We report the long-term survival and functional outcome of the Birmingham Hip Resurfacing (BHR) in patients aged < 50 years at operation, and explore the factors affecting survival. Between 1997 and 2006, a total of 447 BHRs were implanted in 393 patients (mean age 41.5 years (14.9 to 49.9)) by one designing surgeon. The mean follow-up was 10.1 years (5.2 to 14.7), with no loss to follow-up. In all, 16 hips (3.6%) in 15 patients were revised, giving an overall cumulative survival of 96.3% (95% confidence interval (CI) 93.7 to 98.3) at ten years and 94.1% (95% CI 84.9 to 97.3) at 14 years. Using aseptic revision as the endpoint, the survival for men with primary osteoarthritis (n = 195) was 100% (95% CI 100 to 100) at both ten years and 14 years, and in women with primary osteoarthritis (n = 109) it was 96.1% (95% CI 90.1 to 99.9) at ten years and 91.2% (95% CI 68.6 to 98.7) at 14 years. Female gender (p = 0.047) and decreasing femoral head size (p = 0.044) were significantly associated with an increased risk of revision. The median Oxford hip score (OHS, modified as a percentage with 100% indicating worst outcome) at last follow-up was 4.2% (46 of 48; interquartile range (IQR) 0% to 24%) and the median University of California, Los Angeles (UCLA) score was 6.0 (IQR 5 to 8). Men had significantly better OHS (p = 0.02) and UCLA scores (p = 0.01) than women. The BHR provides excellent survival and functional results in men into the second decade, with good results achieved in appropriately selected women.

Cite this article: Bone Joint J 2013;95-B:1172–7.

The systemic use of steroids and habitual alcohol intake are two major causative factors in the development of idiopathic osteonecrosis of the femoral head (ONFH). To examine any interaction between oral corticosteroid use and alcohol intake on the risk of ONFH, we conducted a hospital-based case-control study of 71 cases with ONFH (mean age 45 years (20 to 79)) and 227 matched controls (mean age 47 years (18 to 79)). Alcohol intake was positively associated with ONFH among all subjects: the adjusted odds ratio (OR) of subjects with ≥ 3032 drink-years was 3.93 (95% confidence interval (CI) 1.18 to 13.1) compared with never-drinkers. When stratified by steroid use, the OR of such drinkers was 11.1 (95% CI 1.30 to 95.5) among those who had never used steroids, but 1.10 (95% CI 0.21 to 4.79) among those who had. When we assessed any interaction based on a two-by-two table of alcohol and steroid use, the OR of those non-drinkers who did use steroids was markedly elevated (OR 31.5) compared with users of neither. However, no further increase in OR was noted for the effect of using both (OR 31.6). We detected neither a multiplicative nor an additive interaction (p for multiplicative interaction 0.19; synergy index 0.95), suggesting that the added effect of alcohol may be trivial compared with the overwhelming effect of steroids in the development of ONFH.

Cite this article: Bone Joint J 2013;95-B:320–5.

Back pain is a common symptom in children and adolescents. Here we review the important causes, of which defects and stress reactions of the pars interarticularis are the most common identifiable problems. More serious pathology, including malignancy and infection, needs to be excluded when there is associated systemic illness. Clinical evaluation and management may be difficult and always requires a thorough history and physical examination. Diagnostic imaging is obtained when symptoms are persistent or severe. Imaging is used to reassure the patient, relatives and carers, and to guide management.

Cite this article: Bone Joint J 2014;96-B:717–23.

The Oxford hip and knee scores (OHS and OKS) are validated patient-reported outcome measures used in patients undergoing total hip replacement (THR), hip resurfacing (HR), total knee replacement (TKR) and unicompartmental knee replacement (UKR). We analysed the absolute OHS and OKS and change in scores following THR, HR, TKR, and UKR performed at one specialist centre. All patients undergoing and completing at least one Oxford score were eligible for inclusion in the study which included 27 950 OHS and 19 750 OKS in 13 682 patients. Data were analysed using non-linear quantile regression. The median absolute Oxford scores for THR, HR, TKR and UKR were pre-operative 68.8% (15.0/48), 58.3% (20.0/48), 66.7% (16.0/48), 60.4% (19.0/48) respectively: and post-operative asymptote was 14.6% (41.0/48), 5.8% (45.2/48), 31.2% (33.0/48), 29.2% (34.0/48). The median asymptotic change from the pre-operative score for THR, HR, TKR and UKR were 47.9% (23.0/48), 47.9% (23.0/48), 33.3% (16.0/48) and 32.4% (15.5/48), respectively. The median time at which no further appreciable change in score was achieved post-operatively was 0.7 years for THR, 1.1 years for HR, 0.9 years for TKR and 1.1 years for UKR.

The curves produced from this analysis could be used to educate patients, and to audit the performance of a surgeon and an institution. The time to achieve a stable improvement in outcome varied between different types of joint replacement, which may have implications for the timing of post-operative review.

Cite this article: Bone Joint J 2014; 96-B:928–35.

We report the incidence of and risk factors for complications after scoliosis surgery in patients with Duchenne muscular dystrophy (DMD) and compare them with those of other neuromuscular conditions.

We identified 110 (64 males, 46 females) consecutive patients with a neuromuscular disorder who underwent correction of the scoliosis at a mean age of 14 years (7 to 19) and had a minimum two-year follow-up. We recorded demographic and peri-operative data, including complications and re-operations.

There were 60 patients with cerebral palsy (54.5%) and 26 with DMD (23.6%). The overall complication rate was 22% (24 patients), the most common of which were deep wound infection (9, 8.1%), gastrointestinal complications (5, 4.5%) and hepatotoxicity (4, 3.6%). The complication rate was higher in patients with DMD (10/26, 38.5%) than in those with other neuromuscular conditions (14/84, 16.7% (p = 0.019). All hepatotoxicity occurred in patients with DMD (p = 0.003), who also had an increased rate of deep wound infection (19% vs 5%) (p = 0.033). In the DMD group, no peri-operative factors were significantly associated with the rate of overall complications or deep wound infection. Increased intra-operative blood loss was associated with hepatotoxicity (p = 0.036).

In our series, correction of a neuromuscular scoliosis had an acceptable rate of complications: patients with DMD had an increased overall rate compared with those with other neuromuscular conditions. These included deep wound infection and hepatotoxicity. Hepatotoxicity was unique to DMD patients, and we recommend peri-operative vigilance after correction of a scoliosis in this group.

Cite this article: Bone Joint J 2014; 96-B:943–9.

We report our experience of revision total hip replacement (THR) using the Revitan curved modular titanium fluted revision stem in patients with a full spectrum of proximal femoral defects. A total of 112 patients (116 revisions) with a mean age of 73.4 years (39 to 90) were included in the study. The mean follow-up was 7.5 years (5.3 to 9.1). A total of 12 patients (12 hips) died but their data were included in the survival analysis, and four patients (4 hips) were lost to follow-up. The clinical outcome, proximal bone regeneration and subsidence were assessed for 101 hips.

The mean Harris Hip Score was 88.2 (45.8 to 100) after five years and there was an increase of the mean Barnett and Nordin-Score, a measure of the proximal bone regeneration, of 20.8 (-3.1 to 52.7). Five stems had to be revised (4.3%), three (2.9%) showed subsidence, five (4.3%) a dislocation and two of 85 aseptic revisions (2.3%) a periprosthetic infection.

At the latest follow-up, the survival with revision of the stem as the endpoint was 95.7% (95% confidence interval 91.9% to 99.4%) and with aseptic loosening as the endpoint, was 100%. Peri-prosthetic fractures were not observed.

We report excellent results with respect to subsidence, the risk of fracture, and loosening after femoral revision using a modular curved revision stem with distal cone-in-cone fixation. A successful outcome depends on careful pre-operative planning and the use of a transfemoral approach when the anatomy is distorted or a fracture is imminent, or residual cement or a partially-secured existing stem cannot be removed. The shortest appropriate stem should, in our opinion, be used and secured with > 3 cm fixation at the femoral isthmus, and distal interlocking screws should be used for additional stability when this goal cannot be realised.

Cite this article: Bone Joint J 2014;96-B:889–95.

Revision total hip arthroplasty (THA) is challenging when there is severe loss of bone in the proximal femur. The purpose of this study was to evaluate the clinical and radiographic outcomes of revision THA in patients with severe proximal femoral bone loss treated with a fluted, tapered, modular femoral component. Between January 1998 and December 2004, 92 revision THAs were performed in 92 patients using a single fluted, tapered, modular femoral stem design. Pre-operative diagnoses included aseptic loosening, infection and peri-prosthetic fracture. Bone loss was categorised pre-operatively as Paprosky types III-IV, or Vancouver B3 in patients with a peri-prosthetic fracture. The mean clinical follow-up was 6.4 years (2 to 12). A total of 47 patients had peri-operative complications, 27 of whom required further surgery. However, most of these further operations involved retention of a well-fixed femoral stem, and 88/92 femoral components (97%) remained in situ. Of the four components requiring revision, three were revised for infection and were well fixed at the time of revision; only one (1%) was revised for aseptic loosening. The most common complications were post-operative instability (17 hips, 19%) and intra-operative femoral fracture during insertion of the stem (11 hips, 12%). Diaphyseal stress shielding was noted in 20 hips (22%). There were no fractures of the femoral component. At the final follow-up 78% of patients had minimal or no pain.

Revision THA in patients with extensive proximal femoral bone loss using the Link MP fluted, tapered, modular stem led to a high rate of osseointegration of the stem at mid-term follow-up.

Cite this article: Bone Joint J 2015; 97-B:312–17.

The aim of this study was to perform a cost–utility analysis of total hip (THR) and knee replacement (TKR). Arthritis is a disabling condition that leads to long-term deterioration in quality of life. Total joint replacement, despite being one of the greatest advances in medicine of the modern era, has recently come under scrutiny. The National Health Service (NHS) has competing demands, and resource allocation is challenging in times of economic restraint. Patients who underwent THR (n = 348) or TKR (n = 323) between January and July 2010 in one Scottish region were entered into a prospective arthroplasty database. A health–utility score was derived from the EuroQol (EQ-5D) score pre-operatively and at one year, and was combined with individual life expectancy to derive the quality-adjusted life years (QALYs) gained. Two-way analysis of variance was used to compare QALYs gained between procedures, while controlling for baseline differences. The number of QALYs gained was higher after THR than after TKR (6.5 vs 4.0 years, p < 0.001). The cost per QALY for THR was £1372 compared with £2101 for TKR. The predictors of an increase in QALYs gained were poorer health before surgery (p < 0.001) and younger age (p < 0.001). General health (EQ-5D VAS) showed greater improvement after THR than after TKR (p < 0.001). This study provides up-to-date cost-effectiveness data for total joint replacement. THR and TKR are extremely effective both clinically and in terms of cost effectiveness, with costs that compare favourably to those of other medical interventions.

Cite this article: Bone Joint J 2013;95-B:115–21.

The aim of this study was to assess the role of synovial C-reactive protein (CRP) in the diagnosis of chronic periprosthetic hip infection. We prospectively collected synovial fluid from 89 patients undergoing revision hip arthroplasty and measured synovial CRP, serum CRP, erythrocyte sedimentation rate (ESR), synovial white blood cell (WBC) count and synovial percentages of polymorphonuclear neutrophils (PMN). Patients were classified as septic or aseptic by means of clinical, microbiological, serum and synovial fluid findings. The high viscosity of the synovial fluid precluded the analyses in nine patients permitting the results in 80 patients to be studied. There was a significant difference in synovial CRP levels between the septic (n = 21) and the aseptic (n = 59) cohort. According to the receiver operating characteristic curve, a synovial CRP threshold of 2.5 mg/l had a sensitivity of 95.5% and specificity of 93.3%. The area under the curve was 0.96. Compared with serum CRP and ESR, synovial CRP showed a high diagnostic value. According to these preliminary results, synovial CRP may be a useful parameter in diagnosing chronic periprosthetic hip infection.

Cite this article: Bone Joint J 2015; 97-B:173–6.

The February 2015 Shoulder & Elbow Roundup³⁶⁰ looks at: Proximal Humerus fractures a comprehensive review, Predicting complications in shoulder ORIF, The Coronoid Revisited, Remplissage and bankart repair for Hill-Sach’s lesions, Diabetes and elbow arthroplasty, Salvage surgery for failed bankart repair, Sternoclavicular Joint Reconstruction, Steroids effective in the short-term for tennis elbow

Ceramic-on-metal (CoM) is a relatively new bearing combination for total hip arthroplasty (THA) with few reported outcomes. A total of 287 CoM THAs were carried out in 271 patients (mean age 55.6 years (20 to 77), 150 THAs in female patients, 137 in male) under the care of a single surgeon between October 2007 and October 2009. With the issues surrounding metal-on-metal bearings the decision was taken to review these patients between March and November 2011, at a mean follow-up of 34 months (23 to 45) and to record pain, outcome scores, radiological analysis and blood ion levels. The mean Oxford Hip Score was 19.2 (12 to 53), 254 patients with 268 hips (95%) had mild/very mild/no pain, the mean angle of inclination of the acetabular component was 44.8^o (28^o to 63^o), 82 stems (29%) had evidence of radiolucent lines of > 1 mm in at least one Gruen zone and the median levels of cobalt and chromium ions in the blood were 0.83 μg/L (0.24 μg/L to 27.56 μg/L) and 0.78 μg/L (0.21 μg/L to 8.84 μg/L), respectively. The five-year survival rate is 96.9% (95% confidence interval 94.7% to 99%).

Due to the presence of radiolucent lines and the higher than expected levels of metal ions in the blood, we would not recommend the use of CoM THA without further long-term follow-up. We plan to monitor all these patients regularly.

Cite this article: Bone Joint J 2015;97-B:300–5.

Femoral stem version has a major influence on impingement and early post-operative stability after total hip arthroplasty (THA).

The main objective of this study was to evaluate the validity of a novel radiological method for measuring stem version. Anteroposterior (AP) radiographs and three-dimensional CT scans were obtained for 115 patients (female/male 63/72, mean age 62.5 years (50 to 75)) who had undergone minimally invasive, cementless THA. Stem version was calculated from the AP hip radiograph by rotation-based change in the projected prosthetic neck–shaft (NSA*) angle using the mathematical formula ST = arcos [tan (NSA*) / tan (135)]. We used two independent observers who repeated the analysis after a six-week interval. Radiological measurements were compared with 3D-CT measurements by an independent, blinded external institute.

We found a mean difference of 1.2° (sd 6.2) between radiological and 3D-CT measurements of stem version. The correlation between the mean radiological and 3D-CT stem torsion was r = 0.88 (p < 0.001). The intra- (intraclass correlation coefficient ≥ 0.94) and inter-observer agreement (mean concordance correlation coefficient = 0.87) for the radiological measurements were excellent.

We found that femoral tilt was associated with the mean radiological measurement error (r = 0.22, p = 0.02).

The projected neck–shaft angle is a reliable method for measuring stem version on AP radiographs of the hip after a THA. However, a highly standardised radiological technique is required for its precise measurement.

Cite this article: Bone Joint J 2015; 97-B:306–11.

Flexor digitorum longus transfer and medial displacement calcaneal osteotomy is a well-recognised form of treatment for stage II posterior tibial tendon dysfunction. Although excellent short- and medium-term results have been reported, the long-term outcome is unknown. We reviewed the clinical outcome of 31 patients with a symptomatic flexible flat-foot deformity who underwent this procedure between 1994 and 1996. There were 21 women and ten men with a mean age of 54.3 years (42 to 70). The mean follow-up was 15.2 years (11.4 to 16.5). All scores improved significantly (p < 0.001). The mean American Orthopedic Foot and Ankle Society (AOFAS) score improved from 48.4 pre-operatively to 90.3 (54 to 100) at the final follow-up. The mean pain component improved from 12.3 to 35.2 (20 to 40). The mean function score improved from 35.2 to 45.6 (30 to 50). The mean visual analogue score for pain improved from 7.3 to 1.3 (0 to 6). The mean Short Form-36 physical component score was 40.6 (sd 8.9), and this showed a significant correlation with the mean AOFAS score (r = 0.68, p = 0.005). A total of 27 patients (87%) were pain free and functioning well at the final follow-up. We believe that flexor digitorum longus transfer and calcaneal osteotomy provides long-term pain relief and satisfactory function in the treatment of stage II posterior tibial tendon dysfunction.

Cite this article: Bone Joint J 2015;97-B:346–52.

We report the results of Vulpius transverse gastrocsoleus recession for equinus gait in 26 children with cerebral palsy (CP), using the Gait Profile Score (GPS), Gait Variable Scores (GVS) and movement analysis profile. All children had an equinus deformity on physical examination and equinus gait on three-dimensional gait analysis prior to surgery. The pre-operative and post-operative GPS and GVS were statistically analysed. There were 20 boys and 6 girls in the study cohort with a mean age at surgery of 9.2 years (5.1 to 17.7) and 11.5 years (7.3 to 20.8) at follow-up. Of the 26 children, 14 had spastic diplegia and 12 spastic hemiplegia. Gait function improved for the cohort, confirmed by a decrease in mean GPS from 13.4° pre-operatively to 9.0° final review (p < 0.001). The change was 2.8 times the minimal clinically important difference (MCID). Thus the improvements in gait were both clinically and statistically significant. The transverse gastrocsoleus recession described by Vulpius is an effective procedure for equinus gait in selected children with CP, when there is a fixed contracture of the gastrocnemius and soleus muscles.

Cite this article: Bone Joint J 2015;97-B:564–71.

Between 1999 and 2001, 90 patients underwent total hip replacement using the same uncemented acetabular and femoral components with a 28 mm metallic femoral head but with prospective randomisation of the acetabular liner to either Durasul highly cross-linked polyethylene or nitrogen-sterilised Sulene polyethylene. We assessed 83 patients at a minimum follow-up of ten years. Linear penetration of the femoral head was estimated at six weeks, six and 12 months and annually thereafter, using the Dorr method, given the non-spherical shape of the acetabular component.

There was no loosening of any component; only one hip in the Sulene group showed proximal femoral osteolysis. The mean penetration of the femoral head at six weeks was 0.08 mm (0.02 to 0.15) for the Durasul group and 0.16 mm (0.05 to 0.28) for the Sulene group (p = 0.001). The mean yearly linear penetration was 64.8% lower for the Durasul group at 0.05 mm/year (sd 0.035) for the Sulene group and 0.02 mm/year (sd 0.016) for the Durasul (p < 0.001). Mean linear femoral head penetration at ten years was 61% less in the Durasul than Sulene group. Highly cross-linked polyethylene gives excellent results at ten years.

Cite this article: Bone Joint J 2013;95-B:326–32.

We studied the bone mineral density (BMD) and the bone mineral content (BMC) of the proximal tibia in patients with a well-functioning uncemented Oxford medial compartment arthroplasty using the Lunar iDXA bone densitometer. Our hypothesis was that there would be decreased BMD and BMC adjacent to the tibial base plate and increased BMD and BMC at the tip of the keel.

There were 79 consecutive patients (33 men, 46 women) with a mean age of 65 years (44 to 84) with a minimum two-year follow-up (mean 2.6 years (2.0 to 5.0)) after unilateral arthroplasty, who were scanned using a validated standard protocol where seven regions of interest (ROI) were examined and compared with the contralateral normal knee. All had well-functioning knees with a mean Oxford knee score of 43 (14 to 48) and mean Knee Society function score of 90 (20 to 100), showing a correlation with the increasing scores and higher BMC and BMD values in ROI 2 in the non-implanted knee relative to the implanted knee (p = 0.013 and p = 0.015, respectively).

The absolute and percentage changes in BMD and BMC were decreased in all ROIs in the implanted knee compared with the non-implanted knee, but this did not reach statistical significance. Bone loss was markedly less than reported losses with total knee replacement.

There was no significant association with side, although there was a tendency for the BMC to decrease with age in men. The BMC was less in the implanted side relative to the non-implanted side in men compared with women in ROI 2 (p = 0.027), ROI 3 (p = 0.049) and ROI 4 (p = 0.029).

The uncemented Oxford medial compartment arthroplasty appears to allow relative preservation of the BMC and BMD of the proximal tibia, suggesting that the implant acts more physiologically than total knee replacement. Peri-prosthetic bone loss is an important factor in assessing long-term implant stability and survival, and the results of this study are encouraging for the long-term outcome of this arthroplasty.

Cite this article: Bone Joint J 2013;95-B:1480–3.

We explored the outcome of staged bilateral total knee replacement (TKR) for symmetrical degenerative joint disease and deformity in terms of patient expectations, functional outcome and satisfaction. From 2009 to 2011, 70 consecutive patients (41 female) with a mean age of 71.7 years (43 to 89) underwent 140 staged bilateral TKRs at our institution, with a mean time between operations of 7.8 months (2 to 25). Patients were assessed pre-operatively and at six and 12 months post-operatively using the Short Form-12, Oxford knee score (OKS), expectation questionnaire and satisfaction score. The pre-operative OKS was significantly worse before the first TKR (TKR1), but displayed significantly greater improvement than that observed after the second TKR (TKR2). Expectation level increased from TKR1 to TKR2 in 17% and decreased in 20%. Expectations of pain relief and stair-climbing were less before TKR2; in contrast, expectations of sporting and social activities were greater. Decreased expectations of TKR2 were significantly associated with younger age and high expectations before TKR1. Patient satisfaction was high for both TKR1 (93%) and TKR2 (87%) but did not correlate significantly within individuals. We concluded that satisfaction with one TKR does not necessarily translate to satisfaction following the second.

Cite this article: Bone Joint J 2014;96-B:752–8.

The aims of this study were to evaluate the incidence of local argyria in patients with silver-coated megaprostheses and to identify a possible association between argyria and elevated levels of silver both locally and in the blood. Between 2004 and 2011, 32 megaprostheses with silver coatings were implanted in 20 female and 12 male patients following revision arthroplasty for infection or resection of a malignant tumour, and the levels of silver locally in drains and seromas and in the blood were determined. The mean age of the patients was 46 years (10 to 81); one patient died in the immediate post-operative period and was excluded.

Seven patients (23%) developed local argyria after a median of 25.7 months (interquartile range 2 to 44.5). Patients with and without local argyria had comparable levels of silver in the blood and aspiration fluids. The length of the implant did not influence the development of local argyria. Patients with clinical evidence of local argyria had no neurological symptoms and no evidence of renal or hepatic failure. Thus, we conclude that the short-term surveillance of blood silver levels in these patients is not required.

Cite this article: Bone Joint J 2013;95-B:988–92.

In this in vitro study of the hip joint we examined which soft tissues act as primary and secondary passive rotational restraints when the hip joint is functionally loaded. A total of nine cadaveric left hips were mounted in a testing rig that allowed the application of forces, torques and rotations in all six degrees of freedom. The hip was rotated throughout a complete range of movement (ROM) and the contributions of the iliofemoral (medial and lateral arms), pubofemoral and ischiofemoral ligaments and the ligamentum teres to rotational restraint was determined by resecting a ligament and measuring the reduced torque required to achieve the same angular position as before resection. The contribution from the acetabular labrum was also measured. Each of the capsular ligaments acted as the primary hip rotation restraint somewhere within the complete ROM, and the ligamentum teres acted as a secondary restraint in high flexion, adduction and external rotation. The iliofemoral lateral arm and the ischiofemoral ligaments were primary restraints in two-thirds of the positions tested. Appreciation of the importance of these structures in preventing excessive hip rotation and subsequent impingement/instability may be relevant for surgeons undertaking both hip joint preserving surgery and hip arthroplasty.

Cite this article: Bone Joint J 2015; 97-B:484–91.

Perthes’ disease is an osteonecrosis of the juvenile hip, the aetiology of which is unknown. A number of comorbid associations have been suggested that may offer insights into aetiology, yet the strength and validity of these are unclear. This study explored such associations through a case control study using the United Kingdom General Practice Research database. Associations investigated were those previously suggested within the literature. A total of 619 cases of Perthes’ disease were included, as were 2544 controls. The risk of Perthes’ disease was significantly increased with the presence of congenital anomalies of the genitourinary and inguinal region, such as hypospadias (odds ratio (OR) 4.04 (95% confidence interval (CI) 1.41 to 11.58)), undescended testis (OR 1.83 (95% CI 1.12 to 3.00)) and inguinal herniae (OR 1.79 (95% CI 1.02 to 3.16)). Attention deficit hyperactivity disorder was not associated with Perthes’ disease (OR 1.01 (95% CI 0.48 to 2.12)), although a generalised behavioural disorder was (OR 1.55 (95% CI 1.10 to 2.17)). Asthma significantly increased the risk of Perthes’ disease (OR 1.44 (95% CI 1.17 to 1.76)), which remained after adjusting for oral/parenteral steroid use.

Perthes’ disease has a significant association with congenital genitourinary and inguinal anomalies, suggesting that intra-uterine factors may be critical to causation. Other comorbid associations may offer insight to support or refute theories of pathogenesis.