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Aims Varus-valgus constrained (VVC) devices are typically used in revision settings, often with stems to mitigate the risk of aseptic loosening. However, in at least one system, the VVC insert is compatible with the primary posterior-stabilized (PS) femoral component, which may be an option in complex primary situations. We sought to determine the implant survivorship, radiological and clinical outcomes, and complications when this VVC insert was coupled with a PS femur without stems in complex primary total knee arthroplasties (TKAs). Methods Through our institution’s total joint registry, we identified 113 primary TKAs (103 patients) performed between 2007 and 2017 in which a VVC insert was coupled with a standard cemented PS femur without stems. Mean age was 68 years (SD 10), mean BMI was 32 kg/m2 (SD 7), and 59 patients (50%) were male. Mean follow-up was four years (2 to 10). Results The five-year survivorship free from aseptic loosening was 100%. The five-year survivorship free from any revision was 99%, with the only revision performed for infection. The five-year survivorship free from reoperation was 93%. The most common reoperation was treatment for infection (n = 4; 4%), followed by manipulation under anaesthesia (MUA; n = 2; 2%). Survivorship free from any complication at five years was 90%, with superficial wound infection as the most frequent (n = 4; 4%). At most recent follow-up, two TKAs had non-progressive radiolucent lines about both the tibial and femoral components. Knee Society Scores improved from 53 preoperatively to 88 at latest follow-up (p < 0.001). Conclusion For complex primary TKA in occasional situations, coupling a VVC insert with a standard PS femur without stems proved reliable and durable at five years. Longer-term follow-up is required before recommending this technique more broadly. Cite this article: Bone Jt Open 2021;2(11):921–925.

Background Two-stage exchange arthroplasty with a high-dose antibiotic-loaded bone cement (ALBC) spacer and intravenous or oral antibiotics is the most common method of managing a periprosthetic joint infection (PJI) after a total knee arthroplasty (TKA). However, little is known about the contemporary incidence, the risk factors, and the outcomes of acute kidney injuries (AKIs) in this cohort. Methods We identified 424 patients who had been treated with 455 ALBC spacers after resection of a PJI following a primary TKA from 2000 to 2017. The mean age at resection was 67 years, the mean body mass index (BMI) was 33 kg/m2, 47% of the patients were women, and 15% had preexisting chronic kidney disease (CKD). The spacers (87% nonarticulating) contained a mean of 8 g of vancomycin and 9 g of an aminoglycoside per construct (in situ for a mean of 11 weeks). Eighty-six spacers also had amphotericin B (mean, 412 mg). All of the patients were concomitantly treated with systemic antibiotics for a mean of 6 weeks. An AKI was defined as a creatinine level of ≥1.5 times the baseline or an increase of ≥0.3 mg/dL within any 48-hour period. The mean follow-up was 6 years (range, 2 to 17 years). Results Fifty-four AKIs occurred in 52 (14%) of the 359 patients without preexisting CKD versus 32 AKIs in 29 (45%) of the 65 patients with CKD (odds ratio [OR], 5; p = 0.0001); none required acute dialysis. Overall, when the vancomycin concentration or aminoglycoside concentration was >3.6 g/batch of cement, the risk of AKI increased (OR, 1.9 and 1.8, respectively; p = 0.02 for both). Hypertension (β = 0.17; p = 0.002), perioperative hypovolemia (β = 0.28; p = 0.0001), and acute atrial fibrillation (β = 0.13; p = 0.009) were independent predictors for AKI in patients without preexisting CKD. At the last follow-up, 8 patients who had sustained an AKI had progressed to CKD, 4 of whom received dialysis. Conclusions In our study, the largest series to date that we are aware of regarding this issue, AKI occurred in 14% of patients with normal renal function at baseline, and 2% developed CKD after undergoing a 2-stage exchange arthroplasty for a PJI after TKA. However, the risk of AKI was fivefold greater in those with preexisting CKD. The causes of acute renal blood flow impairment were independent predictors for AKI. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Arthrofibrosis is an abnormal histopathologic response, is debilitating for patients, and poses a substantial unsolved clinical challenge. This study characterizes molecular biomarkers and regulatory pathways associated with arthrofibrosis by comparing fibrotic and non-fibrotic human knee tissue. The fibrotic group encompasses 4 patients undergoing a revision total knee arthroplasty (TKA) for arthrofibrosis (RTKA-A) while the non-fibrotic group includes 4 patients undergoing primary TKA for osteoarthritis (PTKA) and 4 patients undergoing revision TKA for non-arthrofibrotic and non-infectious etiologies (RTKA-NA). RNA-sequencing of posterior capsule specimens revealed differences in gene expression between each patient group by hierarchical clustering, principal component analysis, and correlation analyses. Multiple differentially expressed genes (DEGs) were defined in RTKA-A versus PTKA patients (i.e., 2059 up-regulated and 1795 down-regulated genes) and RTKA-A versus RTKA-NA patients (i.e., 3255 up-regulated and 3683 down-regulated genes). Our findings define molecular and pathological markers of arthrofibrosis, as well as novel potential targets for risk profiling, early diagnosis and pharmacological treatment of patients.

Aims Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis. Cite this article: Bone Joint Res 2020;9(6):302–310.

BACKGROUND Hemochromatosis can result in metabolic bone pathology (due to excessive iron absorption) and degenerative joint disease, leading to total joint arthroplasties. The aim of this study is to analyze the survivorship, complications, radiographic results, and clinical outcomes of patients with hemochromatosis who received either a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). METHODS We identified 34 lower extremity arthroplasties in 29 patients with hemochromatosis performed between 2000 and 2016. There were 17 primary THAs in 15 patients and 17 primary TKAs in 14 patients. Mean age at arthroplasty was 63 years with 76% being male. The mean body mass index was 28 kg/m2. Mean follow-up was 5 years. RESULTS The survivorship free from any revision for THAs was 94% at 10 years. One patient was revised for aseptic loosening of the femoral stem at 6 months. In THA patients, no infections, no other complications, and no radiographic evidence of aseptic loosening were identified. Harris Hip Scores improved from a mean of 55 preoperatively to 94 postoperatively (P < .001). The survivorship free from any revision for TKAs was 100% at 10 years. Two patients (12%) developed acquired idiopathic stiffness postoperatively; no infections were identified. There was no radiographic evidence of aseptic loosening in any TKA. Knee Society Scores improved from a mean of 61 preoperatively to 94 postoperatively (P < .001). CONCLUSION This study found excellent survivorship, significant improvements in clinical outcomes, and a very low complication profile for both THA and TKA in patients with hemochromatosis.

AimsThe prevalence of ipsilateral total hip arthroplasty (THA) and total knee arthroplasty (TKA) is rising in concert with life expectancy, putting more patients at risk for interprosthetic femur fractures (IPFFs). Our study aimed to assess treatment methodologies, implant survivorship, and IPFF clinical outcomes.MethodsA total of 76 patients treated for an IPFF from February 1985 to April 2018 were reviewed. Prior to fracture, at the hip/knee sites respectively, 46 femora had primary/primary, 21 had revision/primary, three had primary/revision, and six had revision/revision components. Mean age and BMI were 74 years (33 to 99) and 30 kg/m2(21 to 46), respectively. Mean follow-up after fracture treatment was seven years (2 to 24).ResultsOverall, 59 fractures were classified as Vancouver C (Unified Classification System (UCS) D), 17 were Vancouver B (UCS B). In total, 57 patients (75%) were treated with open reduction and internal fixation (ORIF); three developed nonunion, three developed periprosthetic joint infection, and two developed aseptic loosening. In all, 18 patients (24%) underwent revision arthroplasty including 13 revision THAs, four distal femoral arthroplasties (DFAs), and one revision TKA: of these, one patient developed aseptic loosening and two developed nonunion. Survivorship free from any reoperation was 82% (95% confidence interval (CI) 66.9% to 90.6%) and 77% (95% CI 49.4% to 90.7%) in the ORIF and revision groups at two years, respectively. ORIF patients who went on to union tended to have stemmed knee components and greater mean interprosthetic distance (IPD = 189 mm (SD 73.6) vs 163 mm (SD 36.7); p = 0.546) than nonunited fractures. Patients who went on to nonunion in the revision arthroplasty group had higher medullary diameter: cortical width ratio (2.5 (SD 1.7) vs 1.3 (SD 0.3); p = 0.008) and lower IPD (36 mm (SD 30.6) vs 214 mm (SD 32.1); p < 0.001). At latest follow-up, 95% of patients (n = 72) were ambulatory.ConclusionInterprosthetic femur fractures are technically and biologically challenging cases. Individualized approaches to internal fixation versus revision arthroplasty led to an 81% (95% CI 68.3% to 88.6%) survivorship free from reoperation at two years with 95% of patients ambulatory. Continued improvements in management are warranted. Cite this article: Bone Joint J 2021;103-B(7 Supple B):122–128.

AimsThere is little literature about total knee arthroplasty (TKA) after distal femoral osteotomy (DFO). Consequently, the purpose of this study was to analyze the outcomes of TKA after DFO, with particular emphasis on: survivorship free from aseptic loosening, revision, or any re-operation; complications; radiological results; and clinical outcome.Patients and MethodsWe retrospectively reviewed 29 patients (17 women, 12 men) from our total joint registry who had undergone 31 cemented TKAs after a DFO between 2000 and 2012. Their mean age at TKA was 51 years (22 to 76) and their mean body mass index 32 kg/m2(20 to 45). The mean time between DFO and TKA was ten years (2 to 20). The mean follow-up from TKA was ten years (2 to 16). The prostheses were posterior-stabilized in 77%, varus-valgus constraint (VVC) in 13%, and cruciate-retaining in 10%. While no patient had metaphyseal fixation (e.g. cones or sleeves), 16% needed a femoral stem.ResultsThe ten-year survivorship was 95% with aseptic loosening as the endpoint, 88% with revision for any reason as the endpoint, and 81% with re-operation for any reason as the endpoint. Three TKAs were revised for instability (n = 2) and aseptic tibial loosening (n = 1). No femoral component was revised for aseptic loosening. Patients under the age of 50 years were at greater risk of revision for any reason (hazard ratio 7; p = 0.03). There were two additional re-operations (6%) and four complications (13%), including three manipulations under anaesthetic (MUA; 10%). The Knee Society scores improved from a mean of 50 preoperatively (32 to 68) to a mean of 93 postoperatively (76 to 100; p < 0.001).ConclusionA cemented posterior-stabilized TKA has an 88% ten-year survivorship with revision for any reason as the endpoint. No femoral component was revised for aseptic loosening. Patients under the age of 50 years have a greater risk of revision. The clinical outcome was significantly improved but balancing the knee was challenging in 13% of TKAs requiring VVC. Overall, 10% of TKAs needed an MUA, and 6% of TKAs were revised for instability. Cite this article: Bone Joint J 2019;101-B:660–666.

Experimental analyses of post-traumatic knee arthrofibrosis utilize a rabbit model as a gold standard. However, a rodent model of arthrofibrosis offers many advantages including reduced cost and comparison with other models of organ fibrosis. This study aimed to characterize the biomechanical, histological, and molecular features of a novel post-traumatic model of arthrofibrosis in rats. 48 rats were divided into two equal groups. An immobilization procedure was performed on the right hind limbs of experimental rats. One group was immobilized for 4 weeks and the other for 8 weeks. Both groups were remobilized for 4 weeks. Limbs were studied biomechanically via assessment of torque versus degree of extension, histologically via whole knee specimen, and molecularly via gene expression of posterior capsular tissues. Significant differences were observed between experimental and control limbs at 4 N-cm of torque in the 4-week (knee extension: 115° ± 8° vs. 169° ± 17°, respectively; p=0.007) and 8-week immobilization groups (knee extension: 99° ± 12° vs. 174° ± 9°, respectively; p=0.008). Histologically, in each group experimental limbs demonstrated increased posterior capsular thickness and total area of tissue when compared to control limbs (p

Arthrofibrosis is characterized by excessive extracellular matrix deposition in patients with total knee arthroplasties (TKAs) and causes undesirable joint stiffness. The pathogenesis of arthrofibrosis remains elusive and currently there are no diagnostic biomarkers for the pathological formation of this connective tissue. Fibrotic soft tissues are known to have elevated levels of plasminogen activator inhibitor-1 (PAI-1) (encoded by SERPINE1), a secreted serine protease inhibitor that moderates extracellular matrix remodeling and tissue homeostasis. The 4G/5G insertion/deletion (rs1799889) is a well-known SERPINE1 polymorphism that directly modulates PAI-1 levels. Homozygous 4G/4G allele carriers typically have higher PAI-1 levels and may predispose patients to soft tissue fibrosis (e.g., liver, lung, and kidney). Here, we examined the genetic contribution of the SERPINE1 rs1799889 polymorphism to musculoskeletal fibrosis in arthrofibrotic (n = 100) and non-arthrofibrotic (n = 100) patients using Sanger Sequencing. Statistical analyses revealed that the allele frequencies of the SERPINE1 rs1799889 polymorphism are similar in arthrofibrotic and non-arthrofibrotic patient cohorts. Because the fibrosis related SERPINE1 rs1799889 polymorphism is independent of arthrofibrosis susceptibility in TKA patients, the possibility arises that fibrosis of joint connective tissues may involve unique genetic determinants distinct from those linked to classical soft tissue fibrosis.

(1) Background: Arthrofibrosis is a common cause of patient debility and dissatisfaction after total knee arthroplasty (TKA). The diversity of molecular pathways involved in arthrofibrosis disease progression suggest that effective treatments for arthrofibrosis may require a multimodal approach to counter the complex cellular mechanisms that direct disease pathogenesis. In this study, we leveraged RNA-seq data to define genes that are suppressed in arthrofibrosis patients and identified adiponectin (ADIPOQ) as a potential candidate. We hypothesized that signaling pathways activated by ADIPOQ and the cognate receptors ADIPOR1 and ADIPOR2 may prevent fibrosis-related events that contribute to arthrofibrosis. (2) Methods: Therefore, ADIPOR1 and ADIPOR2 were analyzed in a TGF&beta, 1 inducible cell model for human myofibroblastogenesis by both loss- and gain-of-function experiments. (3) Results: Treatment with AdipoRon, which is a small molecule agonist of ADIPOR1 and ADIPOR2, decreased expression of collagens (COL1A1, COL3A1, and COL6A1) and the myofibroblast marker smooth muscle &alpha, actin (ACTA2) at both mRNA and protein levels in basal and TGF&beta, 1-induced cells. (4) Conclusions: Thus, ADIPOR1 and ADIPOR2 represent potential drug targets that may attenuate the pathogenesis of arthrofibrosis by suppressing TGF&beta, dependent induction of myofibroblasts. These findings also suggest that AdipoRon therapy may reduce the development of arthrofibrosis by mediating anti-fibrotic effects in joint capsular tissues.

AimsVarus-valgus constrained (VVC) implants are often used during revision total knee arthroplasty (TKA) to gain coronal plane stability. However, the increased mechanical torque applied to the bone-cement interface theoretically increases the risk of aseptic loosening. We assessed mid-term survivorship, complications, and clinical outcomes of a fixed-bearing VVC device in revision TKAs.MethodsA total of 416 consecutive revision TKAs (398 patients) were performed at our institution using a single fixed-bearing VVC TKA from 2007 to 2015. Mean age was 64 years (33 to 88) with 50% male (199). Index revision TKA diagnoses were: instability (n = 122, 29%), aseptic loosening (n = 105, 25%), and prosthetic joint infection (PJI) (n = 97, 23%). All devices were cemented on the epiphyseal surfaces. Femoral stems were used in 97% (n = 402) of cases, tibial stems in 95% (n = 394) of cases; all were cemented. In total, 93% (n = 389) of cases required a stemmed femoral and tibial component. Femoral cones were used in 29%, and tibial cones in 40%. Survivorship was assessed via competing risk analysis; clinical outcomes were determined using Knee Society Scores (KSSs) and range of movement (ROM). Mean follow-up was four years (2 to 10).ResultsThe five-year cumulative incidence of subsequent revision for aseptic loosening and instability were 2% (95% confidence interval (CI) 0.2 to 3, number at risk = 154) and 4% (95% CI 2 to 6, number at risk = 153), respectively. The five-year cumulative incidence of any subsequent revision was 14% (95% CI 10 to 18, number at risk = 150). Reasons for subsequent revision included PJI (n = 23, of whom 12 had previous PJI), instability (n = 13), and aseptic loosening (n = 11). The use of this implant without stems was found to be a significant risk factor for subsequent revision (hazard ratio (HR) 7.58 (95% CI 3.98 to 16.03); p = 0.007). KSS improved from 46 preoperatively to 81 at latest follow-up (p < 0.001). ROM improved from 96° prerevision to 108° at latest follow-up (p = 0.016).ConclusionThe cumulative incidence of subsequent revision for aseptic loosening and instability was very low at five years with this fixed-bearing VVC implant in revision TKAs. Routine use of cemented and stemmed components with targeted use of metaphyseal cones likely contributed to this low rate of aseptic loosening. Cite this article: Bone Joint J 2020;102-B(4):458–462.

The dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically-induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra-articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra-articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition.

BACKGROUND: Stiffness is a common reason for suboptimal clinical outcomes after primary total knee arthroplasty (pTKA). There is a lack of consensus regarding its definition, which is often conflated with its histopathologic subcategory—i.e., arthrofibrosis. There is value in refining the definition of acquired idiopathic stiffness in an effort to select for patients with arthrofibrosis. We conducted a systematic review and meta-analysis to establish a consensus definition of acquired idiopathic stiffness, determine its prevalence after pTKA, and identify potential risk factors for its development. METHODS: MEDLINE, Embase, Cochrane Controlled Register of Trials (CENTRAL), and Scopus databases were searched from 2002 to 2017. Studies that included patients with stiffness after pTKA were screened with strict inclusion and exclusion criteria to isolate the subset of patients with acquired idiopathic stiffness unrelated to known extrinsic or surgical causes. Three authors independently assessed study eligibility and risk of bias and collected data. Outcomes of interest were then analyzed according to age, sex, and body mass index (BMI). RESULTS: In the 35 included studies (48,873 pTKAs), the mean patient age was 66 years. In 63% of the studies, stiffness was defined as a range of motion of 5° at 6 to 12 weeks postoperatively. The prevalence of acquired idiopathic stiffness after pTKA was 4%, and this did not differ according to age (4%, I(2) = 95%, among patients 12 weeks after pTKA in patients in the absence of complicating factors including preexisting stiffness. The mean prevalence of acquired idiopathic stiffness after pTKA was 4%; females and obese patients were at increased risk. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Protein detection techniques such as western blotting and ELISA rely on housekeeping proteins as standards for sample normalization. However, clinical or animal tissue specimens are heterogeneous due to presence of contaminating cell types and tissues (e.g., blood vessels and muscle) or cellular decay during tissue storage and isolation which may compromise protein integrity. This biological heterogeneity may invalidate the assumption that housekeeping proteins are invariable across various specimens. This study provides data that advocate for protein standardization based on total protein staining in rabbit posterior capsular tissues. We compared the classical normalization markers glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-tubulin (TUBB) with other proteins that have low variation in expression (i.e., FTL, FTH1, EEF1A1, TPT1) based on RNAseq data for human posterior capsular tissues. Histological examination revealed a high degree of qualitative variation in microscopic images of capsular tissue specimens. This variation is reflected by significant differences in specific protein signals for all housekeeping proteins as detected by western blot analysis. However, total protein staining, which combines the intensity of multiple gel electrophoretic bands, normalizes natural biological variation observed for individual housekeeping proteins and permits assessment of protein integrity. Therefore, we propose that normalization based on total protein staining increases accuracy of protein quantification of heterogeneous tissue specimen samples.

Total hip arthroplasty (THA) alleviates hip pain and improves joint function. Current implant design permits long-term survivorship of THAs, but certain metal-on-metal (MoM) articulations can portend catastrophic failure due to adverse local tissue reactions (ALTR). Here, we identified biological and molecular differences between periacetabular synovial tissues of patients with MoM THA failure undergoing revision THA compared to patients undergoing primary THA for routine osteoarthritis (OA). Analysis of tissue biopsies by RNA-sequencing (RNA-seq) revealed that MoM patient samples exhibit significantly increased expression of immune response genes but decreased expression of genes related to extracellular matrix (ECM) remodeling. Thus, interplay between local tissue inflammation and ECM degradation may account for the pathology and compromised clinical outcomes in select patients with MoM implants. We conclude that adverse responses of host tissues to implant materials result in transcriptomic modifications in patients with MoM implants that permit consideration of strategies that could mitigate ECM damage.

Trauma, surgery, and other inflammatory conditions can lead to debilitating joint contractures. Adjunct pharmacologic modalities may permit clinical prevention and treatment of recalcitrant joint contractures. We investigated the therapeutic potential of rosiglitazone by intra-articular delivery via oligo[poly(ethylene glycol)fumarate] (OPF) hydrogels in an established rabbit model of arthrofibrosis. OPF hydrogels loaded with rosiglitazone were characterized for drug elution properties upon soaking in minimum essential media (MEM) with 10% fetal bovine serum and measurements of drug concentrations via High Performance Liquid Chromatography (HPLC). Drug-loaded scaffolds were surgically implanted into 24 skeletally mature female New Zealand White rabbits that were divided into equal groups receiving OPF hydrogels loaded with rosiglitazone (1.67 mg), or vehicle control (10 µl DMSO). After 8 weeks of joint immobilization, rabbits were allowed unrestricted cage activity for 16 weeks. Contracture angles of rabbit limbs treated with rosiglitazone showed statistically significant improvements in flexion compared to control animals (mean angles, respectively, 64.4° vs. 53.3°, p