BACKGROUND: Glucocorticoid-induced osteoporosis has relationship with the down-regulation of osteoprotegedn expression. Osteoprotegerin could inhibit bone resorption in the animal experiment and clinical application for treating oestrogenic hormone deficiency osteoporosis. OBJECTIVE: To investigate the effects of exogenous recombinant osteoprotegerin fusion protein on glucocorticoid-induced osteoporosis in rats. DESIGN, TIME AND SETTING: Randomized grouping, controlled animal expenment was performed in the Institute of Orthopedics, Chinese PLA General Hospital between January 2006 and June 2008. MATERIALS: Sixty healthy male Wistar rats of clean grade; Dexamethasone was produced by Tianjin Jinyao Amino Acid Co., Ltd (Licenca No. H12020515). METHODS: Sixty rats were divided into 3 groups randomly with 20 rats in each. Control group: the rats were administrated with 0.9％ sodium chloride. Dexamethasone group: the rats were administrated with dexamethasone intramuscularly. Osteoprotegedn group: the rats were administrated with dexamethasone and recombinant osteoprotegerin intramuscularly. MAIN OUTCOME MEASURES: All rats were sacrificed at 12 weeks after administration. The urine calcium, phosphor, creatinine, bone mineral density, biomechanics tests of femur and vertebral body, were measured. Immunohistochemistry staining were performed to observe osteoprotegerin expression.RESULTS: Sixty rats were all involved in the final analysis. ①Compared with control group, udne calcium increased in the Dexamethasone group (P < 0.05); the bone mineral density of lumbar vertebra and femur decreased significantly (P < 0.05), especially lumbar vertebra (P < 0.01); biomechanics tests of femur and vertebral body (maximum load, maximum stress, elasticity load, elasticity stress, elastic modulus) decreased significantly (P < 0.05); immunohistochemistry staining showed that endogenous osteoprotegerin expressions were reduced significantly in bone marrow of Dexamethasone group (P < 0.01). ②Compared with Dexamethasone group, urine calcium decreased in the osteoprotegerin group (P < 0.01 ); the bone mineral density of lumbar vertebra and femur increased (P < 0.05); the parameters of biomechanics testa of femur and vertebral body increased (P < 0.05); the osteoprotegerin expression was not changed between Dexamethasone group and osteoprotegerin group.CONCLUSION: Glucocorticoid could inhibit osteoprotegerin expression in the bone followed by progressive bone loss and induce osteoporosis. Recombinant osteoprotegerin works effectively in inhibiting bone resorption after administrated with glucocorticoid, reduce bone resorption index, increase bone mineral index and bone strength, thus improving the osteoporosis which is induced by glucocorticoid.

Objective To investigate the clinical outcomes and complications of augmented antibiotic-loaded cement spacer in two-stage infected total hip arthroplasty with acetabular bone defect.Methods The periprosthetic infection (PJI) patients with acetabular bone defect were retrospectively reviewed from January 2007 to June 2016 in our hospital.A total of 26 patients (11 males and 15 females) were eligibly included in the present study.The mean age was 46.7 years old.The two-stage revision arthroplasty included implants removel,meticulous debridement,implantation of antibiotic-loaded cement spacer in firststage.After systemic therapy of antibiotics,the prosthesis was implanted in the second-stage.The supra-acetabular antibiotic cement shelf with screws was used to improve hip stability with acetabular wall defect.The handmade acetabular spacer was able to prevent femoral spacer ifto pelvis in patients with acetabular internal wall defect.The clinical outcomes and complications (spacer dislocation,spacer fracture and acetabular wear) were measured.Results The positive rate of bacteria culture was 80.8％ (21/26)and 57.7％ (15/26) patients were cultured with staphylococcus.The others were 2 fungus,2 Gram-positive rod,1 brucella,1 pseudomonas aeruginosa,1 escherichia coli,1 enterococcus faecalis,1 defective probiotics,1 serratiamarcescens and 1 Kocuriaroseus.Moreover,19.2％ (5/26) patients were mixed infection.There was one patient with spacer dislocation and two with spacer fracture.No patients were recurrent infection.Infection was controlled,and two-stage revision was successfully performed in 24 patients.Twenty-two patients were followed averaging 4.1 years (1-8) and the Harris Hip Score was significantly improved from 40.9± 14.0to 81.2± 11.2 at the final follow-up (P＜0.05).Conclusion The application of augmented antibiotic-loaded cement spacer has satisfactory clinical outcomes in PJI patients with acetabular bone defect.It can provide joint mobility and increase additional joint stability with decreased iatrogenic bone defect caused by acetabular wear.

Objective:To explore the radiology and short-term clinical outcomes of MAKO robotic-assisted total hip arthroplasty (THA).Methods:The present study retrospectively reviewed the medical records of 23 patients (32 hips) who diagnosed as osteonecrosis of the femoral head and underwent MAKO THA from August 1st to December 31st, 2018 as MAKO THA group. A total of 23 patients (32 hips) with the same diagnosis underwent manual THA at the same time as conventional THA group. There was no statistical difference between the two groups in terms of gender, affected side, age, height, weight, Body Mass Index (BMI), stage of the Association Research Circulation Osseous (ARCO), preoperative Harris hip score, WOMAC Osteoarthritis Index and limb length discrepancy. The patients in both groups were operated by the same doctors. The MAKO THA group underwent the acetabular preparation and the acetabular shell impaction with the assistance of the robotic arm. The leg length and offset were adjusted under the feedback of the MAKO system. Other intraoperative procedures and postoperative interventions of MAKO THA group were similar as conventional THA group. The operation duration, incidence of complications, the radiograph parameters (version, leg length discrepancy and offset), consistency of acetabular prosthesis position in MAKO operation plan, position in postoperative X-ray, the consistency of acetabular prosthesis inclination, version in MAKO operation plan, angles in postoperative CT and functional scores (Harris hip score, WOMAC Osteoarthritis Index and forgotten joint score) at 6 months and 12 months after operation were compared between the two groups.Results:The operation duration of the MAKO THA group was longer than that of the conventional THA group (101.2±19.9 min, 65.5±5.6 min, t=7.659, P<0.001). In terms of radiograph parameters, the different of version (22.63°±5.58°, 15.98°±7.13°, t=4.156, P<0.001) and limb length discrepancy (0.35±0.30 cm, 0.87±0.43 cm, t=4.775, P<0.001) and offset (0.27±0.19 cm, 0.49±0.16 cm, t=4.155, P<0.001) between the two groups were statistically significant. The MAKO operative plan and postoperative radiographs were measured. The difference of inclination/version were 1.18°±2.52°/2.06°±2.79° ( r=0.846, P<0.001; r=0.810, P<0.001), respectively. The horizontal/vertical directions of the joint rotation center were 2.25±1.08 mm and 2.20±1.28 mm ( r=0.975, P<0.001; r=0.974, P<0.001), respectively. In terms of functional results at 6 months and 12 months after operation, Harris hip score in MAKO THA group and in conventional THA group was 90.2±5.40/89.9±5.23 ( t=0.188, P=0.851) and 93.9±2.31/94.0±2.61 ( t=0.254, P=0.801), respectively. The WOMAC index was 27.3±10.36/29.1±12.03 ( t=0.623, P=0.535) and 16.4±8.39/15.2±8.35 ( t=0.597, P=0.552). The forgotten joint score was 76.3±6.11/73.7±6.84 ( t=1.560, P=0.124) and 81.7±4.52/80.7±5.11 ( t=0.816, P=0.418), respectively. Transient bleeding in the anterior superior iliac spine pin holes were reported in 4 hips after discharge in MAKO THA group, which were healed after dressing change. No other intraoperative or postoperative complication was reported. Conclusion:Robotic-assisted THA were more accurate and stable than conventional THA. The version of robot-assisted THA was closer to the target of 20° with similar discrepancy in leg length and hip offset. The short-term functional outcomes were similar in the two groups. However, the operation duration of robot-assisted THA was prolonged.

Objective:To explore the learning curve of MAKO-assisted total knee arthroplasty.Methods:From May 2021 to September 2022, 136 patients were conducted MAKO-assisted total knee arthroplasty in the PLA General Hospital, including 37 males and 99 females, 65.53±7.01 years old (range 54-80 years). All cases were patients with unilateral knee osteoarthritis. The operations were performed by three surgeons, respectively. Sixty-one cases were performed by surgeon 1, 47 cases were performed by surgeon 2, and 28 cases were performed by surgeon 3. Record the time of each step during the operation, and measure the limb alignment in X-ray. The statistical difference between the two groups was compared by t test by SPSS. The cumulative sum control chart (CUSUM) learning curve was modeled by curve fitting and R2 was used to testify the goodness. Results:The total operation time of the three surgeons was 114.3±25.1 min, 109.8±10.9 min, and 118.6±15.1 min, respectively. The time of each step in the first 10 cases and the last 10 cases of operator 1-3 was counted. The osteotomy time of surgeons 1, 2 and 3 in the final 10 cases was less than that in the initial 10 cases (surgeon 1: 13.5 ± 3.41 min vs. 8.0±1.58 min, t=4.30, P=0.001; surgeon 2: 13.7±3.02 min vs. 8.0± 2.58 min, t=4.77, P=0.001; surgeon 3: 15.3±3.97 min vs. 11.0±2.38 min, t=2.87, P=0.010), and the difference was statistically significant. The CUSUM of osteotomy was calculated and the curve was fitted. The highest point of the curve of the three surgeons was in the 16th, 18th and 12th patients, respectively, and the time of osteotomy continued to decline after passing the peak. No statistical differences were found in surgery time for the remaining steps. Comparing the lower alignment angles of intraoperative planning and postoperative X-ray films, the overall difference was greater than 1 degree. The difference was 1.41°±1.32° for operator 1, 1.34°±1.22° for operator 2, and 1.04°±0.88° for operator 3. The percentages of fully accurate implant size planning were 85.2%(52/61), 76.7%(36/47), and 85.7%(24/28), respectively. Conclusion:For MAKO-assisted total knee arthroplasty, the operator can decrease the operation time by practice, which is mainly reflected in the shortening of the osteotomy time. The learning curve threshold is around in the 15th case. The increase in the number of surgeries did not bring about changes in the accuracy of lower extremity alignment.

Objective:To explore the impact of robot assisted total hip arthroplasty (THA) on the accuracy of prosthesis placement and its clinical efficacy.Methods:A total of 432 patients (549 hips) who underwent robot-assisted primary THA for various diseases of the hip in the Department of Orthopaedics of the Fourth Medical Center of the PLA General Hospital from August 2018 to October 2022 was retrospectively analyzed. There were 174 male and 258 female with an average age of 54.2±12.7 years old and body mass index (BMI) of 23.2±4.3 kg/m 2. There were 301 left hips and 248 right hips. All patients were operated under general anesthesia using the standard posterior lateral surgical approach to THA. The Harris hip score (HHS), forgotten joint score (FJS), the Western Ontario and McMaster University (WOMAC) osteoarthritis index and patient satisfaction were used to evaluate the clinical outcomes. The anterior inclination, abduction angle, lower extremity discrepancy and the position of the center of rotation (COR) of the hip joint were radiographically accessed preoperatively, intraoperatively and postoperatively. The composition ratio of the acetabular cup in the safe zone was also calculated. Results:Five hundred and forty-nine consecutive hips (432 patients) underwent robotic-assisted THA with a mean follow-up of 23.6±16.2 months. The mean operative time was 86.2±35.4 min, and the mean blood loss was 236.7±94.5 ml. At the last follow-up, the mean HHS score for this group was 91.4±15.4, the WOMAC score was 8.4±6.5, the FJS score was 77.4±23.4, and the satisfaction score was 9.1±2.7 points. The mean postoperative measurement of acetabular cup anteversion was 21.2°±4.8° and abduction was 40.8°±4.3°. About 93.7% (511 patients) had an acetabular cup within the safety zone of ±10° of the target angle, and 84.6% (464 patients) had an acetabular cup within the safety zone of ±5° of the target angle. A total of 4 complications occurred. Acute periprosthesis infection happened in a case of developmental dysplasia of the hip (DDH) and was cured by DAIR (debridement, antibiotics, irrigation, retention of prosthesis). One case of thigh pain of unknown reason was treated with a revision operation, during which no loosening or malposition of the prosthesis was found. After replacing the femoral head component no pain was complained by the patient. One case of hematoma and nerve compression was considered to be caused by blood vessels injury when a titanium cable was used to fix the distal femoral fracture during the surgery. The nerve injury returned to normal within 1 month. One case of dislocation happened immediately after surgery and was revised by replacing a different head. The patient was fully recovered. In addition to software and mechanical failures of the robot itself, complex hip joint diseases would be a risk factor for the termination of robot assisted surgery due to the occurrence of adverse events related to robots in 16 hips. Considering the existence of a certain termination rate in robot assisted surgery, sufficient preparation should be made when applying robot assisted technology in complex hip joint diseases.Conclusion:In robotic-assisted THA, preoperative planning can be achieved with precise and reproducible acetabular cup positions, significantly increasing the chance of locating the acetabular cups in the safety zone, and obtaining satisfactory results in restoring COR and leg length.

Objective:To analyze three reconstruction techniques and mid-term clinical outcomes of hip revision for acetabular bone defect after total hip arthroplasty (THA).Methods:This is a retrospective case series study. Included in the study were 109 patients (109 hips) with acetabular bone defect after THA reconstructions in hip revisions from January 2015 to December 2021 in the Senior Department of Orthopaedics, the Forth Medical Center of Chinese People′s Liberation Army General Hospital and the Department of Orthopaedics, the First Medical Center of Chinese People′s Liberation Army General Hospital. According to the preoperative simulated surgeries and different bone defect reconstruction techniques, patients were divided into a normal cup group, an augment group or a triflange group,respectively. There were 54 patients (54 hips) in the normal cup group, reconstructed with the uncemented porous metal cup (including Jumbo cup), with 23 males and 31 females, aged (59.6±9.9) years (range:32 to 76 years); 44 patients (44 hips) in the augment group, reconstructed with the individualized three-dimensional (3D) printed porous metal augment and uncemented porous metal cup, with 18 males and 26 females, aged (52.8±13.6) years(range:17 to 76 years); 11 patients (11 hips) in the triflange group, reconstructed by the individualized 3D printed porous metal triflange cup, with 5 males and 6 females, aged (59.4±11.2) years (range: 43 to 78 years). Radiographic results, including rotation center height, rotation center offset, and leg length discrepancy (LLD) and clinical results, including Harris hip score (HHS) and visual analogue scale(VAS) were evaluated outpatient at 3, 6, 12 months after the operation and annually thereafter. The last follow-up was completed in March 2024, and all parameters at the last follow-up and before the operation were compared. Paired sample t test and repeated measurement ANOVA were used for the radiographic and clinical parameters before and after the operation. Results:All hip revisions for patients with acetabular bone defect after THA were completed and followed for more than two years. The follow-up time of the normal cup group was (6.5±1.7) years (range: 2.8 to 9.3 years), and that of the augment group was (6.0±1.3) years (range: 3.5 to 9.0 years). The follow-up time of the triflange group was (2.8±0.6) years (range: 2.0 to 3.8 years). At the last follow-up, the rotation center height, rotation center offset and LLD of 54 hips in the normal cup group were (24.2±5.6) mm, (29.1±5.5) mm and (4.6±3.3) mm, respectively, and the rotation center height and LLD were significantly lower than those of the preoperative hips ( t=9.671, P<0.01; t=6.073, P<0.01). In the augment group, the rotational center height, the rotation center offset and the LLD of 44 hips were (22.4±9.0) mm, (25.4±5.5) mm and (6.0±4.0) mm, respectively, which were significantly lower than those of the preoperative hips ( t=9.071, P<0.01; t=11.345, P<0.01; t=4.927, P<0.01). In the triflange group, the rotational center height, the rotation center offset and LLD of 11 hips were (22.7±6.0) mm,(30.9±8.0) mm and (5.3±2.2) mm, respectively, and the rotation center height and LLD were significantly lower than those of the preoperative hips ( t=2.716, P=0.022; t=6.226, P<0.01). At the last follow-up, fractures occurred in 3 patients and dislocation occurred in 1 patient in the normal cup group, and fracture reduction and closed reduction were administered under anesthesia, respectively. In the augment group, dislocation occurred in 1 patient and open reduction under anesthesia was performed. The HHS and VAS of the three groups improved significantly after surgery and the differences were statistically significant (all P<0.01). There was no complication in the triflange group. The X-ray at the last follow-up showed that all prostheses and augments were in stable positions and no loosening or migration was observed. Conclusions:For patients with acetabular bone defect after THA undergoing hip revisions, preoperative surgical simulation and rehearsal could help surgeons choose convenient and efficient reconstruction techniques. The targeted selection of Jumbo cup, individualized 3D printed metal augment, and customized triflange cup could achieve satisfactory clinical outcomes.

Objective:To analyze three reconstruction techniques and mid-term clinical outcomes of hip revision for acetabular bone defect after total hip arthroplasty (THA).Methods:This is a retrospective case series study. Included in the study were 109 patients (109 hips) with acetabular bone defect after THA reconstructions in hip revisions from January 2015 to December 2021 in the Senior Department of Orthopaedics, the Forth Medical Center of Chinese People′s Liberation Army General Hospital and the Department of Orthopaedics, the First Medical Center of Chinese People′s Liberation Army General Hospital. According to the preoperative simulated surgeries and different bone defect reconstruction techniques, patients were divided into a normal cup group, an augment group or a triflange group,respectively. There were 54 patients (54 hips) in the normal cup group, reconstructed with the uncemented porous metal cup (including Jumbo cup), with 23 males and 31 females, aged (59.6±9.9) years (range:32 to 76 years); 44 patients (44 hips) in the augment group, reconstructed with the individualized three-dimensional (3D) printed porous metal augment and uncemented porous metal cup, with 18 males and 26 females, aged (52.8±13.6) years(range:17 to 76 years); 11 patients (11 hips) in the triflange group, reconstructed by the individualized 3D printed porous metal triflange cup, with 5 males and 6 females, aged (59.4±11.2) years (range: 43 to 78 years). Radiographic results, including rotation center height, rotation center offset, and leg length discrepancy (LLD) and clinical results, including Harris hip score (HHS) and visual analogue scale(VAS) were evaluated outpatient at 3, 6, 12 months after the operation and annually thereafter. The last follow-up was completed in March 2024, and all parameters at the last follow-up and before the operation were compared. Paired sample t test and repeated measurement ANOVA were used for the radiographic and clinical parameters before and after the operation. Results:All hip revisions for patients with acetabular bone defect after THA were completed and followed for more than two years. The follow-up time of the normal cup group was (6.5±1.7) years (range: 2.8 to 9.3 years), and that of the augment group was (6.0±1.3) years (range: 3.5 to 9.0 years). The follow-up time of the triflange group was (2.8±0.6) years (range: 2.0 to 3.8 years). At the last follow-up, the rotation center height, rotation center offset and LLD of 54 hips in the normal cup group were (24.2±5.6) mm, (29.1±5.5) mm and (4.6±3.3) mm, respectively, and the rotation center height and LLD were significantly lower than those of the preoperative hips ( t=9.671, P<0.01; t=6.073, P<0.01). In the augment group, the rotational center height, the rotation center offset and the LLD of 44 hips were (22.4±9.0) mm, (25.4±5.5) mm and (6.0±4.0) mm, respectively, which were significantly lower than those of the preoperative hips ( t=9.071, P<0.01; t=11.345, P<0.01; t=4.927, P<0.01). In the triflange group, the rotational center height, the rotation center offset and LLD of 11 hips were (22.7±6.0) mm,(30.9±8.0) mm and (5.3±2.2) mm, respectively, and the rotation center height and LLD were significantly lower than those of the preoperative hips ( t=2.716, P=0.022; t=6.226, P<0.01). At the last follow-up, fractures occurred in 3 patients and dislocation occurred in 1 patient in the normal cup group, and fracture reduction and closed reduction were administered under anesthesia, respectively. In the augment group, dislocation occurred in 1 patient and open reduction under anesthesia was performed. The HHS and VAS of the three groups improved significantly after surgery and the differences were statistically significant (all P<0.01). There was no complication in the triflange group. The X-ray at the last follow-up showed that all prostheses and augments were in stable positions and no loosening or migration was observed. Conclusions:For patients with acetabular bone defect after THA undergoing hip revisions, preoperative surgical simulation and rehearsal could help surgeons choose convenient and efficient reconstruction techniques. The targeted selection of Jumbo cup, individualized 3D printed metal augment, and customized triflange cup could achieve satisfactory clinical outcomes.

Based on the analysis of heart rate variability(HRV),a prediction method for paroxysmal atrial fibrillation(PAF)attacks is proposed.A new adaptive filtering technique is used for smoothing and coarse graining of HRV,followed by entropy-based quantification of HRV complexity at multiple adaptive scales.After the features are normalized by Min-Max,feature subsets are selected by sequential forward selection method,and then input to support vector machine to identify HRV types and predict PAF attacks.Through 5-fold cross-validation on a set of 50 HRV sequences each lasting 5 minutes,the optimal prediction results are obtained:98%accuracy,100%sensitivity,96%specificity,demonstrating excellent performance.In addition,the experiment shows significant changes(P<0.05)in the complexity eigenvalues of HRV far away from and close to PAF at different frequency bands,reflecting alterations in nervous system regulation of cardiac rhythm and a decline in the ability to adapt to external environmental changes such as stress regulation.

OBJECTIVETo evaluate the application of tendon-derived stem cells (TDSC) and bone marrow-derived mesenchymal stem cells (BMSC) for patellar tendon injury repair in rat model.

METHODSTDSCs and BMSCs were isolated from patellar tendons or bone marrow of healthy SD rats. The patellar tendon injury model was induced in 60 SD rats, then the animals were divided into 3 groups with 20 in each group: rats in TDSC group received transplantation of TDSC with fibrin glue in defected patellar tendon, rats in BMSC group received BMSC with fibrin glue for transplantation and those in control group received fibrin glue only. The gross morphology, histology and biomechanics of the patellar tendon were examined at 1, 2, 4, 6 and 8 weeks after the treatment.

RESULTSGross observation showed that the tendon defects in TDSC group and BMSC group almost disappeared in week 8, while the boundary of tendon defects in control group was still visible. Histology examination showed that the neo-tendon formation in TDSC group and BMSC group was observed at week 8, while there was no neo-tendon formation in control group. Biomechanics study showed that the ultimate stress and Young Modulus, relative ultimate stress and relative Young Modulus increased with the time going in all groups(all P<0.05); the ultimate stress and Young Modulus, relative ultimate stress and relative Young Modulus of TDSC and BMSC groups were significantly higher than those in control group at week 4, 6 and 8(all P<0.05). There was no difference in ultimate stress and Young Modulus between TDSC group and BMSC group(P>0.05), however, the relative Young Modulus of TDSC group was significantly higher than that in BMSC group at week 8(P<0.05).

CONCLUSIONAllogeneic TDSC and BMSC transplantation facilitates the repair of tendon injury and improves the biomechanics of tendon. TDSC is more suitable for in vivo tendon regeneration than BMSC.

Animals ; Bone Marrow ; Elastic Modulus ; Mesenchymal Stromal Cells ; cytology ; Rats ; Rats, Sprague-Dawley ; Regeneration ; Tendon Injuries ; therapy ; Tendons ; cytology ; Wound Healing

Femoral neck fracture (FNF) in the elderly patients is currently a major health challenge worldwide, with excessive consumption of medical resources, high incidence of complications as well as suboptimal outcome and prognosis. Hip joint arthroplasty (HJA) has been the mainstream treatment for FNF in the elderly, but the conventional surgical approaches and techniques are still confronted with a series of bottlenecks such as dislocation, limp and limb length discrepancy. In recent years, direct anterior approach (DAA) for HJA (DAA-HJA) has been a major new choice in the field of joint replacement, which achieves improved clinical effectiveness of HJA in the treatment of elderly FNF, due to the fact that DAA approach involves the neuromuscular interface and accords with the idea of soft tissue retention and enhanced recovery after surgery. However, there is still a lack of unified understanding of standard technique and procedure of DAA-HJA in the treatment of elderly FNF. Therefore, relevant experts from the Hip Joint Group of Chinese Orthopedics Association of Chinese Medical Association, Youth Arthrology Group of Orthopedic Committee of PLA, Orthopedic Committee of Chongqing Medical Association, Branch of Orthopedic Surgeons of Chongqing Medical Doctor Association and Sport Medicine Committee of Chongqing Medical Association were organized to formulate the " Chinese expert consensus on the technical standard of direct anterior hip arthroplasty for elderly femoral neck fracture ( version 2023)" based on evidence-based medicine. This consensus mainly proposed 13 recommendations covering indications, surgical plans, prosthesis selections, surgical techniques and processes, and postoperative management of DAA-HJA in elderly patients with FNF, aiming to promote standardized, systematic and patient-specific diagnosis and treatment to improve the functional prognosis of the patients.