Autologous chondrocyte implantation (ACI) is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee. Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover (ACI-C) and matrix-induced autologous chondrocyte implantation (MACI) using a collagen bilayer seeded with chondrocytes. We have performed a prospective, randomised comparison of ACI-C and MACI for the treatment of symptomatic chondral defects of the knee in 91 patients, of whom 44 received ACI-C and 47 MACI grafts. Both treatments resulted in improvement of the clinical score after one year. The mean modified Cincinnati knee score increased by 17.6 in the ACI-C group and 19.6 in the MACI group (p = 0.32). Arthroscopic assessments performed after one year showed a good to excellent International Cartilage Repair Society score in 79.2% of ACI-C and 66.6% of MACI grafts. Hyaline-like cartilage or hyaline-like cartilage with fibrocartilage was found in the biopsies of 43.9% of the ACI-C and 36.4% of the MACI grafts after one year. The rate of hypertrophy of the graft was 9% (4 of 44) in the ACI-C group and 6% (3 of 47) in the MACI group. The frequency of re-operation was 9% in each group. We conclude that the clinical, arthroscopic and histological outcomes are comparable for both ACI-C and MACI. While MACI is technically attractive, further long-term studies are required before the technique is widely adopted

Matrix-induced autologous chondrocyte implantation (MACI) is an established technique used to treat osteochondral lesions in the knee. For larger osteochondral lesions (> 5 cm²) deeper than approximately 8 mm we have combined the use of two MACI membranes with impaction grafting of the subchondral bone. We report our results of 14 patients who underwent the ‘bilayer collagen membrane’ technique (BCMT) with a mean follow-up of 5.2 years (2 to 8). There were 12 men and two women with a mean age of 23.6 years (16 to 40). The mean size of the defect was 7.2 cm² (5.2 to 12 cm²) and were located on the medial (ten) or lateral (four) femoral condyles. The mean modified Cincinnati knee score improved from 45.1 (22 to 70) pre-operatively to 82.8 (34 to 98) at the most recent review (p < 0.05). The visual analogue pain score improved from 7.3 (4 to 10) to 1.7 (0 to 6) (p < 0.05). Twelve patients were considered to have a good or excellent clinical outcome. One graft failed at six years.

The BCMT resulted in excellent functional results and durable repair of large and deep osteochondral lesions without a high incidence of graft-related complications.

We describe two cases of osteochondritis dissecans (OCD) affecting both femoral condyles in the same knee. The patients presented with recurrent episodes of pain and swelling, but these were initially thought to be ‘growing pains’. Eventually, a delayed diagnosis of bicondylar OCD was established and both patients were referred for further management. After assessing the extent of the disease on MRI, matrix-induced autologous chondrocyte implantation was performed to treat the defects of the lateral condyle in each case, with a plan to address the medial defects at a later stage. Proposed theories on the aetiology of the condition and available methods of treatment are discussed. A diagnosis of OCD should be considered in young patients with persistent knee pain and effusions, and MRI is the investigation of choice for early detection

Purpose. We report on minimum 2 year follow-up results of 71 patients randomised to autologous chondrocyte implantation (ACI) using porcine-derived collagen membrane as a cover (ACI-C) and matrix-induced autologous chondrocyte implantation (MACI) for the treatment of osteochondral defects of the knee. Introduction. ACI is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee. Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover (ACI-C) and matrix-induced autologous chondrocyte implantation (MACI) using a collagen bilayer seeded with chondrocytes. Results. 71 patients with a mean age of 33 years (15-48) were randomised to undergo either an ACI-C or a MACI. 37 had ACI-C and 34 MACI. The mean size of the defect was 5.0cm2. Mean duration of symptoms was 104.4 months (9-456). Mean follow-up was 33.5 months (24-45). Functional assessment using the modified Cincinnati knee score, the Bentley functional rating score and the visual analogue score was carried out. Assessment using the modified Cincinnati knee score showed a good to excellent result in 57.1% of patients followed up at 2 years, and 65.2% at 3 years in the ACI-C group; and 63.6% of patients at 2 years, and 64% at 3 years in the MACI group. Arthroscopic assessments showed a good to excellent International Cartilage Repair Society score in 81.8% of ACI-C grafts and 50% of MACI grafts. Hyaline-like cartilage or hyaline-like cartilage with fibrocartilage was found in biopsies of 56.3% of the ACI-C grafts and 30% of the MACI grafts after 2 years. Conclusion. At this stage of the trial we conclude that the clinical, arthroscopic and histological outcomes are comparable for both ACI-C and MACI

Autologous chondrocyte implantation (ACI) is a technique used for the treatment of symptomatic osteochondral defects of the knee. A variation of the original periosteum membrane technique is the matrix-induced autologous chondrocyte implantation (MACI) technique. The MACI membrane consists of a porcine type-I/III collagen bilayer seeded with chondrocytes. Osteochondral defects deeper than 8 to 10 mm usually require bone grafting either before or at the time of transplantation of cartilage. We have used a variation of Peterson’s ACI-periosteum sandwich technique using two MACI membranes with bone graft which avoids periosteal harvesting. The procedure is suture-free and requires less operating time and surgical exposure. We performed this MACI-sandwich technique on eight patients, five of whom were assessed at six months and one year post-operatively using the modified Cincinnati knee, the Stanmore functional rating and the visual analogue pain scores. All patients improved within six months with further improvement at one year. The clinical outcome was good or excellent in four after six months and one year. No significant graft-associated complications were observed. Our early results of the MACI-sandwich technique are encouraging although larger medium-term studies are required before there is widespread adoption of the technique

The present study analysed the clinical outcome and the histological characteristics of membrane-seeded autolo-gous chondrocytes implantation at 24 month after surgery for chondral defects. A prospectic study was performed on fifteen patients (8 males and 7 females, mean age 38 years) suffering from cartilage lesions of the knee (12 cases) and the ankle (3 case). The patients underwent matrix-induced autologous chondrocyte implantation (MACI). Clinical outcomes were assessed by revised IKDC form and Knee Osteoarthritis and Injury Outcome Score (KOOS). At 12 months after implantation biopsy samples were obtained from 7 patients. The specimens were analysed by histochemistry, immunohistochemistry (ICRS visual histological assessment scale) and histomorphometry (Quantimet 500+). Improvement 12 months after operation was found subjectively (39.7 to 57.9) and in articular function levels. IKDC scores showed marked improvement at 12 months (88% A/B). 90% of biopsies showed: smooth articular surface, hyaline-like matrix, columnar cell distribution, viable cells, normal subchondral bone, tide-mark. All sections were clearly stained with safranin-O, alcian blue, and revealed immunoreaction for S-100 protein, chondroitin-S and type II collagen. Clinical improvement and hyaline-like appearance of the repair tissue indicate that MACI implantation is an effective technique for the treatment of cartilage lesions

Methods: The implantation procedure was performed on two male patients affected by traumatic chondral lesions, sized respectly 2.5 and 2 cm. 2. The operations were performed through traditional artrhoscopic portals and the seeded membrane was þxed with þbrin glue. Clinical-functional evaluation was performed acc. Aims: Matrix-induced autologous chondrocyte implantation (MACÏ) is a tissue engineering technique which requires the use of a collagen membrane on which the cultured chondrocytes are seeded. We report the arthroscopic MACÏ technique for the treatment of chondral defects interesting the lateral tibial ording to ICRS score, modiþed Cincinnati knee score, IKDC, Lysholm II and Tegner scales. MRIs were taken 6 and 12 months postoperatively. Results: After one year all the clinical scores were improved in both patients. MRI showed þlling of the defects with hyaline-like tissue with reduction of subchondral bone edema. Conclusions: Even though the MACÏ technique is mostly performed with an open procedure, the site of these lesions could not be reached without sacrifying tendinous and ligamentous structures of the knee. The arthroscopic approach allowed to achieve an optimal view of the lesion and appeared the best solution for these patients. The size of these defects was too large for bone marrow stimulation techniques and/or osteochondral grafts to be successful. The development of dedicated instruments for arthroscopic MACÏ will allow to improve and simplify the surgical procedure

Purpose. Osteochondral lesions (OCL) of the talus remain a challenging therapeutic task to orthopaedic surgeons. Several operative techniques are available for treatment, e.g. autologous chondrocyte implantation (ACI), osteochondral autograft transfer system (OATS), matrix-induced autologous chondrocyte implantation (MACI). Good early results are reported; however, disadvantages are sacrifice of healthy cartilage of another joint or necessity of a two-stage procedure. This case describes a novel, one-step operative treatment of OCL of the talus utilizing the autologous matrix-induced chondrogenesis (AMIC) technique in combination with a collagen I/III membrane. Method. 20 patients (8 female, 12 male; mean age 36, range 17–55 years) were assessed in our outpatient clinic for unilateral OCL of the talus. Preoperative assessment included the AOFAS hindfoot scale, conventional radiography, magnetresonancetomography (MRI) and SPECT-CT. Surgical procedure consisted of debridement of the OCL, spongiosa plasty from the iliac crest and coverage with the I/III collagen membrane (Chondrogide, Geistlich Biomaterials, Wolhusen, Switzerland). Clinical and radiological followup was performed after one year. Results. The mean preoperative AOFAS hindfoot scale was poor with 63.1 points (SD 19.6). At one year followup the score improved significantly (p<0.01) to 86 points (SD 12). At one year followup conventional radiographs showed osseous integration of the graft in all cases. MRI at one year showed intact cartilage covering the lesions in all cases. Conclusion. The initial results of this ongoing study are encouraging. The clinical and radiological results at one year followup are comparable with the results of ACI, OATS and MACI. The AMIC procedure is a readily available, economically efficient, one step surgical procedure. No culturing after chondrocyte harvesting or destruction of viable cartilage is necessary

Matrix-induced autologous chondrocyte implantation (MACI) is a tissue engineering technique which requires the use of a collagen membrane on which the cultured chondrocytes are seeded. We report on the arthroscopic MACI technique for the treatment of chondral defects in the lateral tibial plate of the knee. The implantation procedure was performed on two male patients affected by traumatic chondral lesions, 2.5 and 2 cm. 2. in size, respectively. The procedures were performed through traditional artrhoscopic portals and the seeded membrane was fixed with fibrin glue. Clinical-functional evaluation was performed according to ICRS score, modified Cincinnati knee score, IKDC, Lysholm II and Tegner scales. MRIs were taken 6, 12 and 24 months postoperatively. After 2 years all the clinical scores were improved in both patients. MRI showed filling of the defects with hyaline-like tissue with reduction of subchondral bone oedema and restoration of a regular articular surface. Even though the MACI technique is mostly performed with an open procedure, the site of these lesions could not be reached without sacrifying tendinous and ligamentous structures of the knee. With the arthroscopic approach an optimal view of the lesion could be achieved and appeared to be the best solution for these patients. The size of these defects was too large for bone marrow stimulation techniques and/or osteochondral grafts to be successful. By using fibrin glue for fixating the seeded membrane the procedure could be performed arthroscopically in a simple and safe way. No specifically designed instruments were used in these cases

We prospectively evaluate clinical results and MRI findings on a series of 47 patients, with an average age of 31.7 years, treated by matrix-induced autologous chondrocyte implantation (MACI) for knee and ankle chondral defects. As isolated lesions, the joints affected were 37 knees and five ankles. As combined lesions, there were four knees and one kissing lesion in the ankle. The average size of the defects was 3.5 cm. 2. Clinical-functional evaluation was carried out according to ICRS, modified Cincinnati knee, Lysholm II and Tegner scales. The AOFAS score was used for the evaluation of the ankle. MRIs were taken before the operation as well as at 6, 12 and 24 months postoperatively. Among 10 second arthroscopic studies (four knees, six ankles), two biopsies were carried out after 2 years, from the medial femoral condyle and the patella, respectively. These specimens were evaluated by light microscopy, immunohistochemistry (type I and II collagen), SEM and TEM analysis. Follow-up averaged 25.6 months. At the latest follow-up, knee scores improved after surgery. AOFAS did not improve in the patient with the kissing lesion. MRIs showed hyaline-like cartilage at the site of implantation in all treated joints with exception of the kissing lesion; four knees showed recurrence of subchondral bone oedema 1 year after surgery. Histological analysis on the biopsies revealed good definition of the tidemark and presence of type II collagen. Clinical results and MRI findings support the efficacy of the MACI technique. Morphological findings are indicative for hyaline-like tissue formation in the implant site

Introduction and aim: Early symptomatic osteoarthritis (OA) of the knee poses a difficult challenge to orthopaedic surgeons, particularly in the presence of malalignment. Most surgical options are palliative. Our aim was to assess combined high tibial osteotomy (HTO) and matrix-induced autologous chondrocyte implantation (MACI) as a curative option. Methods Patients with localised medial compartment OA and varus malalignment were identified. Suitability for the above procedure was confirmed at arthroscopy and specimen taken for culture. HTO and MACI procedures were performed in one sitting by a single surgeon. Patients received three months rehabilitation and function was assessed preoperatively and at three-monthly intervals. Results Twelve patients were identified: nine male; average age 46 years (27–58). Mean varus deformity was 6 degrees. Two patients also had evidence of osteochondritis dissecans, and two early patello-femoral OA. Eight patients had had previous surgery to the knee. Eleven patients had a lateral closing wedge osteotomy; the medial opening wedge was performed in a case of leg shortening. Mean operation duration was 72 minutes (60–90). The graft was fixed with fibrin glue in all cases, and augmented with stitches or vicryl pins in five cases. Mean defect size was 6.2cm2 (2–12). There were three complications: one DVT, a haemarthrosis and a graft detachment. Average follow-up was 16 months. MRI scans at three months show oedematous tissue at the defect sites, contrasting with the fluid filled defects seen preoperatively. Scans at one-year show hyaline-like cartilage infill with similar signal characteristics to native hyaline cartilage. Six minute walk test and knee injury and osteoarthritis outcome score indicate significantly improved functional capacity at six months and one year. Conclusions Preliminary results suggest combined HTO and MACI is successful for young patients with early OA associated with malalignment

Introduction: ACI is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee. Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover (ACI-C) and matrix-induced autologous chondrocyte implantation (MACI) using a collagen bilayer seeded with chondrocytes. We report the minimum 2 year follow-up results of 192 patients randomised to autologous chondrocyte implantation (ACI) using porcine-derived collagen membrane as a cover (ACI-C) and matrix-induced autlogous chondrocyte implantation (MACI) for the treatment of osteochondral decfects of the knee. Methods: 192 patients (mean age 34.2) were randomised to have either ACI (86 patients) or MACI (106 patients). 1 year following surgery patients underwent check arthroscopy (with or without biopsy) to assess the graft. Functional assessment was performed yearly by using the modified Cincinatti knee score, the Bentley functional rating score and the visual analogue score. Results: 24 patients were excluded from the study as they underwent additional procedures (e.g. high tibial osteotomy). In the ACI group the modified Cincinatti score increased from 42.5 pre-operatively to 56.7, 54.1, and 60.4 at 1 year, 2 years and 3 years respectively. In the MACI group the Cincinatti scores increased from 46.0 pre-operatively to 59.9, 58.9, and 58.4. Arthroscopic assessment showed a good to excellent International Cartilage Repair Society score in 90.7% of ACI-C grafts and 68.4% of MACI grafts. Hyaline-like cartilage or hyaline-like with fibrocartilage was found in biopsies of 51.9% of ACI-C grafts and 25.9% of MACI grafts. Conclusions: ACI grafts are more likely to produce hyaline-like or mixed hyaline-like cartilage and fibro-cartilage with better ICRS grades than MACI grafts. However, this does not translate to better a clinical functional outcome. More importantly, ACI and MACI had similar results that were maintained at 3 years

Purpose: We report on minimum 2 year follow-up results of 71 patients randomised to autologous chon-drocyte implantation (ACI) using porcine-derived collagen membrane as a cover (ACI-C) and matrix-induced autologous chondrocyte implantation (MACI) for the treatment of osteochondral defects of the knee. Introduction: ACI is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee. Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover (ACI-C) and matrix-induced autolo-gous chondrocyte implantation (MACI) using a collagen bilayer seeded with chondrocytes. Results: 71 patients with a mean age of 33 years (15–48) were randomised to undergo either an ACI-C or a MACI. 37 had ACI-C and 34 MACI. The mean size of the defect was 5.0cm2. Mean duration of symptoms was 104.4 months (9–456). Mean follow-up was 33.5 months (24–45). Functional assessment using the modified Cincinnati knee score, the Bentley functional rating score and the visual analogue score was carried out. Assessment using the modified Cincinnati knee score showed a good to excellent result in 57.1% of patients followed up at 2 years, and 65.2% at 3 years in the ACI-C group; and 63.6% of patients at 2 years, and 64% at 3 years in the MACI group. Arthroscopic assessments showed a good to excellent International Cartilage Repair Society score in 81.8% of ACI-C grafts (22 patients) and 50% of MACI grafts (6 patients). Fisher’s exact test showed a p value of p=0.35 (not statistically significant). Hyaline-like cartilage or hyaline-like cartilage with fibrocartilage was found in biopsies of 56.3% of the ACI-C grafts (9 out of 16 patients) and 30% of the MACI grafts (3 out of 10 patients) after 2 years. Fisher’s exact test showed a p value of p=0.25 (not statistically significant). Conclusion: At this stage of the trial we conclude that the clinical, arthroscopic and histological outcomes are comparable for both ACI-C and MACI

Introduction and Aims: The aim of this study was to use biological, functional and radiographic evaluation to demonstrate that cultured autologous chondrocytes implanted using a type I/III collagen membrane leads to regeneration of hyaline-like articular cartilage in the knee. Method: Approximately 70,000 knee arthroscopies are performed every year in Australia; 60% involve chondral surface defects. Three regenerative autologous cell therapy techniques have been used in Australia to treat full thickness chondral lesions:. periostial-covered autologous chondrocyte implantation (PACI);. collagen-covered autologous chondrocyte implantation (CACI);. matrix-induced autologous chondrocyte implantation (MACI). The team at the University of Western Australia has concentrated on CACI and MACI techniques because of concerns over fibroblast formation and hypertrophy with PACI. Definitive evidence regarding the role of the membrane in enhancing chondrocyte-mediated cartilage regeneration is lacking. Results: The series consists of a total of 71 patients who had failed previous surgical treatment prior to definitive collagen-covered ACI (32 implantations in 31 patients) or MACI (43 implantations in 40 patients). Biological, functional and radiographic evaluations were conducted pre-operatively, and post-operatively in order to determine the success of integration of implanted chondrocytes and categorise the level of restoration in knee joint function. Post-operative MRI scans at three months show oedematous tissue at the defect sites, contrasting with the fluid-filled defects seen pre-operatively. MRI scans at one, two and three years (collagen-covered) and one year (MACI) show normal cartilage signal. Apopototic test of chondrocytes before implantation showed that viability of chondrocytes was over 85% where apopototic rate of chondrocytes was less than 2%. Six-minute walk test and KOOS results indicate improved functional capacity following collagen covered and MACI. Conclusion: Results from this clinical study indicate that the use of a type I/III collagen membrane in conjunction with ACI is a valid new approach for the treatment of chondral defects. Results from radiographic, functional and biological evaluations are encouraging. Ongoing follow-up will reveal the durability of reconstructions with CACI and MACI

Manufacturing of autologous chondrocytes presents unique challenges, and robust and reliable release assays are required to ensure product quality. We have discovered markers that correctly identify chondrocytes and predict potency. Novel qPCR assays developed with these markers for our Matrix-induced Autologous Chondrocyte Implant product (MACI. ®. implant) are described. An identity assay must distinguish chondrocytes from potentially contaminating cell types, such as synovial fibroblasts. Microarray analysis of more than 47,000 transcripts led to the discovery of two markers, currently aliased “Cart1” and “Synov1”, that have been characterized as the two most differentially expressed mRNAs between chondrocyte and synovial fibroblast cultures. A potency assay must identify cells that have the potential to form hyaline-like cartilage. We examined expression of critical components of hyaline cartilage during the chondrocyte manufacturing process and in re-differentiation assays. From these studies a gene, which we call “Hyaline1”, was identified as a candidate potency marker. Using an assay measuring the ratio of Cart1:Synov1, a large population study of chondrocyte and synovial fibroblast cultures examined the assay’s suitability for identity classification with our proposed Cart1:Synov1 acceptance boundary. In this study, assay specificity and sensitivity were both observed to be 100%. The utility of the assay was further demonstrated in mixing experiments, where a majority of chondrocytes (in mixtures with synovial fibroblasts) was required to pass the assay acceptance. These results indicate that the assay is useful for determination of both culture identity and culture homogeneity, and thus represents a significant improvement over previous identity assays. The potency assay is also a real-time quantitative RT-PCR assay that measures levels of Hyaline1. Characterization of MACI. ®. implants indicated that Hyaline1 is stable in long-term culture of chondrocytes but not fibroblasts on ACI-Maix membrane, and is overexpressed in chondrocytes compared fibroblasts that had been recovered from MACI. ®. implants and tested in various redifferentiation assays. These data suggest that Hyaline1 is predictive of the chondrogenic potential of cells used to manufacture MACI. ®. implants. After comparing may cell strains, a threshold level which indicates product potency was established. The identification of genetic markers that unambiguously identify cultured chondrocytes has been a long-standing challenge. Another challenge has been the ability to predict re-differentiation capacity of cultured chondrocytes. Modern techniques like whole genome microarray analysis have enabled us to develop novel identity and potency assays for quality control of MACI. ®. implants

The February 2023 Hip & Pelvis Roundup³⁶⁰ looks at: Total hip arthroplasty or internal fixation for hip fracture?; Significant deterioration in quality of life and increased frailty in patients waiting more than six months for total hip or knee arthroplasty: a cross-sectional multicentre study; Long-term cognitive trajectory after total joint arthroplasty; Costal cartilage grafting for a large osteochondral lesion of the femoral head; Foley catheters not a problem in the short term; Revision hips still a mortality burden?; How to position implants with a robotic arm; Uncemented stems in hip fracture?

Chondral damage to the knee is common and, if left untreated, can proceed to degenerative osteoarthritis. In symptomatic patients established methods of management rely on the formation of fibrocartilage which has poor resistance to shear forces. The formation of hyaline or hyaline-like cartilage may be induced by implanting autologous, cultured chondrocytes into the chondral or osteochondral defect.

Autologous chondrocyte implantation may be used for full-thickness chondral or osteochondral injuries which are painful and debilitating with the aim of replacing damaged cartilage with hyaline or hyaline-like cartilage, leading to improved function. The intermediate and long-term functional and clinical results are promising.

We provide a review of autologous chondrocyte implantation and describe our experience with the technique at our institution with a mean follow-up of 32 months (1 to 9 years).

The procedure is shown to offer statistically significant improvement with advantages over other methods of management of chondral defects.

Orthopaedic surgery is in an exciting transitional period as modern surgical interventions, implants and scientific developments are providing new therapeutic options. As advances in basic science and technology improve our understanding of the pathology and repair of musculoskeletal tissue, traditional operations may be replaced by newer, less invasive procedures which are more appropriately targeted at the underlying pathophysiology. However, evidence-based practice will remain a basic requirement of care. Orthopaedic surgeons can and should remain at the forefront of the development of novel therapeutic interventions and their application. Progression of the potential of bench research into an improved array of orthopaedic treatments in an effective yet safe manner will require the development of a subgroup of specialists with extended training in research to play an important role in bridging the gap between laboratory science and clinical practice. International regulations regarding the introduction of new biological treatments will place an additional burden on the mechanisms of this translational process, and orthopaedic surgeons who are trained in science, surgery and the regulatory environment will be essential. Training and supporting individuals with these skills requires special consideration and discussion by the orthopaedic community.

In this paper we review some traditional approaches to the integration of orthopaedic science and surgery, the therapeutic potential of current regenerative biomedical science for cartilage repair and ways in which we may develop surgeons with the skills required to translate scientific discovery into effective and properly assessed orthopaedic treatments.

Chronic patellofemoral instability can be a disabling condition. Management of patients with this condition has improved owing to our increased knowledge of the functional anatomy of the patellofemoral joint. Accurate assessment of the underlying pathology in the unstable joint enables the formulation of appropriate treatment. The surgical technique employed in patients for whom non-operative management has failed should address the diagnosed abnormality. We have reviewed the literature on the stabilising features of the patellofemoral joint, the recommended investigations and the appropriate forms of treatment.