and their responses were recorded. Patient-reported changes in sensation and motor strength were also assessed from the medical record and recorded.SPSS software  was used to perform the statistical analysis. A previous study involving the use of ultrasound-guided ESPBs for liver resection showing a mean ± standard deviation (SD) cumulative postoperative opioid consumption at 24 hours of 48.2 mg (17.1 mg) was used to calculate the sample size, with a 30% reduction in opioid consumption considered clinically significant . AssuminContinuous data were summarized as mean ± SD for normally distributed variables or as mean and 95% confidence interval (CI). Categorical data were summarized as frequency and percentages. Using normal probability plots, assumptions of normality for continuous variables were assessed. Based on the viability of normality assumption for continuous variables, Student’s t-test or Mann-Whitney U-test were used to make baseline comparisons between the two treatment groups. A repeated-measures analysis of variance (ANOVA) model with one within-subject (time) and one between-subject (treatment group) factor was used to analyze pain scores of patients at rest and during deep inspiration for each time point. This was followed up with pairwise comparisons between groups. Fisher’s exact test was used to compare incidences of nausea, vomiting, muscle weakness, sensory changes, and hypotension at each time point. Bonferroni corrections were used for multiple comparisons and statistical significance was set at p <0.05. Patients receiving TEA (n=25) and ESPB (n=25) were comparable with respect to patient demographics , duration of anesthesia, duration of PACU stay, mean blood pressure, the incidence of PONV, time to catheter removal, and time to discharge Table . The numOpioid requirements in the TEA group were significantly lower for the first 24 hours (primary outcome measure) and 48 hours postoperatively (p<0.002) Table . OverallThis quality improvement project demonstrated that the use of TEA was associated with significantly lower postoperative opioid consumption compared to the use of ESPB. In addition, pain scores were lower with the use of TEA. This suggests that TEA provides superior pain relief compared with ESPB. Notably, there were no differences between the groups with regard to opioid-related adverse events such as PONV or limited mobility due to lower extremity weakness. Similarly, there were no differences in clinical outcomes that could be affected by pain, such as time to ambulation.Lower opioid use and lower pain scores with TEA may be due to greater potential for the sympathetic blockade, which may reduce visceral pain resulting during hepatectomy. Somatic and visceral pain during hepatic resection is related to a variety of factors including an incision through the skin, soft tissue, and muscle, rib retraction, as well as diaphragmatic and peritoneal irritation . SomaticWhile there were no differences in time to catheter removal in our study between the two groups, the potential advantages of early catheter removal in high-risk, coagulopathic or anticoagulated patients are undeniable . ESPB catheters are considered a low-risk, easy-to-perform analgesic technique that can be safely performed in coagulopathic or anticoagulated patients ,17,18, mThis study has several limitations. Patients were not randomized, and the determination of regional technique was left solely to the discretion of the attending anesthesiologist. Secondly, the study was not blinded, introducing a potential risk for bias. Additionally, due to ethical concerns, there was no non-regional anesthetic control group, limiting the ability to define the role of the systemic analgesic effects of local anesthesia, as well as the role of fentanyl in the TEA group. We used a right-sided catheter because the surgical incision was located in the right upper quadrant. Perhaps the use of bilateral ESPBs would have covered nerves that cross the midline. Other limitations included failure to assess the adequacy and sensory level of the block prior to surgery to preemptively identify a failed or inadequate block and the lack of clinical studies using these techniques, which limited results comparison.In summary, this quality improvement project showed an analgesic advantage of TEA over right-sided ESPB placement in patients undergoing open hepatic resection as measured by opioid consumption and pain scores at rest and on deep inspiration. While ESPB might be a safer alternative to TEA in patients at a high risk of coagulopathy, ESPB may not effectively block visceral pain associated with open liver surgery. A randomized controlled trial to assess the efficacy and safety of ESPB as a viable alternative to TEA is warranted.


Meaning is an important psychological resource both in situations of accomplishment and in situations of ongoing adversity and psychological crisis. Meaning in life underlies the reasons for staying alive both in everyday and in critical circumstances, fulfilling a buffering function with respect to life adversities.The aim of the present study was to reveal the role of both meaningfulness, including specific sources of meaning and reasons for living, and meaninglessness  in patients suffering from profound crisis situations with or without suicidal intentions and behavior.The sample included 148 patients  who were referred to a crisis center in Moscow, Russia. Seventy-seven patients  reported a current crisis situation in their life but denied suicidal thoughts or behavior. Twenty-nine patients  reported suicidal ideations but denied suicidal attempts or self-harming behavior. Forty-two patients  had episodes of suicidal attempts or self-harming behavior accompanied by suicidal intentions. There were no significant gender or age differences between groups.N = 74), a clinical checklist was completed by their doctors assessing 28 various characteristics associated with the patient’s clinical status.Participants completed a number of measures of different aspects of meaning and meaninglessness, well-being, ill-being and psychological resources. For some patients  than were measures of well-being, ill-being, meaning crisis or personality resources. In both suicidal and non-suicidal crisis patients meaningfulness predicted more positive reasons for living. The relationship between meaningfulness and most reasons for living remained significant after controlling for clinically appraised suicidal “readiness,” acute stress and lack of social support. Self-transcendence was the major specific source of meaning predicting higher reasons for living after adjusting for general meaningfulness.to be, through enhancing meaningfulness and reasons for living.The data cast some light on the psychological meaning of suicide. It follows that prevention efforts are to be focused not on eliminating the factors “pushing” one to suicidal behavior, but rather on supporting inner strengths conducive of a positive decision,  Meaning in life is a double-edged psychological resource: it plays an important role both when one’s life is heading toward positive accomplishments and when, on the contrary, one is facing adversities, suffering, or psychological crises  of life is a relational construct referring to the ties which connect our life to some superordinate context see , 2017. MProbably the most prominent effect of meaning is visible in extreme, highly challenging situations which may destroy people’s habitual activities, put into question their values and even their reasons for living. There are multiple studies, though the data are poorly systematized, on the role of meaning as a coping resource in times of psychological crisis, stress and trauma. In particular, Park described the model of meaning-making, noting that this process, if successful, leads to a better adaptation to the stressful event . Her papFollowing are some more specific results, obtained mostly recently.In a study of people after the collective trauma created by the 9/11 terrorist attacks, both searching for and finding meaning were important for successful adaptation , p. 718.positive reinterpretation and proactive planning ; indeed, the presence of such reasons is viewed as a buffer against acute experiences of depression, loneliness, loss and hopelessness . ReasonsDistinguishing between suicidal ideation and suicidal behavior or combining them is still an open issue in the present-day empirical studies. Though most studies combine suicidal ideation with suicidal behavior e.g., , in someThe distinction between suicidal ideation and suicidal action has been most pointedly articulated by Leslie Farber, who spoke of “the life of suicide, as distinguished from the act itself” , p.77. FIn the middle of the 20th century existential philosophers  added a new angle on viewing the problem. Considering the possibility of suicide meant for them ascending to a higher level of philosophical thinking, taking a conscious attitude toward one’s own life, making the latter an object of conscious choice, becoming “the master of one’s own death” , p. 336.It is important to note that these authors referred to suicidal ideation, rather than suicidal actions. Suicidal ideation, that is emergence of thoughts about the possibility of ending one’s life, quite often is viewed in research context as indistinguishable from practical suicidal attempts, as a similar phenomenon. We think that they must be distinguished, and that suicidal ideation is not necessarily a negative phenomenon: it may more likely, on the contrary, bring the person to saying “no” to the option of suicide and “yes” to living, and such a person will value life more than ever, based on this conscious choice made in view of the available alternative to it. For some people, suicidal ideation can, we believe, serve as the basis for the intention to live. Exploring this proposition is one of the aims of the present paper.We should take into consideration that a completed suicide is not so much an isolated action but rather a sad outcome of a more or less persistent dilemma, “to be or not to be,” in which life and death appear as two competing alternatives see also . Each ofThe idea of choosing between living and dying and the concept of a reflective “life of suicide” suggests that the person with suicidal ideations has not only urges toward a suicidal decision but also inner barriers against this decision, in favor of life. Emphasis on these positive barriers which serve as buffers against suicidal choice is in line with the message of positive psychology, stating that the royal road to mental health is supporting a person’s inner strengths which function as buffers against adversities, rather than trying to exclude negative influences. This resonates also with As Victor per se; on the contrary, it seems that those who have reflected much on this issue are less vulnerable to impulsive, self-destructive urges. The second aspect, the moment of choice, is the critical act that, for some, launches suicidal attempts.It is thus important to distinguish two aspects of the eventually suicidal path: (1) Becoming aware of the inevitability of death and the possibility of mastering it, and (2) Choosing in favor of either life or death . The firaim of the present study was to reveal the role of both meaningfulness, including specific sources of meaning and reasons for living, and meaninglessness  in perceived reasons for living in patients suffering from profound crisis situations with or without suicidal intentions and behavior.It follows from the above considerations that meaning in life appears as an important factor to some degree predictive of the outcomes of profound life crises. Meaning is to be treated both in its positive aspects (meaningfulness as perceived presence of meaning in life being a buffer against worst outcomes) and negative aspects . The hypothesized that:We Hypothesis 1 (H1): In patients suffering from profound crises without suicidal intentions, life meaningfulness, reasons for living, self-regulatory, or stress-buffering resources  and well-being  are higher than in patients suffering from profound crises with suicidal ideations and suicidal behavior.Hypothesis 2 (H2): Both higher meaningfulness and lower crisis of meaning predict higher reasons for living in both groups. We also hypothesized that in patients with suicidal intentions and behavior these effects would be stronger, such that meaningfulness and lower crisis of meaning would better predict reasons for living in this group. As well, we predicted an interaction effect between meaningfulness and crisis of meaning, such that crisis of meaning would have a more negative effect on reasons for living in those with lower meaningfulnessHypothesis 3 (H3): The effects of meaningfulness, crisis of meaning and, probably, specific sources of meaning on reasons for living remain stable after adjusting for clinical appraisals of patients.Data were collected through 2010–2016 from residents of the special clinics of crisis care, Crisis Department №2 of Eramishantsev Moscow City Clinical Hospital. This department was established for patients voluntarily requesting help because of their psychological crisis or difficult life obstacles, including thinking about suicide or suicidal attempts. Most of the patients are without manifest psychiatric diagnoses; those with acute psychoses, serious alcohol or drug addictions and major somatic or neurological diseases are typically not admitted. Data collection was conducted in the middle of their inpatient treatment period which lasted about 1 month, in the clinic. We excluded from the sample patients with organic and psychotic disorders–18 cases in total.The initial sample included 148 inpatients 18–65 years old., 105 of them females. Of them 75, or 49.3% had completed university level education and 24 (15.8%) had started but not completed university, 32 (21.1%) had completed high school level; 2 (1.3%) reported middle school level, and 19 (12.5%) gave no education data. Diagnoses by ICD-10 included: F20-28 – 23 participants ; F31-34 – 17 participants (Mood [affective] disorders); F40-48 – 83 participants ; F50 – 1 participant ; F60-69–24 participants . We considered mixed diagnosis sample acceptable, because in the domain of suicide research and treatment transdiagnostic approach focusing on behavior rather than clinical diagnosis is often applied; there have been attempts to include suicidal behavior disorder as a separate DSM-5 entity .post-hoc, by an expert psychologist who was not directly involved in treating the patient, based on their final medical history . These records contained psychiatric anamnesis, concomitant diagnoses, biographical information, admission obstacles, cases of suicidal affects, ideations, or actions, the character and the result of treatment.Patients were classified into three groups Seventy-seven patients  reported a current crisis situation in their life but denied suicidal thoughts or behavior (group NO). Twenty-nine patients  reported suicidal ideations but denied suicidal attempts or self-harming behavior (group ID). Forty-two patients  had experience of suicidal attempts or self-harming behavior accompanied by suicidal intentions (group BE). It should be noted that self-harming behavior is considered in the clinic only in case of prominent suicidal behavior. Minimal and non-suicidal injuries are typically not admitted to the clinic and are not included in the diagnostic descriptions of behavior. Consequently, we treated both patients with suicidal attempts or self-harming behavior as the same group.There were no significant gender and age differences found between groups. The differences on most of the additional measures (see below) were also insignificant, including subjective happiness, subjective vitality, anxiety, depression, hardiness, cognitive insight, ways of coping, action control, subjective alienation, and tolerance for ambiguity. On the contrary, significant differences between the groups were found on sources of meaning and reasons for living (see below in the results section).All the patients in the course of an individual session with the psychologist were asked to complete a battery of inventories printed on paper; prior to completion, an informed consent was obtained.The survey data reflected the patients’ current situation which typically did not change much after getting to the clinic. We did not consider the impact of therapy or other interventions. (ry (RFL) . The RFLThe sources of meaning and meaning in life questionnaire (SoMe) (e (SoMe) . The fule (SoMe)  which reNoetic orientations test (NOT) (st (NOT)  is a modst (NOT) . It inclSubjective alienation inventory  (7. e (HADS) . This scHardiness survey  (9. e (BCIS) . The BCIWays of coping questionnaire , characteristics of emotional, cognitive, value, behavioral aspects . Twenty-eight clinical characteristics were formulated for five domains . Due to smaller sample size for clinical appraisals we added them into separate analysis after the major part of results including the whole sample. There were no significant gender or age differences between the subsample and the initial sample.Data were processed in SPSS Statistics 23.0. Descriptive statistics and Cronbach’s alphas are presented in To reveal whether not only meaningfulness and crisis of meaning but also specific sources of meaning  were important for RFL all the moderation analyses were repeated. As before, step 1 included dummy-coded group membership and step 2 included centered variables of crisis of meaning and meaningfulness as well as their interactions with group variables. However, unlike in the previous section, we used at step 2 stepwise analysis to reduce the number of variables that were unrelated to RFL. Step 3 included centered sources of meaning . At step 4 we added their interactions with the dummy-coded group variables. At both steps only variables that predicted the dependent variable at least in one group remained in the equation. Thus, improvement of the model at step 3 indicated that there were sources of meaning that predicted RFL independently of general meaningfulness and meaning crisis. Improvement at step 4 indicated that there were meaning sources which were related to RFL only in some groups.To reveal the relationships between clinical characteristics and RFL in the three groups of patients a series of seven separate moderation analyses (for each RFL) was performed. At the first step we added dummy-coded variables to reflect clinical group membership (the group ID was the reference group) and all five clinical characteristics.The three groups of patients differed by four out of six scales of RFL Questionnaire  . In genep > 0.15) on happiness, vitality, anxiety, depression, hardiness, cognitive insight, coping strategies, action control, subjective alienation, or tolerance to ambiguity.The groups did not significantly differ from each other . Moreover, in the BE group this relationship was less prominent than in the NO group (p < 0.05) and marginally less prominent than in the group ID (p < 0.10).In line with Schnell’s hypothesis, meaningfulness and the crisis of meaning appeared as related but different constructs . Simple regressions demonstrated that in the BE group moral RFL were related neither to meaningfulness, nor to crisis of meaning nor to their interaction. In the NO group more moral reasons were associated with higher meaningfulness  while in the ID group the disbalance between meaningfulness and crisis of meaning  was related to less moral RFL .There were significant moderation effects between meaningfulness and meaninglessness regarding moral RFL: the interaction between meaningfulness and crisis of meaning and its second order interactions with groups reached the level of significance We repeated all the analyses using other variables of meaningfulness and meaninglessness: Meaningfulness by NOT and Alienation (Vegetativeness) as alternative measures. For coping with problems and relationships with children, we found the same positive relationship between meaning in life and reasons to live. However, we did not find three-level interactions for moral reasons to live.β = −0.55, p < 0.05). However, this relationship was stronger in the BE group  as compared to both other groups. In other words, alienation was a more important negative factor of the coping with problems reason in patients with self-harming behavior than in the ID and NO groups.In should be noted that for the coping with problems reason after adding interactions of meaningfulness by NOT and vegetativeness with groups of patients there was a clear negative relationship between vegetativeness and life for coping with problems . Furthermore, fear of suicide was associated to alienation after adjusting for groups and meaningfulness by NOT . Fear of social disapproval was not predicted by group, meaningfulness or crisis of meaning.Fear of suicide was not predicted by group or meaningfulness but it was positively related to the crisis of meaning after adjusting for dummy-coded groups  RFL a stepwise regression revealed sources of meaning that were associated to them after adjusting for dummy-coded groups, meaningfulness and meaninglessness . RelatioHigh self-actualization as a meaning source predicted low RFL in all cases but one (the coping with problems reason).β = −0.32, p < 0.01, ΔR2 = 5.5%, p < 0.01). Probably patients with experience of self-destructive behavior were more tolerant to poor well-being, as For fear of social disapproval reason and, marginally significantly, for moral reasons, there were moderation effects: higher horizontal self-transcendence and lower self-actualization were related to these reasons only in the BE and NO groups, but not in the ID group. Lower coping with problems reason was predicted by higher well-being source of meaning in group BE . If significant interaction effects were found, the relevant clinical characteristic was added at step 1 to check whether the moderation effect would remain.As can be seen from It is interesting that no specific RFL were predicted by clinical characteristics.β = 0.35, p < 0.05, ΔR2 = 20.4%, p < 0.01) and NO group . This result was not surprising taking into account that the experience of suicide was much more real for people who made an attempt (BE group). In all three groups there was a major effect of actual stress : the higher the stress experienced by the patients, the higher was the fear of suicide RFL. This effect was not moderated by group.The fear of suicide reason was higher in the BE group as compared to patients of the ID group , meaningfulness still predicted coping with problems reason , relationship with children reason  and moral RFL  but not for responsibility for family, fear of suicide or fear of social disapproval reasons where the effect of meaningfulness did not reach p < 0.05 significance level after adjusting for clinical variables.After stepwise adjusting for group membership, suicidal readiness, social support deficit and their interactions , nor self-regulatory resources , nor crisis of meaning and alienation differed between those patients who made suicidal attempts, those with suicidal ideation and those who came to crisis clinics by other reasons and who denied suicidal thoughts. Rather, the differences between these three groups referred to meaningfulness and reasons for living. This confirmed Hypothesis 1a and disconfirmed Hypotheses 1b and 1c.It is interesting that reasons for living  were higher in the NO group and hardly differed in the two other groups, while meaningfulness and some sources of meaning were equally high in the NO and ID groups and decreased in the BE group . It lookClinically appraised suicidal readiness was higher in patients with suicidal attempts but did not significantly differ in the ID and NO groups ; it follClear clinical “signs” of suicidal risk might be not very helpful in prevention because they are mostly based on already existing history of previous attempts, actual impulsivity and self-harming behavior. In other words, clinical appraisals seem to detect well suicidal risk in those who have already made suicidal attempts but fail to predict it in those who did not. In this context it is interesting that suicidal “readiness” was related to fewer reasons for living  and lower meaningfulness, but in patients with suicidal attempts only.The relations among meaningfulness, crisis of meaning, and reasons for living. While fewer reasons for living seem to be the major indicator of suicidal ideations and attempts, our further aim was revealing their psychological predictors. In line with Schnell’s theory, in all the three groups meaningfulness predicted more positive reasons for living. These effects were replicated using other measures of meaningfulness and alienation . Meaningfulness and reasons for living justify the choice in favor of life and empower one to reject the option of killing oneself.The data cast some light on the role of life meaning in suicide prevention. The role of meaningfulness as a buffering factor has received new support. Specifically, life meaningfulness predicted stronger reasons for living, while meaning deficit, or existential frustration (Frankl) seemed to be less critical. Qualitative characteristics of meaning in life in terms of its sources made some moderate contribution varying in the effect size. It follows that prevention efforts are to be focused not on eliminating the factors ‘pushing’ one to suicidal behavior, but rather on supporting inner strengths, conducive toward a positive decision, The data collection for this study was very complicated and took years. The results were encouraging; they seem to open interesting perspectives but hardly give definite answers. The key ideas underlying the study proved to be fruitful: the emphasis on meaning, the differentiation of positive and negative predictors (the former were stronger), the differentiation of suicidal behavior and mere ideation. Indeed, “though the physicality of death destroys man, the idea of death saves him” , p.30.The study had some important limitations. One is that we failed to use a follow-up assessment that would add much to our cross-sectional design. Secondly, although we used independent evaluation of the patients’ clinical status, these evaluations were made by clinical staff who already knew of the patient’s past suicide attempt history, and this knowledge likely contributed a substantial part of the variance of the clinical checklist scores.New studies should address these limitations. A special task would be elaborating and testing interventions based on reflection upon the issue of suicide, as in psychotherapeutic approaches mentioned above.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.OK: data collection and research planning, DL: methodology, study design, and overall project administration, ER: controlled statistical analysis of the data, and OT was responsible for: literature overview and data administration. All authors contributed to the article and approved the submitted version.The study was supported by the HSE University Basic Research Program. The paper was prepared within the framework of the HSE University Basic Research Program.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.


To investigate the clinical effect of minocycline plus zinc oxide eugenol cement in the treatment of acute pulpitis and its effect on the levels of HIF-1α and B-lymphocyte tumor (Bcl)-2 positive rate, and tumor necrosis factor (TNF-α).  A total of 286 patients with acute pulpitis who were treated in our hospital from January 2019 to October 2020 were recruited and assigned (1 : 1) via random number table method to receive either minocycline (control group) or minocycline plus zinc oxide eugenol cement (study group). Outcome measures included treatment effect, tooth mobility, tooth percussion pain score, hypoxia-inducible factor (HIF)-1p < 0.05). Minocycline plus zinc oxide eugenol cement resulted in a significantly higher treatment efficacy (97.20%) versus minocycline alone (72.73%) (p < 0.05). Minocycline plus zinc oxide eugenol cement was associated with significantly lower positive rates of HIF-1α and Bcl-2 and lower levels of TNF-α versus minocycline alone (p < 0.05). The patients receiving minocycline plus zinc oxide eugenol cement showed significantly lower visual analogue scale (VAS) scores and faster pain relief versus those given minocycline alone (p < 0.05).  Minocycline plus zinc oxide eugenol cement was associated with significantly lower scores of teeth mobility and percussion pain versus minocycline alone (α and Bcl-2, so it is worthy of clinical promotion. Minocycline plus zinc oxide eugenol cement offers a viable alternative for acute pulpitis as it mitigates the pain of patients, alleviates inflammatory responses, and lowers the positive rate of HIF-1 Pulpitis is a disease of dental pulp tissue infection caused by periodontal inflammation , 2. Acut2, with the average of (24.7 ± 1.13) kg/m2. In the study group, there were 85 males and 58 females; the age ranged from 30 to 65 years old, with average of (40.58 ± 3.32) years; the disease duration was 2–20 days, with average of (5.34 ± 2.89) days; body mass index was 21–29 kg/m2, with an average of (24.4 ± 1.25) kg/m2. The baseline features such as gender, age, and course of disease in the two groups were comparable (p < 0.05). Inclusion criteria were as follows: (1) patients who met the diagnostic criteria for acute retrograde pulpitis; (2) patients who exhibited severe pain after stimulation; (3) patients who had dental caries; (4) patients who had extensive destruction of periodontal tissue; and (5) patients who had complete clinical data. Exclusion criteria were as follows: (1) patients with primary dental pulp disease; (2) patients with inflammation in the periodontal region deep into the apical position; (3) patients with severe heart, liver, and other vital organ damage diseases; and (4) pregnant, lactating, or menstrual women.This is a prospective randomized controlled trial. A total of 286 patients with acute pulpitis who were treated in our hospital from January 2019 to October 2020 were selected and assigned at a 1 : 1 ratio to a control group or a study group via the random number table method. The study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Shandong First Medical University (20180987), and the patients and their families provided written informed consent. In the control group, there were 87 males and 56 females; the age ranged from 31 to 66 years old, with an average age of (41.54 ± 3.27) years; the disease duration was 3–19 days, and the average disease duration was (6.03 ± 2.54) days; body mass index was 20 ∼30 kg/mAll patients were treated with open pulp extraction, enlarged root canal, and irrigated with sodium chloride injection with a concentration of 0.9%. The control group was treated with minocycline ointment , and the root canal was sealed with zinc chloride after medicine. The dressing was replaced every 7 days, and the treatment lasted for 30 consecutive days. The patients in the observation group were given minocycline ointment (same as the control group) and zinc oxide eugenol cement , with an appropriate amount of the drug being sprayed around the pulp for topical application; the dressing was replaced every 7 days, and the treatment lasted for 30 consecutive days.Therapeutic Effect. Markedly effective: the patient's symptoms such as bad breath, loose teeth, and occlusal pain completely disappeared, and the masticatory function has returned to normal; effective: the patient's symptoms such as bad breath, loose teeth, and occlusal pain were mitigated, and the chewing function basically returned to normal; ineffective: the patient's symptoms were not relieved, and the masticatory function did not return to normal. The treatment efficacy = (markedly effective cases + effective cases)/total number of cases ∗ 100%. (2) The Degree of Tooth Loosening. 1 point indicates mild tooth loosening, 2 points indicate moderate loosening, and 3 points indicate severe loosening. (3) The Score of Percussion Pain. 1 point indicates discomfort, 2 points indicate mild pain, and 3 points indicate severe pain. (4) Inflammatory Indicators. Before and after treatment, the levels of inflammatory factors were determined. After the gingival plaque was removed, the tip of a sterile absorbent paper was placed in the gingival sulcus on the side of the tooth and placed in 250 mL of phosphate-buffered saline. HIF-1α, Bcl-2, and tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay. (5) Visual Analogue Scale (VAS) Score. The score ranges from 0 to 10 points. The higher the score, the more severe the pain.(1) t-test. Count data were described by percentage and tested by X2. A p value of less than 0.05 was used as the threshold for statistical significance for all tests. The graphics software was GraphPad Prism 8.All data analysis was performed with SPSS23.0 statistical software. Measurement data were expressed as mean ± standard deviation (±s) and were calculated by independent samples p < 0.05)  .p < 0.05) (Minocycline plus zinc oxide eugenol cement resulted in a significantly higher treatment efficacy (97.20%) versus minocycline alone (72.73%) ( < 0.05) .α and Bcl-2 and lower levels of TNF-α versus minocycline alone (p < 0.05) (Minocycline plus zinc oxide eugenol cement was associated with significantly lower positive rates of HIF-1 < 0.05) .p < 0.05)  scores and faster pain relief versus those given minocycline alone ( < 0.05) .As a pulp lesion secondary to periodontal infection, acute retrograde pulpitis can cause periodontal infection. The disease onset may result in higher sensitivity of the patient's teeth to stimuli such as cold, heat, and acidic food, which leads to severe pain and compromises the patient's quality of life . Consequp < 0.05). Minocycline plus zinc oxide eugenol cement resulted in a significantly higher treatment efficacy (97.20%) versus minocycline alone (72.73%) (p < 0.05). Minocycline plus zinc oxide eugenol cement was associated with significantly lower positive rates of HIF-1α and Bcl-2 and lower levels of TNF-α versus minocycline alone (p < 0.05). The patients receiving minocycline plus zinc oxide eugenol cement showed significantly lower visual analogue scale (VAS) scores and faster pain relief versus those given minocycline alone (p < 0.05).Minocycline plus zinc oxide eugenol cement was associated with significantly lower scores of teeth mobility and percussion pain versus minocycline alone (α and Bcl-2 and lower levels of TNF-α versus minocycline alone. HIF-1α is produced under hypoxic conditions, which can induce inflammation. Bcl-2 is secreted in the early stage of pulpitis, which will further aggravate tissue damage [The present study showed that minocycline plus zinc oxide eugenol cement was associated with lower scores of teeth mobility, percussion pain, and VAS score, and a shorter pain relief time versus minocycline alone. The reason may be that minocycline caused little irritation to the apical tissue of the tooth during root canal treatment, and the sealing of the drug inside the root canal allows for long-lasting efficacy and maximum antibacterial effects. In addition, minocycline lacks immunogenicity and has fluidity and formability, with simple tube sealing operation and easy injection and drug replacement. –19. Moree damage , 22. Thee damage , in whice damage . After tα and Bcl-2, so it is worthy of clinical promotion.To sum up, minocycline plus zinc oxide eugenol cement offers a viable alternative for acute pulpitis as it mitigates the pain of patients, alleviates inflammatory responses, and lowers the positive rate of HIF-1


Knee osteoarthritis (OA) is a leading cause of disability in the elderly population. Chronic disabling pain is associated with maladaptive neuroplastic changes in brain networks, commonly associated with central sensitization. The main clinical features of nociplastic pain conditions include combined peripheral and central sensitization, and it is crucial to recognize this type of pain, as it responds to different therapies than nociceptive and neuropathic pain.To report the effect of the Institute of Physical Medicine and Rehabilitation (IMREA) comprehensive rehabilitation program to reduce pain and to improve functioning in elderly people with knee OA, under the DEFINE cohort.t-test.This is a retrospective observational cohort of 96 patients with knee OA, recruited from October 2018 to December 2019. All patients were evaluated by a trained multidisciplinary team using the Kellgren Lawrence classification, bilateral knee ultrasonography, the visual analog scale (VAS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, rigidity and difficulty scores, the Timed Up and Go Test (TUG), 10-m and 6-min walking test (10 and 6 MWT), Berg Balance Scale, isokinetic dynamometry for knee extension and flexion strength, and pain pressure thresholds. The rehabilitation program included paraspinous lidocaine blocks, focal extracorporeal shockwaves combined with radial pressure waves and functional electrical stimulation according to individual needs. The baseline was compred with the treatment results with a paired n = 81, 84.38%), with bilateral osteoarthritis , and a mean age of 68.89 (SD 9.73) years. Functional improvement was observed in TUG (p = 0.019), 6-mwt (p = 0.033), right knee flexion strength (p < 0.0001), WOMAC rigidity and difficulty domains (p < 0.0001). Pain was reduced from baseline as measured by WOMAC pain domain (p < 0.0001), VAS for both knees (p < 0.0001), and SF-36 pain domain (p < 0.0001). Pressure pain threshold was modified above the patella , at the patellar tendons , left S2 dermatome (p = 0.017), and L1-L2 (p = 0.008).The study sample is composed of 96 participants, mostly females (The IMREA comprehensive rehabilitation program improved functioning and reduced disabling pain in elderly people with knee OA. We highlight the relevance and discuss the implementation of our intervention protocol. Although this is an open cohort study, it is important to note the significant improvement with this clinical protocol. Knee osteoarthritis (OA) is a leading cause of disability and source of societal cost in older adults, and is the most common form of arthritis worldwide . PreviouSeveral non-pharmacological and non-surgical interventions are recommended as the first line of treatment for OA. These measures relieve pain while maximizing functioning and quality of life, and reducing adverse effects from drugs and invasive interventions .However, comorbid conditions and concurrent interventions may influence the outcome of rehabilitation interventions –5. UnforChronic disabling pain is associated with maladaptive neuroplastic changes in brain networks, commonly associated with central sensitization , 8. ThisMain clinical features of nociplastic pain conditions include combined peripheral and central sensitization, spinal cord reorganization, hyper-responsiveness to painful and non-painful sensory stimuli, associated with fatigue, sleep and cognitive disturbances, anxiety and depression mood , 11. It Retrospective open cohort is composed of patients with knee osteoarthritis. All subjects were admitted to the conventional outpatient rehabilitation program of the Institute of Physical Medicine and Rehabilitation Hospital das Clínicas (HCFMUSP) University of São Paulo School of Medicine (IMREA).For this study, 113 patients with knee osteoarthritis (OA) were recruited from October 2018 to December 2019, the sample was selected by convenience. The sample size of 100 patients was determined for the longitudinal cohort (DEFINE Study) . The FigParticipants of both sexes were included in the study if they were older than 50 years, have confirmed clinical stability verified by medical evaluation , have siConcomitant manifestations in other joints, secondary knee osteoarthritis, clinical instability, and social conditions.After a full patient's history and physical examination, knee OA was confirmed using RX and classified in the Kellgren Lawrence criteria. Sociodemographic data included age, sex, and body mass index. We reported the main medications used by recruited patients when included in the study. The medication regimen was not modified during the interventions. Simple analgesics were used by 32.3% of the patients, non-steroidal anti-inflammatory drugs by 9.4%, muscle relaxants by 13.5% and weak opioids (tramadol or codeine) by 6.3%.Pain intensity was obtained by a visual analog scale (VAS) , 14 per Knee functioning was evaluated using the WOMAC scores (WOMAC rigidity and WOMAC difficulty) per person , 16, TimWe assessed three incidences: anteroposterior (AP) with load, lateral and axial patella, using a Luminus RF X-ray equipment . Classification of KOA severity was performed using the Kellgren-Lawrence scores. The same radiologist analyzed all X-ray exams.Zero (without osteoarthritis) to four .Knee USG evaluations were performed using Siemens Sonoline G40 USG equipment with multi-frequency linear transducers of 5–13 MHz . Images were obtained in the axial plane  to assess the patellar region, followed by the longitudinal plane, the enthesis with insertion of the quadriceps tendon, the patellar tendon , as well as the medial and lateral collateral ligaments, the topography of the iliotibial tract and the components of the pes anserinus bursa. Subsequently, patients were placed in ventral decubitus where the axial and longitudinal planes allowed the visualization of the popliteal fossa. In this view, we were able to assess the presence of effusion as well as of a popliteal cyst, also known as Baker's cyst.The rehabilitation program provided at the Institute of Physical Medicine and Rehabilitation (IMREA) consisted of weekly visits, administered once or twice a week, according to the individualized and personalized rehabilitation needs based on the results of the multidisciplinary evaluations. Pain was managed according to clinical and functional findings, in a hierarchical scheme .2 for all regions and patients, and deliver up to 2,000 pulses per treated segment.The treatment was delivered through an electromagnetic generator Duolith Ultra SD1 . The focal shockwave was set to reach between 4.0 and 6.0 cm depth (5.0 cm center of focus), with energy flux density fixed at 0.12 mJ/mmThis original approach, are applied in IMREA since 2017, and it allowed the development of a new method of intraosseous algometry, diverging from the current methods that register the painful pressure threshold at soft tissues. A verbal pain score was registered at the beginning of the stimulus and at the end of the shock waves train of 2,000 pulses for each segment treated. When the level zero of pain was achieved before reaching these 2,000 pulses, the application was interrupted and the number of pulses was registered .n = 68) who received an average of 3.86 sessions (Table 2).The sessions were conducted once a week for five consecutive weeks or as needed. We have systematically searched for areas of hyperalgesia at the femoral greater trochanter, and the three knee compartments: medial, patellofemoral and lateral, emphasizing specific areas of main clinical relevance, medial tibial plateau, trans patellar, femoral trochlea and the medial posterior area of the tibial plateau and femoral condyle. Focal shock wave therapy was applied in 70.8% of the participants . We used the Power® handpiece, at a frequency of 15–20 Hz, and with individual acoustic pressure of 2.5–4.0 bar, selected according to the patient's pain tolerance. Radial pressure waves were applied weekly, for three consecutive weeks over areas previously identified by the ultrasonographic evaluations including the pes anserinus bursitis, patella tendinitis, quadriceps tendinitis and at the tensor fascia lata. We also included the application over the medial intra articular line. The radial pressure waves therapy was applied in 47.91% of the participants (n = 46) who received a mean of 2.13 sessions (Table 2).We applied 2,000 radial pressure waves using a pneumatic generator, Swiss DolorClastn = 44) who received an average of 2 blocks (Table 2).When dermatomal and subcutaneous sensitization at a metameric distribution was clinically detected by the pinch and roll maneuver , even afvastus medialis and vastus lateralis muscles was induced by neuromuscular electrical stimulation using FESMED IV equipment , which, in Functional Electrical Stimulation (FES) mode, produces a biphasic, square and pulsed wave. The active electrode was positioned over the vastus medialis and vastus lateralis muscles and the neutral electrode in the proximal anterior region of the thigh. The stimulation began after mapping and placing the electrodes on specific sites to obtain the best muscle contraction. The following stimulation parameters were used: ascent time: 0 s; descent time: 1.0 s; duration of stimulation time: 5 s; duration of rest time: 10 s; pulse width: 500 μs (microseconds); stimulation frequencies: 8, 20, and 60 Hz; stimulus intensity (milliamperes): according to the patient's tolerance and progressive external load. The frequency of 8 Hz was used for hyperalgesia of the dermatome  who received an average of 13.64 sessions (Table 2).The patient was positioned in the supine position, with a cushion below the knee in 30° flexion. When the knee was fully extended during electrical stimulation an external load was gradually applied on the distal third of the leg until it reached the functional goal of 10% of body weight. The patient achieving complete electrically induced knee extension for 30 min, without active movement after reaching the functional goal, the patient was discharged from the NMES program. The session lasted 45 min and was conducted twice a week. The neuromuscular electrical stimulation therapy was applied in 100% of the participants .Data collection was performed by the main researcher with the help of residents and doctors of the knee osteoarthritis outpatient clinic of the Institute of Physical Medicine and Rehabilitation, Hospital das Clínicas (HCFMUSP). The data entry was performed by two people from the administrative sector of the research team, and subsequently these data were checked by the main researcher. The results were tabulated in the electronic database using ExcelParticipants with a clinical and radiological diagnosis of knee osteoarthritis were invited to participate in the study and included after signing the informed consent form previously approved by the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Ethics Committee for Research Protocol Analysis CAAE: 86832518.7.0000.0068.t-test given the sample size and the possibility of applying the central limit theorem , with bilateral osteoarthritis , and mean age of 68.89 (SD 9.73) years. The baseline characteristics of the participants are shown in The analyzed sample were mostly composed of females , considering either the NMES as a single intervention or the combination of interventions.t-tests for function and pain improved after the interventions are described on The paired The IMREA comprehensive rehabilitation program for elderly people with knee osteoarthritis reduces pain and improves their functioning status in a short period of time of 5.93 weeks (IQR 2.43–13). The rehabilitation program significantly improved VAS scores, WOMAC pain, rigidity and difficulty subscales and the SF-36 pain subscale. Other parameters including the TUG, 6-min walking test, flexor isokinetic muscle strength also improved after the intervention. The present report presented the rehabilitation program in detail, as it employed a combination of strategies to reduce sensitization at the peripheral and spinal levels, as well as the vastus medialis and vastus lateralis muscle capacity. The IMREA approach rationale was patient centered, strategizing to target individual needs. As a cohort study, the DEFINE primary goal was not to test the efficacy of individual interventions, included in the rehabilitation program.Interestingly, IMREA program focused on previously described physical examination findings of dermatomal, myotomal and sclerotomal hyperalgesia . We emplThe IMREA rehabilitation program based on data from previous findings that centrally induced neuroplastic changes measured by a decreased pressure pain threshold over superficial and deep structures may also occur in areas distant from the knee area. For example, spinal segmental sensitization is a hyperactive state of the spinal cord caused by repeated stimulation of nociceptive receptors from impulses sent by sensitized damaged tissue to the dorsal horn neurons . The mechanisms of spinal segmental sensitization include neuron hypertrophy and up-regulation of excitatory neurons and of pro hyperalgesic peptides, and neurotransmitters at the dorsal horn of the spinal cord. This result in a mismatch of inflammation and pain, as pain does not indicate worsening of inflammation and vice versa.This phenomenon is recently recognized and classified as nociplastic pain . It is dIt is interesting to note that pain in people with knee osteoarthritis may be influenced by involvement of central sensitization at L3, L4, and S2 spinal segments . RehabilIt is important to highlight that nociplastic changes occur not only in the spinal cord, but also in other structures of the central nervous system. Pain due to hip osteoarthritis, for example, is correlated with augmented brain activity at the cingulate cortex, amygdale and thalamus . It is vLiterature review of current interventions to reduce pain and improve functioning in patients with knee osteoarthritis demonstrate low and very low magnitudes of effect for pain and functioning , 33. EstAccording to the current health definition based on “health is not absence of diseases” but physical, social and emotional well-being, a treatment that addresses not only the pain but the weakness, bad habits, malnutrition, sedentarism, poor sleep, and misconceptions. Current guidelines target the symptoms, joint disease, including the anatomical deformities, cartilage damage, but do not address the bone marrow edema (BME) and intraosseous pain perpetuation phenomena. Such interventions are related to low effect size . SeveralPatients diagnosed with nociplastic pain present with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs, opioids, surgeries and invasive procedures. First line interventions include non-pharmacological treatments, patient education, promotion of self-management control measures, including proper lifetime habits and psychological therapies. Petersen et al., already reported poor clinical results of 3 weeks of a combination of NSAIDs, analgesics in patients presenting with low pressure pain threshold (PPT) values . These a2 with high-energy machines  . HoweverNeuromuscular electrical stimulation (NMES) was used to reduce pain and induce muscle contraction. The frequency of 8 Hz with motor level intensity, produces muscle jerks inducing muscle contraction and relaxation without a tetanic fusion of the muscles .Muscle evaluation of aerobic and anaerobic fibers was performed with electrically induced contraction with NMES. The stimulation parameters followed physiological data according to the composition of the muscle fibers. The vastus medialis muscle is composed almost entirely of type I (aerobic) and type IIa (aerobic and anaerobic) fibers, with the proportion of type I fibers being almost twice that of type IIa fibers . These dThe vastus medialis muscle has the function of extending the knee, allowing the individual to support their own body weight. For the individual to be able to move from sitting to standing, the quadriceps muscle of each lower limb must be able to support 50% of body weight. Of this percentage approximately 21% represents the strength of the vastus medialis alone which is proportional to the cross-sectional area of the muscle . TherefoAfter evaluation of the musculature with 20 and 60 Hz, when the musculature did not reach the functional goal of muscle load, treatment was initially performed with 20 Hz until the functional goal and followed with 60 Hz when necessary to reach the functional goal.We followed the overload principle , which cThe study's strength is the individualized treatment, centered on patient's individual needs, based on systematized assessments of multiple systems. We have obtained significant improvement in pain and functioning in a short period of time, even for patients with severe osteoarthritis. interventions according to specific findings (biomarkers). We consider it as an appropriate strategy for managing chronic pain conditions in the elderly population, due to its effect, in a short duration, demanding few health professionals and low operational costs. This program should be considered for implementation in middle resourced settings.Our study has some limitations. Magnetic resonance imaging (MRI) was not used to identify bone or intraosseous changes in our patients. A future study from our research team is already studying the MRI findings in these patients. As an open cohort study, other factors associated with pain improvement are possible, such as a placebo effect. It is also important to highlight that genetic polymorphisms and other biological factors could have influenced overall treatment responses. The present report demonstrated the usefulness of focal extracorporeal shockwaves, radial pressure waves and paraspinous blocks combined with neuromuscular electrical stimulation in the rationale for management of patients with knee OA. The individualized and the multi modal nature for the indication of each intervention according to our decision tree, preclude the possibility to differentiate the effects of the individual treatment modalities.The IMREA comprehensive rehabilitation program improved functioning and reduced disabling pain and quality of life in elderly people with knee OA. We highlight the relevance and discuss the implementation of our intervention protocol.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by CAAE: 86832518.7.0000.0068. The patients/participants provided their written informed consent to participate in this study.LB, MI, and FF contributed equally to conceptualization, investigation, methodology, supervision, and validation. LB and FF further contributed to funding acquisition and managing resources. LB, MI, MS, AdS, and FF contributed to data curation and visualization. AdS conducted formal analysis. LB, MI, MS, GS, SU, AdS, ATS, DM, DA, and TA contributed to writing the original draft, reviewing, and editing. VR assisted with project administration. LB, MI, GS, SU, ATS, DM, and DA all contributed to the investigation. FF provided critical review. All authors contributed to the article and approved the submitted version.This study was supported by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo . TA was supported by a scholarship from HCFMUSP with funds donated by NUBANK under the #HCCOMVIDA scheme.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.


To investigate white matter microstructural alterations in Parkinson's disease (PD) patients with depression using the whole-brain diffusion tensor imaging (DTI) method and to explore the DTI–based machine learning model in identifying depressed PD (dPD).The DTI data were collected from 37 patients with dPD and 35 patients with non-depressed PD (ndPD), and 25 healthy control (HC) subjects were collected as the reference. An atlas-based analysis method was used to compare fractional anisotropy (FA) and mean diffusivity (MD) among the three groups. A support vector machine (SVM) was trained to examine the probability of discriminating between dPD and ndPD.As compared with ndPD, dPD group exhibited significantly decreased FA in the bilateral corticospinal tract, right cingulum (cingulate gyrus), left cingulum hippocampus, bilateral inferior longitudinal fasciculus, and bilateral superior longitudinal fasciculus, and increased MD in the right cingulum (cingulate gyrus) and left superior longitudinal fasciculus-temporal part. For discriminating between dPD and ndPD, the SVM model with DTI features exhibited an accuracy of 0.70 in the training set [area under the receiver operating characteristic curve (ROC) was 0.78] and an accuracy of 0.73 in the test set (area under the ROC was 0.71).Depression in PD is associated with white matter microstructural alterations. The SVM machine learning model based on DTI parameters could be valuable for the individualized diagnosis of dPD. Parkinson's disease (PD) is the second most common neurodegenerative disease . ParkinsDiffusion tensor imaging (DTI) can quantitatively evaluate microstructural alterations of white matter (WM) tracts in vivo . FractioAt present, the most effective diagnostic criterion of dPD is based on neuropsychological examinations but often shows some clinical challenges and limitations . CurrentThe purpose of this study was to conduct whole-brain DTI data analyses using the ABA approach to explore WM microstructural changes in patients with dPD. In addition, SVM was trained with FA and MD values of different WM tracts to determine the probability of discriminating dPD from ndPD.We recruited 37 patients with dPD and 35 patients with ndPD from our institution from July 2014 to December 2019, and 25 healthy control (HC) subjects matched for age and gender were also enrolled. All patients with PD were diagnosed according to clinical diagnostic criteria from the UK Parkinson's Disease Brain Bank by two experienced physicians  by a cliExclusion criteria were as follows: (1) major psychiatric disorders ; (2) history of a brain tumor, cerebrovascular disorders, or brain trauma; (3) obvious encephalatrophy; (4) history of antidepressant medication use; (5) MMSE score <24 or H-Y scale score > 4; and (6) obvious motion artifacts in imaging studies. This study was approved by our Institutional Ethics Committee, and written informed consent was obtained from all participants.Magnetic resonance imaging data of all patients were performed using a 3.0 T MR scanner  with an eight-channel head coil. Any anti-Parkinsonian medications were discontinued 12 h before the imaging studies to decrease the effects of the drug(s) on brain neural activity. All subjects were instructed to not move during the MR scan, and foam padding and earplugs were used to limit head movement and decrease the impact of acoustic noise.2, the total number of the images = 1,560, and scan time = 7 min and 8 s. The Array Spatial Sensitivity Encoding Technique (ASSET) was used to decrease the acquisition time and image distortion.The DTI data were obtained using an echo planar imaging (EPI) sequence with the following scan parameters: Repetition time/echo time (TR/TE) = 15,275/76.7 ms, FOV (field of view) = 320 × 320 mm, matrix = 128 × 128, slice thickness = 2.5 mm with no gaps, 25 different diffusion directions with b = 1,000 s/mmHigh resolution, 3D T1-weighted data was obtained using a Fast Spoiled Gradient Recalled Echo Inversion Recovery (FSPGRIR) sequence with the following parameters: TR = 8.4 ms, TE = 3.3 ms, flip angle (FLA) = 13°, matrix = 256 × 256, voxel size = 0.94 × 0.94 × 1 mm, slice thickness = 1 mm, and the total number of the sagittal slices = 146.http://www.nitrc.org/projects/panda) based on the MATLAB R2016a program . PANDA is a pipeline toolbox for fully automated to perform analyses and calculations of brain diffusion images. The main processing steps include the following: (a) The DICOM data are converted to NIFTI data format; (b) The brain mask is estimated and non-brain tissues are removed; (c) Eddy-current effect and head movement are corrected; (d) The DTI metrics, including FA and MD, are calculated; (e) All of the individual FA images of the native space are registered non-linearly into a FA standard template in the Montreal Neurological Institute (MNI) space using the fnirt command of FSL; (f) The data are output for atlas-based analysis. We defined the ROIs on the Johns Hopkins University (JHU) WM tractography atlas  for an estimator  was used to identify brain areas that had significant differences across the three groups. The post hoc analyses were performed to further explore the between-group differences using LSD's post hoc tests after ANCOVA analysis with years of education, gender, and age as covariates. A false discovery rate (FDR) was used to correct for multiple comparisons. The DTI features with FDR-corrected p < 0.05 after analysis was selected to build the SVM model.Statistical analysis was performed using SPSS version 20 software . For statistical analysis of any group differences in age, education, and neuropsychological scores, a one-way ANOVA test was applied. Differences in gender between the groups were examined with the χp < 0.001), which is consistent with previous studies revealing that dPD often coexisted with anxiety disorder. There were no significant differences in gender, age, years of education, or MMSE, and MoCA among the three groups. There were no differences in disease duration, H-Y scale, and UPDRS-III between the two groups .The patient's detailed demographic and clinical characteristics are presented in post hoc comparisons showed significant differences in DTI features between dPD and ndPD with p < 0.05 (after FDR corrected) as shown in We compared the changes in FA and MD among three groups using ABA analysis. The The prediction summary of the SVM is shown in In this study, the ABA method was used to examine alterations of WM microstructural integrity in patients with dPD. First, we found WM tract impairment of the limbic system and non-limbic system in the dPD group. Second, we established an SVM machine learning model to classify dPD employing the diffusion metrics  that exhibited the performance of features that had an acceptable accuracy. The findings in this study support the contention that WM damage is a common pathology in dPD, and this may assist in understanding the pathophysiological mechanism of depression in PD. The SVM classification model based on DTI features might promote the individualized diagnosis of dPD.In the present study, patients with dPD showing microstructural alteration of WM tracts were mainly located in the limbic system. The cingulum is a core structure in the Papez circuit of the cholinergic system that connects limbic and prefrontal cortex regions and plays an important role in emotional regulation and reward behavior . The disIn this study, we also found microstructural alterations in non-limbic fibers of the brain in patients with dPD, such as decreased FA values in the bilateral corticospinal tract, bilateral inferior longitudinal fasciculus, bilateral superior longitudinal fasciculus, and left superior longitudinal fasciculus-temporal part in patients with dPD. The superior longitudinal fasciculus contains connections between the temporal, occipital, parietal, and frontal lobes and the limbic system, and is an important mediator of mood-related function . The infBased on DTI parameters obtained by the ABA method, the SVM classifier exhibited moderate accuracy in classifying dPD and ndPD. SVM machine learning model is a useful machine learning classification algorithm and has been shown to successfully discriminate Alzheimer's disease from normal cognition groups using diffusion metrics as features . The preWe recognize some limitations to this study. First, the numbers of patients were relatively small, however, despite the small sample size, we were able to identify the WM microstructural integrity was impaired in patients with dPD. Second, brain abnormalities in some regions could influence the quality of template matching when using the ABA method. Thus, the patients with obvious encephalatrophy identified on conventional MRI scanning sequences were excluded. Finally, our study investigated microstructural changes only in the WM and the depression in PD involved WM and the gray matter, thus it is possible to later combine both WM and gray matter to analyze the disease.In conclusion, the present study detected WM microstructural abnormalities in patients with dPD using atlas-based DTI analysis. Depression in PD was associated with white matter microstructural alterations in the limbic and non-limbic systems. Furthermore, the SVM machine learning model based on DTI data had an acceptable accuracy to identify dPD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Guangdong Provincial People's Hospital. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the article and gave the final approval for the manuscript to be published.The study was supported by the National Natural Science Foundation of China (Grant Number: 82071871).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.


The routine monitoring of direct oral anticoagulants (DOACs) may be considered in patients with renal impairment, patients who are heavily obese, or patients requiring elective surgery. Using the heparin-binding copolymer (HBC) and polybrene, we aimed to develop a solution for monitoring the anticoagulant activity of DOACs in human plasma in the interfering presence of unfractionated heparin (UFH) and enoxaparin. The thrombin time (TT) and anti-factor Xa activity were monitored in pooled plasma from healthy volunteers. In these tests, plasma with dabigatran or rivaroxaban was mixed with UFH or enoxaparin and then incubated with HBC or polybrene, respectively. HBC and polybrene neutralized heparins and enabled monitoring of anticoagulant activity of dabigatran in the TT test. Both agents allowed for accurate measurement of anti-factor Xa activity in the plasma containing rivaroxaban and heparins in the concentration range reached in patients’ blood. Here, we present diagnostic tools that may improve the control of anticoagulation by eliminating the contamination of blood samples with heparins and enabling the monitoring of DOACs’ activity. Unfractionated heparin (UFH) or low-molecular-weight heparins (LMWHs) are parenteral anticoagulants used in the prophylaxis and treatment of patients with thrombotic disorders. Heparins are also administered to prevent blood clotting during hemodialysis or surgical procedures involving extracorporeal circulation or central venous catheters (CVCs). Because of a more convenient route of their administration and a more predictable pharmacokinetic profile, direct oral anticoagulants (DOACs) have become an attractive alternative to parenteral anticoagulants. In contrast to vitamin K antagonists, DOACs do not usually require dose adjustment based on the results of laboratory tests, although the measurement of their anticoagulant activity may be needed in patients with renal impairment, patients who are heavily obese, when switching from one anticoagulant to another, and to assess compliance or requiring elective surgery ,2,3. ThrTo enable monitoring of anticoagulant activity of different anticoagulant drugs or hemostasis pathology in the presence of heparins, heparin inhibitors such as protamine, heparinase, and polybrene were used in several clotting assays ,13,14,15Recently, we have developed a heparin-binding copolymer (HBC) composed of a neutral poly(ethylene glycol) (PEG) block and a cationic poly(3-(methacryloylamino) propyl trimethylammonium chloride) (PMAPTAC) block. The mechanism of HBC action involves electrostatic binding between cationic groups of HBC and anionic groups of heparin-based anticoagulants. We have proven its high efficacy in reversing the effects of heparins and heparin mimetics in vitro in human plasma and in vivo in rats and mice ,23,24,25The International Council for Standardization in Haematology guidelines recommended measuring heparin independently of DOACs while heparin bridging in DOAC-treated patients ,27. In tWe used polybrene , UFH , enoxaparin , dabigatran and rivaroxaban plasma calibrators , phosphate-buffered saline (PBS) , TT reagents , and anti-factor Xa assay kits . HBC was synthesized as previously described .v/v) vacuettes . The group consisted of four women and four men between the ages of 25 and 45 years, with a negative history of bleeding and thrombosis, with clotting times in the normal range  = 33.8 ± 1.7 s (s), prothrombin time (PT) = 10.4 ± 0.2 s, international normalized ratio (INR) = 1.2 ± 0.1, and TT = 14.3 ± 1.4 s), and without taking any medications at the time of sample collection. The demographic and clinical characteristics of the healthy volunteers are summarized in g for 20 min at 4 °C. The final concentrations of DOACs  were derived by diluting calibrators in normal human pooled plasma. Heparins, HBC, and polybrene solutions were diluted in saline solution accordingly to obtain final concentrations: 0.25, 0.5, 1.0, 1.5, and 2.0 U/mL for UFH; 2.5, 5, 10, 15, and 20 µg/mL for enoxaparin; and 10, 25, 50, and 100 µg/mL for HBC and polybrene. Pooled plasma spiked with PBS served as a control group.Blood samples were collected from eight healthy volunteers into trisodium citrate . The TT reagent contained bovine thrombin at a concentration of 3.0 UNIH/mL. Samples without DOAC were prepared by mixing pooled plasma (200 µL) with increasing concentrations of UFH  or enoxaparin  and HBC or polybrene (10 µL of 50 µg/mL). Plasmas with dabigatran (50 ng/mL) were divided into three groups: (1) dabigatran alone, (2) mixed with UFH or enoxaparin, and (3) mixed with UFH or enoxaparin and HBC or polybrene in chosen concentrations. After 2 min of incubation (37 °C), thrombin (100 µL) was added to the mixture (100 µL) and TT was measured immediately. If TT was more than or equal to 300.0 s, a value of 300.0 s was ascribed for the sake of statistical analysis. The results from the TT test were presented in seconds and, additionally, converted to ng/mL using a dabigatran calibrator.The anti-factor Xa activity was measured in a 96-well plate reader  according to the modified kit manufacturer’s instructions. In brief, a solution (10 µL) of UFH  or enoxaparin  and HBC (10 µg/mL) or polybrene (50 µg/mL) was added to pooled plasma (200 µL). Then, an antithrombin III reagent (80 µL) was added to the previously prepared mixture (10 µL) and incubated at 37 °C for 2 min. Then, bovine factor Xa reagent (80 µL) was added, mixed, and incubated at 37 °C for 1 min. After incubation, spectrozyme factor Xa (80 µL) was added, mixed, and incubated at 37 °C for 5 min, and the anti-factor Xa activity was measured at 405 nm. Plasmas with rivaroxaban (50 ng/mL) were divided into three groups: (1) rivaroxaban alone, (2) mixed with UFH or enoxaparin, and (3) mixed with UFH or enoxaparin and HBC or polybrene in chosen concentrations, and the anti-factor Xa activity was measured as described previously. The results from the anti-factor Xa assay were presented as anti-factor Xa activity based on the UFH calibration curve (U/mL) and, additionally, converted to ng/mL using a rivaroxaban calibrator.p < 0.05 was considered statistically significant. The data were analyzed using GraphPad Prism 8 .Shapiro–Wilk’s test was used for data distribution analysis. The data were presented as violin plots with minimum and maximum values and analyzed using the non-parametric Mann-Whitney test. A two-tailed Enoxaparin, UFH, and dabigatran prolonged TT in a concentration-dependent manner A–C. NeitBoth HBC and polybrene at a concentration of 50 µg/mL neutralized the anticoagulant activity of UFH and lowered TT to levels achieved in plasma samples containing only dabigatran. We observed lower values of TT (by 15–23%) after adding HBC or polybrene to plasma with UFH and dabigatran in comparison with dabigatran alone A–E. We oBoth HBC and polybrene at a concentration of 50 µg/mL restored TT prolonged by enoxaparin to levels achieved by dabigatran itself. Compared with dabigatran alone, we found lower (6–12%) values of TT in the presence of HBC and polybrene if enoxaparin was added at a concentration up to 10 µg/mL A–C, and The enoxaparin, UFH, and rivaroxaban increased anti-factor Xa activity in a concentration-dependent manner A–C. HBC HBC bound UFH completely up to the concentration of 1 U/mL, with slight (5–6%) differences between groups: rivaroxaban + UFH + HBC versus rivaroxaban alone A–C, and Similarly to the experiment with UFH, HBC effectively neutralized enoxaparin up to the concentration of 10 µg/mL, and polybrene at the full enoxaparin concentration range, with slight differences when compared with samples with rivaroxaban alone A–E. We oThe DOACs’ levels or their anticoagulant effect should be measured in particular conditions; for example, in patients at risk of bleeding, overdosed, or requiring invasive procedures ,28. TT iBlood collection should be performed via peripheral veins. In the case of the unavailability of peripheral veins, patients being in critical condition, and pain during repeated blood sampling , the bloCurrently, there is evidence that monitoring of rivaroxaban in the presence of UFH is possible , althougAs the oral route of administration is more convenient than the injection, patients will always preferably be switched from parenteral to oral anticoagulant therapy. DOACs are generally started after the discontinuation of heparins . HoweverOur study has some limitations. Only a single concentration of dabigatran and rivaroxaban was assessed. It fits the lowest concentration considered important for presurgical interventions. However, patients on DOAC therapy are likely to have higher levels than that. We assessed only dabigatran and rivaroxaban as two representative DOACs. It would be expected that other DOACs  would behave likewise owing to their similar mechanism of action to rivaroxaban.We found that HBC and polybrene effectively neutralize the anticoagulant effect of heparins in human plasma in two coagulation tests: TT and anti-factor Xa activity. We have clearly shown that the use of both compounds eliminates the result of contamination of blood samples with heparins enabling accurate monitoring of dabigatran or rivaroxaban efficacy. It is necessary to expand our studies to develop standard protocols for the combinations of particular coagulation tests and the anticoagulation agent.


Methods: A cross-sectional descriptive study was carried out with 38 patients at a hospital in Vietnam. Ponnaiyan classification and the Hedin melanin index were used to assess the distribution and extent of gingival pigmentation in the study. Pain assessment was performed using the Visual Analog Scale (VAS) to evaluate the intensity of pain during the laser treatment. In addition, clinical evaluation  of each treatment procedure was conducted using the three level Dummett–Gupta Oral Pigmentation Index (DOPI) assessment. Results: This study showed that less pain was experienced by patients treated by CO2 laser; the rates of no pain, mild pain and moderate pain after treatment were, respectively, 21%, 76% and 2.6%; there was 100% complete epithelization after 1 week. The DOPI rates for turning from a DOPI score of 1, 2 or 3 to a DOPI score of 0 after a 12-week treatment were 87.5%, 76.9% and 24%, respectively. Conclusions: Using a CO2 laser for gingival melanin pigmentation treatment is a safe and effective procedure.Background: Smile aesthetics has a vital role to play in an individual’s life and one of the factors affecting the beauty of the smile is gingival color. A gingival color change or gingival hyperpigmentation causes an unesthetic smile line, especially in patients with a gummy smile, which is also known as a black gummy smile. Numerous gingival depigmentation methods have been performed successfully for ablating gingival melanin pigmented epithelium. Thus, the aim of this study is to evaluate the treatment efficacy of gingival hyperpigmentation by using a carbon dioxide (CO Smile aesthetics are a significant part of a person’s daily life, and are influenced by various factors such as the teeth, lips and, especially, gingival color . A smileMelanin pigmentation is prevalently found in African and East Asian populations. Gingival hyperpigmentation is not just localized in a specific geographic area but can occur in any populations ,3. Some 2 laser [Gingival depigmentation is a treatment for removing melanin hyperpigmentation from gingiva. Several methods have received recognition from many authors including the use of a scalpel , electro2 laser ,15,16. T2 laser ,18.2 laser has the advantage of hemostasis with a shallow depth of penetration into soft tissue [2 laser treatment is often performed in soft tissue surgery, set at 5–15 watts with either a pulsed or continuous mode [2 laser applied for gingival depigmentation.Due to different wavelengths, lasers have been employed for multi-purposes, namely, gingivectomy, gingivoplasty, frenectomy, incisional and excisional biopsy, soft tissue tuberosity reduction, operculectomy, coagulation of donor sites and soft tissue augmentation around osseointegrated implants ,20,21. It tissue ,23. It at tissue ,23. Hencous mode . This stThis cross-sectional descriptive study was conducted from March 2020 to January 2021. Thirty-eight patients, who complained of black gums and requested cosmetic correction, were selected from the outpatient section of Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy Hospital, Vietnam.In the study, 10 maxillary teeth of each patient from tooth 15–25, exhibiting moderate to severe melanin pigmentation in the maxillary anterior gingiva region from the right canine to the left canine (aesthetic zone), were selected. Patients with habit of smoking or abuse of any other oral substances, gum recession, missing teeth in the anterior region, patients on any forms of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), pregnant women, lactating mothers and patients with any systemic conditions were excluded from the study.Initially, patients were given a topical spray anesthesia in the operating area and, if prolonged pain, were given a second anesthesia in the form of injection during the procedure.2 laser  was used with 10,600 nm wavelength, 2.5 W power, 20 Hz frequency with a pulse duration 160 ms, energy density 79.5 J/cm2 per pulse, 1590 J/cm2 per second, continuous emission, with noncontact mode and beam diameter of 0.8 mm. Melanin pigmented gingivae were ablated by CO2 laser vaporization. Adjacent teeth were protected from the laser beam by applying an acrylic template to cover the labial of teeth. The procedure was repeated until ooze of small amount of blood was found, which meant that the laser had eliminated the epithelium, whereas leaving connective tissue layer and the desired depth of gingival tissue removal was attained. Preoperative and postoperative images were taken using a digital camera  in 50 mm focal length, aperture f11, ISO 100 with ring flash. The photographs were taken by the camera with the same focal length, light intensity, and the distance from the camera to the subject of 30 cm.COAfter completion of each procedure, the operated area was finally cleaned with gauze soaked with normal saline, and no dressing was given in any of the treated sites. The patient was instructed to avoid spicy, hard, sour and hot food, avoid smoking and brushing on the treated area, maintain oral hygiene by regular rinsing after meals, and advised to use warm saline rinses in the next days. The postoperative evaluation was carried out on the 1st, 7th day, and subsequently after 21 days from the depigmentation treatment about gingival color, gingival healing, pain intensity, bleeding and postoperative patient satisfaction.In this study, the parameters used were:The classification of gingival pigmentation based on anatomic delineation was presented with 6 classes by Deepa Ponnaiyan in 2013 , includiClass I: only in attached gingiva.Class II: both attached gingiva and interdental gingiva.Class III: all parts .Class IV: only in marginal gingiva.Class V: only in interdental gingiva.Class VI: both marginal gingiva and interdental gingiva.Hedin’s melanin index classified gingival pigmentation , as follDegree 1: one or two solitary unit(s) of pigmentation without the formation of a continuous ribbon.Degree 2: more than three units of pigmentation without the formation of continuous ribbon.Degree 3: one or more short continuous ribbons of pigmentation.Degree 4: long continuous ribbon.Pain assessment was performed using Visual Analog Scale (VAS) to measure intensity of pain experienced after 1 week, 4 weeks, 12 weeks of treatment . Pain in0: no pain.0.1–3: mild pain.3.1–6: moderate pain.6.1–10: severe pain.The clinical evaluation of gingival wound healing was used after 1 day, 1 week, 4 weeks and 12 weeks . Scores 0: tissue defect or necrosis.1: ulcer.2: incomplete or partial epithelization.3: complete epithelization.The Dummett–Gupta Oral Pigmentation Index (DOPI) index was recorded to compare preoperative and postoperative measurement . It was DOPI score 0: no clinical pigmentation (pink-colored gingiva).DOPI score 1: slight hyperpigmentation, light brown tissue.DOPI score 2: moderate hyperpigmentation, medium brown tissue or a blend of pink and brown.DOPI score 3: severe hyperpigmentation, dark brown or green/black tissue.p-value ≤ 0.05 was considered statistically significant.Descriptive statistics were summarized for categorical (proportions and frequencies) and continuous variables . Statistical analysis was conducted by using SPSS 22.0 software for Windows , and Wilcoxon Signed Ranks Test was used to analyze DOPI index at baseline and 4 weeks posttreatment. A Ethical clearance for the study was obtained from the Ethics Committee of Can Tho University of Medicine and Pharmacy . The purpose and procedures of the study were clearly given to patients and their volunteer participation was agreed by written informed consent.Among the studied subjects, 50.0% of participants were males and 50.0% were females. The average age was 22.75 age years (standard deviation = 0.93), with 97.4% in the 20–24 years age range.Removal of the gingival pigmentation was performed without any bleeding. No carbonization happened in the process of laser treatment. No repetition of the hyperpigmentation method was performed during the postoperative interval. The wound healed completely in 4 weeks without any scar, infection or complication, which resulted in a significant improvement in esthetic appearance.In the study, 36.8% had pigmentation in attached gingiva; 34.2% in attached, marginal and interdental gingiva; 18.4% in attached and marginal gingiva; 7.9% in marginal gingiva; and 2.7% in interdental gingiva. There were no cases with pigmentation in marginal gingiva and interdental gingival .This study presented all four degrees of gingival pigmentation as in Hedin’s classification. Out of 38 patients, two patients (5.2%) had one or two solitary unit(s) of pigmentation without the formation of a continuous ribbon; five patients (13.1%) had more than three units of pigmentation without the formation of continuous ribbon; nine patients (23.7%) had one or more short continuous ribbons of pigmentation; and 22 patients (57.8%) had one continuous ribbon .As shown in The result in p < 0.001)  had a DOPI score of 0, while one patient (12.5%) still had a DOPI score of 1 after treatment. Out of 13 patients with a DOPI score of 2, three patients (23.1%) had a DOPI score of 1 and the remaining 10 patients (76.9%) had a DOPI score 0 at 1 week, 4 weeks and 12 weeks posttreatment. Of 17 patients with a DOPI score of 3, thirteen patients (76%) had a DOPI score of 1 and four patients (24%) had a DOPI score of 0. The changes in DOPI indices from baseline to 3 months were 55.6% for CO2-laser-treated sites . The DOP< 0.001) .In the present study, gingival hyperpigmentation in the attached gingiva had the highest number of cases and no melanin pigmentation in marginal gingiva and interdental gingiva was observed, unlike in the previous study of Ponnaiyan et al.  who repoThe rate of solitary and continuous pigmentation in the present study was lower than in the study of Hanioka et al. (2005) , who cla2 laser causes prompt evaporation of the fluid in the cells, then destroys the cellular structure and may not release inflammatory chemical mediators. In addition to the evaporation of extracellular fluid, the denaturation of the protein structure occurs. A thin modified collagen layer on the surface of the laser-illuminated area can reduce the irritability of the tissue from causes in the oral cavity as an impermeable area as soon as the laser is introduced. Moreover, coagulation and the sealing of blood vessels 0.5 mm in diameter stop the bleeding [A saline swab was used to scrub and remove the chromosome epithelium in the applied gingival areas and then a few small bleeding spots were found, but after the treatment, bleeding was no longer seen. A similar study was conducted by Hedge et al. (2013) , where tbleeding .2 laser had mild to moderate pain, and two patients had severe pain. Less pain after using the Er:YAG laser  was due to the nerve endings sealing with the dense dry protein network in the gingival surface acting as a biofilm and the heat generation of the Er:YAG laser was shallower than the CO2 laser [The study conducted by Raaman et al. (2016)  reportedO2 laser . 2 laser at 3 W average power level and reported a similar result. The study conducted by Nagpal et al. (2015) [In this study, all patients had partial epithelization on post-operative day 1 b and had. (2015)  applied . (2015)  using a . (2015) .The present study revealed that 17 patients with a DOPI score of 3 had mild pigmentation (DOPI score 1) 4 weeks after treatment. It was consistent with the study conducted by Sukumar (2015) , in whic2 laser for gingival hyperpigmentation was 22.8%, and the time to recurrence was 3 months after treatment.The relapse of pigmentation in interdental papilla and a few in attached gingiva was observed in the present study, which is similar to the study of Kishore et al. (2014) . Moreove2 laser has advantages over gingival melanin hyperpigmentation treatment, such as hemostasis and less gingival deformity in gingival margin or interdental papilla. Nevertheless, the limitation of a CO2 laser is that it cannot entirely remove melanin pigment in deep layers due to the effect on the bone and tooth structure. Additionally, the overactivity, proliferation and transfer of residual pigment cells after performing the CO2 laser procedure explains the repigmentation in our study [The current study recognized that the use of a COur study .2 laser was a safe and effective modality for removing melanin pigmented gingiva. Patients’ pain experience was reduced after 1 week of treatment and a better healing process was shown at 7 days post-operatively. Moreover, the aesthetic outcome after CO2 laser-assisted treatment of pigmentation was improved. Therefore, it is clear that the efficacy of the CO2 laser method is obtained, and it is recommended that clinicians consider the CO2 laser method as an option for pigmented gingiva removal for their patients’ treatment.According to the results of the study, using a super-pulsed CO