Gender-Specific Risk Factors for Asymmetric Bone Density in Adult Degenerative Lumbar Scoliosis: A Retrospective Cohort Analysis.

BACKGROUND This study aimed to evaluate the performance of Hounsfield Unit (HU) value on the vertebral bone mineral density associated with adult degenerative lumbar scoliosis (ADLS) and to compare the HU and coronal height changes of the lumbar spine on the concave and convex sides. The secondary aim was to investigate the risk factors for increased asymmetric ratio of HU (ARH) by concave-to-convex. MATERIAL AND METHODS A total of 74 patients aged ≥50 years were retrospectively reviewed. The height and the HU values of the region of interest were measured and compared. Multiple linear regression and gender-stratified analyses were performed to explore risk factors. Restricted cubic spline (RCS) was used to visually assess the dose-effect relationship between the Cobb angle and ARH. RESULTS The heights on the concave sides were significantly lower while HU values were significantly higher than that of the convex side. Cobb angle (95% CI: 0.001 to 0.009, P=0.034) was positively correlated with the increased ARH, while apex orientation to the right (95% CI: -0.152 to -0.013, P=0.022) was negatively associated. Gender-stratified analyses showed age and apex vertebrae location are 2 additional risk factors in male patients but not in female patients. Cobb angle was identified by RCS as a risk factor both in males and females and the inflection points were 15 and 17.5, respectively. CONCLUSIONS HU values on the concave side are significantly higher than on the convex side, showing the asymmetrical bone mass distribution of ADLS patients. Several gender-related risk factors for increased ARH have been identified.

Efficient, Color-Stable, Pure-Blue Light-Emitting Diodes Based on Aromatic Ligand-Engineered Perovskite Nanoplatelets.

Perovskite nanoplatelets (NPLs) show great potential for high-color-purity light-emitting diodes (LEDs) due to their narrow line width and high exciton binding energy. However, the performance of perovskite NPL LEDs lags far behind perovskite quantum dot-/film-based LEDs, owing to their material instability and poor carrier transport. Here, we achieved efficient and stable pure blue-emitting CsPbBr3 NPLs with outstanding optical and electrical properties by using an aromatic ligand, 4-bromothiophene-2-carboxaldehyde (BTC). The BTC ligands with thiophene groups can guide two-dimensional growth and inhibit out-of-plane ripening of CsPbBr3 NPLs, which, meanwhile, increases their structural stability via strongly interacting with PbBr64- octahedra. Moreover, aromatic structures with delocalized π-bonds facilitate charge transport, diminish band tail states, and suppress Auger processes in CsPbBr3 NPLs. Consequently, the LEDs demonstrate efficient and color-stable blue emissions at 465 nm with a narrow emission line width of 17 nm and a maximum external quantum efficiency (EQE) of 5.4%, representing the state-of-the-art CsPbBr3 NPL LEDs.

Bias-Switchable Dual-Mode Organic Photodetector with High Operational Stability Using Self-Trapped Cs3Cu2I5 Interfacial Layer.

Conventional photovoltaic (PV)-photodetectors are hard to detect fainted signals, while photomultiplication (PM)-capable devices indispensable for detecting weak light and are prone to degrade under strong light illumination and large bias, and it is urgent to realize highly efficient integrated detecting system with both PM and PV operation modes. In this work, one lead-free Cs3Cu2I5 nanocrystals with self-trapping exciton nature was introduced as interfacial layer adjacent to bulk and layer-by-layer heterojunction structure, and corresponding organic photodetectors with bias-switchable dual modes are demonstrated. The fabricated device exhibits low operating bias (0 V for PV mode and 0.8 V for PM mode), high specific detectivity (~1013 Jones), fast response speed as low as 1.59 µs, large bandwidth over 0.2 MHz and long-term operational stability last for 4 months in ambient condition. This synergy strategy also validated in different materials and device architectures, providing a convenient and scalable production process to develop highly efficient bias-switchable multi-functional organic optoelectrical applications.

The magnetic resonance imaging-based vertebral bone quality scoring system: A novel method to evaluate endplate changes in patients with primary single-level disk herniation and Modic changes.

OBJECTIVES: This study aimed to investigate differences in vertebral fat distribution and bone density between patients with and without Modic changes (MCs) using a magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) scoring system. PATIENTS AND METHODS: In this retrospective study, 189 patients (95 males, 94 females; mean age: 54±2.2 years; range, 18 to 82 years) with primary single-level disk herniation were reviewed between June 2021 and June 2022. The patients were divided into the MC group (n=99) and the non-MC (NMC) group (n=90). The subcutaneous fat tissue thickness and bone mineral density were determined. The system consisted of two scores: the VBQ score, which reflected the fatty infiltration within the vertebral body, and the endplate bone quality (EBQ) score, which reflected the signal intensity (SI) of the upper and lower endplates. The EBQ score is a novel measurement that we introduced in this study. The VBQ and EBQ were measured and scored using MRI scans. The mean SI of the upper and lower endplates (endplate SI)/the bone marrow SI (marrow SI) was measured. RESULTS: There was a considerable difference in subcutaneous fat tissue thickness between the MC and NMC groups (1.40 vs. 1.16 cm, p=0.01). The EBQ scores of the L4 and L5 vertebrae and endplate SI/marrow SI of all vertebral body levels were significantly higher in the MC group. CONCLUSION: The occurrence of MCs in the lumbar spine may be associated with abnormal fat distribution. The distribution of vertebral fat in patients with MCs is distributed earlier in the upper and lower endplates of the vertebral body, and this trend is not observed in patients without MC. The thickness of subcutaneous fat tissue is a key factor in the occurrence of MCs.

Refracture-related bone transport of tibia: technical notes and preliminary clinical results in nineteen cases.

PURPOSE: Refracture is one of the main complications of bone transport, which brings additional physical and mental burden to surgeries and patients. We aimed to raise a new classification system of refracture-related bone transport based on the Simpson classification and to present our experience on treatment. METHODS: This retrospective analysis included 19 patients with refracture-related bone transport (average age of 37.7 years; 18 men). We developed a modified Simpson classification system to assist decision-making (conservative versus surgical). The ASAMI criteria were used to assess the outcomes at last follow-up. RESULTS: The mean follow-up was 12.3 ± 3.2 months. Complete union was achieved in all patients, with no reinfection. Based on the modified Simpson classification, refracture was Ia type (within regeneration area) in three cases, Ib (collapsed fracture at the regeneration area) in one case, Ic (stress fracture) in three cases, II (at the junction between the regenerate and original bone) in one case, III (at the docking site) in nine cases, and V (at distant site) in two cases. Refracture was managed conservatively in six cases and surgically in 13 cases. Average time to bone union was 2.8 ± 1.2 months in the conservative group versus 4.4 ± 1.4 months in the surgery group. Assessment at the final follow-up using the ASAMI criteria revealed excellent bone result in all patients, excellent functional results in six patients (31.6%), and good functional results in 13 patients. CONCLUSIONS: The modified Simpson classification could include refracture at the docking site and stress fracture in the regeneration zone and provide some guidance in determining the appropriate treatment strategy.

Effects of depressive symptoms on osteoporotic bone metabolism and prognosis of joint replacement surgery in elderly male patients with femoral neck fracture.

OBJECTIVE: To investigate the effect of depressive symptoms on osteoporotic bone metabolism and prognosis of joint replacement surgery in elderly male patients with femoral neck fractures. METHOD: 102 elderly male patients with femoral neck fractures hospitalized in the Beijing Hospital from January 2017 to January 2019 were included. The patients with femoral neck fractures were divided into the depression group and the control group. The observation indicators included: bone mineral density, serum alkaline phosphatase, serum calcium, serum phosphorus, 25-hydroxy-vitamin D, osteocalcin, Type I procollagen amino-terminal propeptide, serum ß-isomer of C-terminal telopeptide of type I collagen, hip function scores, and pain visual analogue scale at pre- and post-operative examinations. RESULTS: The BMD was significantly lower in the depressed group than in the control group [either for lumbar spine or hip, P < 0.05]. Serum 25-(OH)-D levels and serum OC levels were lower (both P < 0.05) in the depression group, while serum -CTX levels were higher in the depression group than in the control group (P < 0.05). Depression severity (GDS score) was negatively correlated with BMD (r = -0.456, P < 0.05), 25(OH)D (r = -0.546, P < 0.05), and OC (r = -0.215, P < 0.05), while positively correlated with ß-CTX (r = 0.372, P < 0.05). The Harris scores of the depression group were lower than the control group (P < 0.001). In the control group, VAS scores decrease at 12 months postoperatively while in the depressed group, VAS scores increased (P < 0.001). CONCLUSION: Depression is a risk factor for low bone mineral density and fracture, and adversely affects functional recovery and pain relief after artificial femoral head replacement. Special care should be taken for those patients with depressive symptoms in orthopedic practice.

Uniform nucleation and growth of Cs3Cu2I5 nanocrystals with high luminous efficiency and structural stability and their application in white light-emitting diodes.

Copper-based ternary halide composites have attracted great attention due to their superior chemical stability and optical properties. Herein, we developed an ultrafast high-power ultrasonic synthesis strategy to realize the uniform nucleation and growth of highly luminescent and stable Cs3Cu2I5 nanocrystals (NCs). The as-synthesized Cs3Cu2I5 NCs show uniform hexagonal morphology with an average mean size of 24.4 nm and emit blue light with a high photoluminescence quantum yield (PLQY) of ∼85%. Moreover, the Cs3Cu2I5 NCs exhibit a remarkable stability during continuous eight times heating/cooling cycling tests (303-423 K). We also demonstrated an efficient and stable white light-emitting diode (WLED) with a high luminous efficiency (LE) of 41.5 lm W-1 and a Commission Internationale de l'Eclairage (CIE) color coordinate of (0.33,0.33).

Characteristics of MRI­based vertebral bone quality scores in elderly patients with vertebral fragility fractures.

OBJECTIVE: To explore the characteristics of vertebral bone quality (VBQ) scores in patients with vertebral fragility fractures, including VBQ score and single-level VBQ score, and evaluate their effectiveness as predictors. METHODS: The VBQ scores were measured using T1-weighted MRI images. VBQ scores were compared in patients with different times of previous fragility fractures. In addition, patients with fractures were matched for age and sex with patients without fractures, and VBQ scores were compared between the two groups. Finally, the predictive efficiency of VBQ scores for vertebral fragility fractures was analyzed by the receiver-operator curve (ROC). RESULTS: The average VBQ score and single-level VBQ score in patients with fractures were 3.48 ± 0.56 and 3.60 ± 0.60 and no difference among patients with different times of previous fractures. As for the age- and sex-matched patients, fracture patients had higher VBQ scores (VBQ score: 3.48 ± 0.56 vs. 2.88 ± 0.40, p < 0.001; single-level VBQ score: 3.60 ± 0.60 vs. 2.95 ± 0.44, p < 0.001). The AUCs using the VBQ score and single-level VBQ score to predict fragility fractures were 0.815 and 0.817, respectively. The optimal thresholds of the VBQ score and single-level VBQ score for predicting fragility fractures were 3.22 and 3.16, respectively. CONCLUSION: MRI­based VBQ scores are important predictors of vertebral fragility fracture but have no predictive value for the recurrence of fractures in patients with a history of fragility fractures. The VBQ score of 3.22 and single-level VBQ score of 3.16 are optimal thresholds that can be used when using lumbar MRI scans to identify individuals at high risk for fragility fractures.

Clinical Outcomes of Cannulated Screws versus Ring Pin versus K-Wire with Tension Band Fixation Techniques in the Treatment of Transverse Patellar Fractures: A Case-Control Study with Minimum 2-Year Follow-Up.

Purpose: K-wire with tension band (KTB) technique has long been the primary surgical method for transverse patella fractures; however, it also has shortcomings. This study is aimed at evaluating the three different techniques to see whether the cannulated screw tension band (CSTB) or ring pin tension band (RPTB) techniques could decrease complications and achieve better knee function compared with KTB. Methods: We conducted a retrospective comparison of the KTB, CSTB, and RPTB fixation techniques. We selected and reviewed 90 patients (30 patients in each fixation group) with follow-up at least 2 years. Duration of operation, intraoperative blood loss, mean healing time, visual analog scale score, range of motion, Böstman score, Iowa knee score, modified Lysholm rating scale, and postoperative complications were compared. Multivariate analyses were performed to identify the independent risk factors for fracture healing time, postoperative complications, and knee function recovery. Results: After adjusting for confounding factors, multivariate regression analysis revealed that CSTB was 0.26 times (95% CI: 0.08-0.86, p = 0.027) less likely to prolong fracture healing time, 0.20 times (95% CI: 0.06-0.64, p = 0.007) lesser risk of postoperative complications, and more than four times (95% CI: 1.41-13.56, p = 0.011) as likely to improve the knee function score compared with KTB. Besides, RPTB were also superior to KTB in reducing the incidence of postoperative complications (OR: 0.21, 95% CI: 0.07-0.64, p = 0.006) and improved knee function score (OR: 3.96, 95% CI: 1.30-12.08, p = 0.016); however, the CSTB group being more superior. In addition, AO/OTA C2 fractures (OR, odds ratio: 10.68, 95% CI: 1.30-87.70, p = 0.027) and high-energy fracture (OR: 8.78, 95% CI: 1.57-49.17, p = 0.013) were also associated with prolonged fracture healing time but not with postoperative complications and knee function. No significant differences in related indicators such as gender, age, BMI, AO/OTA classification, fracture side, injury mechanism, duration of operation, and intraoperative blood loss were detected among the three groups. Conclusion: This study demonstrated that the CSTB technique is superior to KTB and RPTB techniques in reducing the incidence of postoperative complications, and it also has advantages in accelerating fracture healing, achieving better VAS, ROM, and functional recovery. Further long-term large-sized prospective randomized trials are needed to evaluate the efficacy of the KTB in treating transverse patellar fractures.

Use of Intravenous Paracetamol Preoperatively Favors Lower Risk of Delirium and Functional Recovery in Elderly Patients with Hip Fracture: A Propensity Score-Matched Analysis.

We aimed to investigate whether the use of intravenous paracetamol (IVP) preoperatively in intertrochanteric fracture (IF) patients aged 65 years or over receiving intramedullary fixation had significantly benefits on the pain score at discharge, delirium incidence, length of hospital stay (LOS), functional outcomes, and mortality. A retrospective analysis of all surgically treated patients presenting with IF was conducted at a single Level I trauma center in China between Jan. 2016 and Jan. 2020. The data concerning patients' demographics, injury-related data, surgery-related data, operation-related data, in-hospital data, and postoperative outcomes were extracted. To minimize potential confounding and selection bias, the propensity score matching (PSM) method was performed via the caliper matching method by using a 1 : 1 ratio. After PSM, McNemar's chi-square tests were used to examine the association of using IVP with outcome analyses. The Spearman correlations of IVP using, pain scores, and the factors which may influence them were also computed. After screening 2963 consecutive patients, 2166 were included finally, including 1576 in the non-IVP group and 590 in the IVP group. After PSM, 531 remained in each group. The pain scores at discharge were significantly between the two groups before and after matching (all p < 0.001). The differences of delirium rate and functional outcomes became significant after propensity score-based matching (p=0.001 and 0.033, respectively), although they were not significant before matching. No significant difference was observed in other operation-related data, LOS, and crude mortality rates at 30-day, 90-day, and 12-month before and after PSM. In conclusion, this study highlights the need for preoperative IVP use to optimize pain control, postoperative functional recovery, and minimize pain-related comorbidities such as delirium in elderly patients with hip fracture.

Corrigendum: Global Trends in Intertrochanteric Hip Fracture Research From 2001 to 2020: A Bibliometric and Visualized Study.

[This corrects the article DOI: 10.3389/fsurg.2021.756614.].

Global Trends in Intertrochanteric Hip Fracture Research From 2001 to 2020: A Bibliometric and Visualized Study.

Background: Intertrochanteric femur fractures, which are common geriatric osteoporotic fractures, have imposed a huge economic and social burden. This study clarified the global status of research on intertrochanteric fractures between 2001 and 2020 and predicted future research trends in this field using bibliometric and visualized studies. Methods: Publications related to intertrochanteric fractures were retrieved from the Web of Science (WoS) database. All studies were published between 2001 and 2020. Bibliometric and co-occurrence analyses were conducted using VoS viewer software. Results: In total, 2,632 studies were retrieved. The number of global publications regarding intertrochanteric fractures increased annually. The United States was the largest contributor, ranking first in total publications, citations, and the H-index. Switzerland had the highest average citation frequency among the 10 countries with the highest number of publications. The journal that published the most articles regarding intertrochanteric fractures was the Injury International Journal of The Care of The Injured, with 290 articles published. This journal also ranked first in the citation frequency. MJ Parker, an author, published the most papers in the field, and the University of California research team at San Francisco contributed the most publications in this field. During the co-occurrence analysis, all keywords were divided into four clusters: internal fixation study, complication study, risk-factor study, and survival and prognosis analysis study. The internal fixation and survival and prognosis analysis studies were predicted as the next hot topics in the field of intertrochanteric fractures. Conclusions: Intertrochanteric fractures are gaining increasing research attention according to the current global trend, and the number of publications regarding intertrochanteric hip fractures will continue to increase. The United States currently publishes the most articles on intertrochanteric fractures. The number of studies related to internal fixation, survival, and prognosis analysis is increasing, suggesting that these topics may become the next research hotspots in the area of intertrochanteric fractures.

Oxycodone-paracetamol tablet exhibits increased analgesic efficacy for acute postoperative pain, higher satisfaction and comparable safety profiles compared with celecoxib in patients underwent arthroscopic knee surgery.

This randomized, controlled study compared the efficacy and safety between oxycodone-paracetamol tablet and celecoxib for postoperative analgesia in patients who underwent arthroscopic knee surgery (AKS). Totally, 232 patients scheduled to undergo AKS were enrolled and were randomly assigned to either the oxycodone-paracetamol (OPT group) or the celecoxib group (CEL group). Pain at rest/motion (based on pain visual analog scale (VAS) score), rescue analgesia consumption, satisfaction level and adverse events were assessed after AKS. Pain VAS score at rest was decreased at 6 h, 12 h post-AKS in the OPT group compared with the CEL group. Similarly, pain VAS score at motion was reduced at 6 h, 12 h, 24 h post-AKS in the OPT group compared to the CEL group. Furthermore, both rescue analgesia rate (14.7% vs. 33.6%) and accumulated pethidine consumption (3.7 ± 8.9 mg vs. 14.0 ± 21.2 mg) were lower in OPT group compared with the CEL group. Patients satisfaction score was either at 24 h, 48 h in OPT group compared with the CEL group. Further subgroup analyses indicated that the effect of oxycodone-paracetamol versus (vs. celecoxib) on post-AKS management was more apparent in the elderly patients and male patients. In addition, the adverse events were well tolerable (including nausea, constipation, vomiting, drowsiness and dizziness) and were of no different between the two groups. In conclusion, oxycodone-paracetamol tablet presents increased analgesic efficacy for acute postoperative pain, with higher patient satisfaction and comparable safety profiles compared with celecoxib in patients underwent AKS.

Using a Combined Classification of Increased Signal Intensity on Magnetic Resonance Imaging (MRI) to Predict Surgical Outcome in Cervical Spondylotic Myelopathy.

BACKGROUND The aim of this study was to verify whether the combined classification of increased signal intensity (ISI) on magnetic resonance imaging is more closely related to surgical outcomes than signal quality changes or signal longitudinal extent changes alone and to evaluate whether the combined classification ISI method could be used to predict surgical outcomes in cervical spondylotic myelopathy. MATERIAL AND METHODS Eighty-four patients (61 men and 23 women) who underwent surgery for cervical spondylotic myelopathy were included in this retrospective study. The patterns of ISI were classified into 3 categories based on (1) the quality of ISI into Grade 0: none, Grade 1: faint (fuzzy), and Grade 2: intense (sharp); (2) the longitudinal extent of ISI into none, focal, and multisegmental; and (3) the combined classification of the quality and longitudinal extent into Type 1 (none/none), Type 2 (focal/faint), Type 3 (focal/intense), Type 4 (multisegmental/faint), and Type 5 (multisegmental/intense). The multifactorial effects of variables were studied. A stepwise regression analysis was performed to verify whether this combined classification could predict outcome. RESULTS Of the 3 categories, the combined classification type of ISI was most closely related to recovery rate. Stepwise regression analysis confirmed the significance of combined classification of ISI as a predictor for surgical outcome. CONCLUSIONS A combined classification of ISI is more closely related to surgical outcomes than either signal quality changes or signal longitudinal extent changes alone and it could be used as a meaningful indicator for predicting surgical outcomes. We recommend further studies to confirm this finding.

Super elderly patients with intertrochanteric fractures do not predict worse outcomes and higher mortality than elderly patients: a propensity score matched analysis.

We aimed to investigate whether super elderly patients aged over 90 years had significantly worse functional outcomes, perioperative complications, and survival rates. Among 3560 patients aged over 65 years presenting with intertrochanteric fractures and treated surgically between Jan 2014 and Jan 2019, 2242 patients were included, including 206 in super elderly group and 2036 in elderly group. After using propensity score matching to minimize the effects of possible confounding variables, 192 remained in each group. No significant difference was observed in functional outcomes, perioperative complications, or 30-day, 90-day, and 1-year mortality after propensity score matching and McNemar's tests (p>0.05). After an average follow-up of 37 months, the Kaplan-Meier survival curve showed no significant difference between the two groups in terms of cumulative survival rate (p=0.081, log-rank). Our data demonstrated progressive increases in mortality and poor outcomes with increasing Elixhauser comorbidity scores, which represented the severity index of patients preoperatively. Our study also found that there were weak correlations between five characteristics and the patient age. These results all suggested that it is not the advanced age itself but other concomitant factors, that appear to be responsible for the adverse functional outcomes, perioperative complications, and mortality in super elderly patients.

Minocycline impedes mitochondrial-dependent cell death and stabilizes expression of hypoxia inducible factor-1α in spinal cord injury.

INTRODUCTION: One of the crucial mechanisms following spinal cord injury is mitochondria-associated cell death. Minocycline, an anti-inflammatory drug, is well known to impede mitochondrial cell death. However, there has been no study on the effect of minocycline linking Fas cell surface death receptor (FAS)-mediated cell death and hypoxia inducible factor (HIF-1α), the targets involved in mitochondrial cell death. MATERIAL AND METHODS: Male Sprague Dawley rats (N = 15, divided into three groups) were subjected to traumatic spinal cord injury and were injected with minocycline (n = 5) (90 mg/kg and later a 45 mg/kg dose twice a day (every 12 h)). Injection with sterile PBS in injured animals served as the vehicle (n = 5) and another group comprised healthy animals (n = 5). TUNEL assay was used to quantify cell death. The release of Smac/Diablo, cytochrome-c (cyt-c), HIF-1α, FAS ligand (FASL) and tumour necrosis factor-α (TNF-α) was measured using ELISA. Expression of HIF-1α, FASL and other cell death associated factors was quantified at the mRNA and protein level and confirmed with immunohistochemistry. RESULTS: There was a marked reduction in the HIF-1α and FASL expression levels in the minocycline-treated group compared to the vehicle. The reduction of HIF-1α and FASL was associated with other factors linked to cell death (Smac/Diablo, cyt-c, TNF-α, p53, caspase-8 and BH3 interacting domain death agonist (BID)) (p < 0.5; *p < 0.05 vs. vehicle group, **p < 0.01 vs. vehicle group). CONCLUSIONS: The present study focuses on the investigation of minocycline in inhibiting mitochondria-associated cell death by modulating FASL and HIF-1α expression, which are seemingly interlinked mechanisms contributing to cell death.

WITHDRAWN: Minocycline an antimicrobial agent attenuates the mitochondrial dependent cell death and stabilizes the expression of HIF-1α in spinal cord injury.

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[Clinical efficacies of different internal fixation materials in the treatment of senile proximal humerus fractures].

OBJECTIVE: To explore the clinical efficacies of different internal fixation materials in the treatment of senile proximal humerus fractures. METHODS: A total of 284 hospitalized patients of proximal humerus fractures over 60 years of age cases from October 2009 to February 2012 were randomly divided into two groups of locking proximal humeral plate (LPHP) and PHILOS (n = 142 each). And the clinical efficacies of two groups were compared. RESULTS: For PHILOS and LPHP groups, the fracture healing periods were (11.64 ± 3.81) and (14.95 ± 3.95) weeks. And there was statistical significance (P < 0.05). At 3 months post-surgery, the incidence of pain was 72.41% and 64.81%. And there was statistical significance (P < 0.05). At 2 years,Neer shoulder function score had inter-group statistically insignificant difference (P > 0.05). CONCLUSION: Both PHILOS and LPHP are effective in the treatment of senile proximal humeral fractures.However, the former is conducive to fracture healing and has shorter healing time and lowered postoperative pain.