Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.

BACKGROUND: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. METHODS: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov. FINDINGS: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected. INTERPRETATION: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment. FUNDING: Novartis Pharma.

Minimally Invasive Inlay Prosthesis Unicompartmental Knee Arthroplasty for the Treatment of Unicompartmental Osteoarthritis: A Prospective Observational Cohort Study with Minimum 2-Year Outcomes and up to 14-Year Survival.

There are limited medium-term outcome data available for the Repicci II device in unicompartmental knee arthroplasty (UKA). The purpose of this study was to report the medium-term (minimum 2 years) patient-reported outcomes and long-term (up to 14 years) procedure survival in a consecutive series of patients undergoing an inlay prosthesis UKA (Repicci II) at an independent orthopaedic clinic. Patients presenting with medially localized unicompartmental knee osteoarthritis and meeting the criteria appropriate for UKA were recruited to a clinical patient registry at the time of presentation. A cemented unicompartmental prosthesis (Repicci II) was implanted using minimally invasive techniques with rapid postoperative mobilization. Patients were asked to complete patient-reported outcomes preoperatively and annually postoperatively. A procedure list was cross-matched with the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), and an analysis of procedure survival was performed with comparison to the national data for UKA. Data from a cohort of 661 primary medial compartment UKA procedures performed in 551 patients over a 15-year period were extracted from the clinical patient registry. Significant improvements were maintained in general health, disease symptoms, pain, and function at an average follow-up of 9 years compared with preoperative data. Threshold analysis revealed that >65% of patients exceeded Patient Acceptable Symptom State at the latest follow-up, with >80% within or exceeding age-matched norms for general health. Cumulative revision rate was significantly lower than that reported for UKA in the AOANJRR at up to 13 years follow-up. This series represents a lower cumulative revision rate than previously reported, with >65% of patients reporting satisfactory functional outcomes at an average of 9 years from surgery. Surgical options for treating unicompartmental knee osteoarthritis could include UKA as a viable alternative; however, clear definitions of procedure success and its overall cost-benefit ratio in the context of ongoing management of knee osteoarthritis remain to be elucidated.

Limited penetration of cobalt and chromium ions into the cerebrospinal fluid following metal on metal arthroplasty: a cross-sectional analysis.

Background: The purpose of this study was to determine the concentration of cobalt (Co) and chromium (Cr) ions in synovial fluid, blood plasma and cerebrospinal fluid (CSF) of patients with metal-on-metal (MoM) implants, and to assess the relationship between implant history and patient characteristics with ion concentrations in CSF.Methods: An observational, non-randomised cross-sectional study was conducted with patients presenting to a single surgeon for treatment of degenerative conditions of the hip and knee. Blood and fluid samples were collected intraoperatively and analysed for proteins and trace elements.Results: Overall, the presence of an implant was associated with significantly higher Co and Cr concentrations in plasma (controls 5-115 nmol/L Co, 5-232 nmol/L Cr; well-functioning implant recipients 5-469 nmol/L Co, 5-608 nmol/L Cr; hip revisions 6-546 nmol/L Co, 5-573 nmol/L Cr), and for Cr concentrations in CSF (controls 5-24 nmol/L; well-functioning implant recipients 6-36 nmol/L, hip revisions 7-32 nmol/L). In absolute terms, <1% of the levels observed in the joint fluid and <15% of plasma metals appeared in the CSF. Multivariable regression models suggested different transfer mechanisms of Co and Cr to the CSF, with the presence of an implant not associated with ion levels.Conclusion: The presence of MoM implants is associated with significantly higher plasma levels of Co and Cr but not CSF levels, and the CSF/plasma ratio appears to be influenced by the plasma concentration in a nonlinear fashion. Co and Cr may be transferred to the CSF by different mechanisms, and their concentrations appears dependent on other factors yet to be identified. Although higher levels of plasma ions are associated with above average CSF metal concentrations, the thresholds for neurotoxicity remain unclear and require further study.

Impaired Neurobehavioural Performance in Untreated Obstructive Sleep Apnea Patients Using a Novel Standardised Test Battery.

OBJECTIVE/BACKGROUND: Although polysomnography (PSG) is the gold-standard measure for assessing disease severity in obstructive sleep apnea (OSA), it has limited value in identifying individuals experiencing significant neurobehavioural dysfunction. This study used a brief and novel computerised test battery to examine neurobehavioural function in adults with and without OSA. PATIENTS/METHODS: 204 patients with untreated OSA [age 49.3 (12.5) years; body mass index, [BMI] 33.6 (8.0) kg/m2; Epworth sleepiness scale 12 (4.9)/24; apnea hypopnea index 33.6 (25.8)/h] and 50 non-OSA participants [age 39.2 (14.0) years; BMI 25.8 (4.2) kg/m2, ESS 3.6 (2.3)/24]. All participants completed a computerised neurobehavioural battery during the daytime in the sleep clinic. The OSA group subsequently underwent an overnight PSG. The 30 min test battery assessed cognitive domains of visual spatial scanning and selective attention (Letter Cancellation Test), executive function (Stroop task) and working memory (2- and 3-Back tasks), and a validated sustained attention task (psychomotor vigilance task, PVT). Group differences in performance were compared. Associations between disease severity and performance were examined in the OSA group. RESULTS: After controlling for age, gender and education, OSA patients demonstrated impaired performance on the Stroop-Text, 2 and 3-Back tasks, and the PVT compared with the non-OSA group. OSA patients had worse performance on the LCT with fewer average hits albeit with better accuracy. Some OSA polysomnographic disease severity measures were weakly correlated with performance. CONCLUSIONS: This brief test battery may provide a sensitive, standardised method of assessing daytime dysfunction in OSA.

Fracture behavior of inlay and onlay fixed partial dentures - An in-vitro experimental and XFEM modeling study.

OBJECTIVES: This study aimed to explore the "sensitivity" of the fracture load and initiation site to loading position on the central occlusal surface of a pontic tooth for both all-ceramic inlay retained and onlay supported partial denture systems. MATERIALS AND METHODS: Three dimensional (3D) finite element (FE) inlay retained and onlay supported partial denture models were established for simulating crack initiation and propagation by using the eXtended Finite Element Method (XFEM). The models were subjected to a mastication force up to 500N on the central fossa of the pontic. The loading position was varied to investigate its influence on fracture load and crack path. RESULTS: Small perturbation of the loading position caused the fracture load and crack pattern to vary considerably. For the inlay fixed partial dentures (FPDs), the fracture origins changed from the bucco-gingival aspect of the molar embrasure to the premolar embrasure when the indenter force location is slightly shifted from the mesial to distal side. In contrast, for onlay FPDs, cracking initiated from bucco-gingival aspect of the premolar embrasure when the indenter is slightly shifted to the buccal side and from molar embrasure when the indenter is shifted to the lingual side. CONCLUSIONS: The fracture load and cracking path were found to be very sensitive to loading position in the all-ceramic inlay and onlay FPDs. The study provides a basis for improved understanding on the role of localized contact loading of the cusp surface in all-ceramic FPDs.

Do Nonsteroidal Anti-Inflammatory Drugs Cause Endoprosthetic Loosening? Mid- to Long-Term Follow-Up of 100 Total Hip Arthroplasties after Local NSAID Infiltration.

We evaluated the effect of local infiltration of NSAIDs on prosthetic fixation at mid- to long-term follow-up of total hip arthroplasties. Intra-articular local NSAID (ketorolac) was injected into hip joints and surrounding tissues intraoperatively and postoperatively as a part of multimodal pain management protocol. Clinical and radiographic evaluation was performed for any evidence of component loosening or failure and clinical outcomes in 100 total hip joint arthroplasties with a mean follow-up of 7.3 years (4.9 to 11 yrs). Radiographic analysis at the most recent follow-up showed no evidence of loosening, subsidence, or migration and no evidence of impending failure. Clinical outcomes showed improved Harris hip scores. Intra-articular NSAID used in the intraoperative/postoperative period in hip arthroplasty showed no evidence of prosthetic loosening at mid- to long-term follow-up.

Femoral neck remodelling after hip resurfacing surgery: a radiological study.

BACKGROUND: Narrowing of the femoral neck under the femoral component of the hip resurfacing has been noted previously and has raised concern. In this study we examined the X-rays of patients following Birmingham hip resurfacing surgery at 6-years follow-up. METHODS: Bony changes proximally and distally were measured. Fifty-two patients were available for evaluation. RESULTS: There were 40 (76.9%) men and 12 (23.1%) women, with a mean age of 52 years (25-64). The unoperated contralateral femoral neck was measured as a control. We found femoral neck narrowing proximally in 82.7% of patients and distally in 26.9% and on the contralateral side in 54.5%. The average narrowing was 3.6%. Widening was observed proximally in 17.3% and distally in 73.1% and on the contralateral side in 45.5%. The average widening was 3.9%. Four of the 52 patients had proximal narrowing exceeding 10% of the femoral neck diameter, and one of the 52 patients had inferior narrowing exceeding 10%. CONCLUSION: Gender, body mass index, component size and age did not affect remodelling. We conclude that the observed findings are likely to be a manifestation of a generalized remodelling response in the femoral neck rather than a localized and isolated narrowing at the junction of the component and the femoral neck.

Early complications of hip resurfacing.

There has been a rapid increase in the number of hip resurfacing procedures for the treatment of symptomatic osteoarthritis over the last decade. We examine our early complications associated with this procedure. Eight hundred forty consecutive hip resurfacing procedures by 1 surgeon using 1 prosthesis were assessed. The complications seen within the first 12-month postoperative period were analyzed. Specific patient selection criteria were used. Complications such as loosening, femoral neck notching, femoral neck fracture, deep vein thrombosis, stress fracture, nerve palsy, and infection were noted. Complications linked with loosening were categorized to either the femoral or acetabular component. A total of 86 early complications were observed in the 840 resurfacings. Twenty-three (2.7%) required operative intervention, and 10 (1.2%) were converted to stemmed hip arthroplasties. Of these 86 complications, the most common complication was deep vein thrombosis, 19 instances (2.26% occurrence in 840), followed by femoral neck fracture, 11 (1.31%); infection, 10 (1.19%); femoral notching, 10 (1.19%); transient nerve palsy, 8 (0.95%); acetabular loosening, 6 (0.71%); hematoma, 5 (0.60%); and stress fracture, 4 (0.48%). The fractures occurred mostly in patients older than 60 years.

A comparative mechanical and bone remodelling study of all-ceramic posterior inlay and onlay fixed partial dentures.

OBJECTIVES: Comparative studies of bone remodelling and mechanical stresses between inlay and onlay fixed partial dentures (FPD) are rather limited. The purpose of this paper was to evaluate the biological consequence in posterior mandibular bone and the mechanical responses in these two different prosthetic configurations. METHODS: Three-dimensional (3D) finite element analysis (FEA) models are created to explore the mechanical responses for the inlay and onlay preparations within the same oral environment. Strain induced bone remodelling was simulated under mastication. The remodelling adopted herein relates the strain in the bone to the change of Hounsfield Unit (HU) value in proportion to the surface area density (SAD) of bony morphology, which allows directly correlating to clinical computerised tomography (CT) data. RESULTS: The results show that both FPD designs exhibit a similar resultant change in bone mineral density (BMD) though the onlay configuration leads to a more uniform distribution of bone density. The inlay design results in higher mechanical stresses whilst allowing preservation of healthy tooth structure. CONCLUSIONS: This study provides an effective means to further clinical assessment and investigation into biomechanical responses and long-term restorative outcome with different FPD designs. CLINICAL SIGNIFICANCE: Quantifying in vivo stress distributions associated with inlay/onlay FPDs can further supplement clinical investigations into prosthetic durability, FPD preparation techniques (i.e., taper angles, material development), consequent stress distributions and the ongoing biomechanical responses of mandibular bone.

Clinical equipoise in sleep surgery: investigating clinical trial targets.

OBJECTIVE: Surgical approaches for alleviating snoring and/or obstructive sleep apnea (OSA) have been questioned because of a lack of evidence from high-quality randomized controlled trials (RCTs). An ethical requirement for RCTs is that they must test questions where community equipoise (ie, uncertainty) exists as to the correct treatment. We aimed to measure perceived importance, community equipoise, and willingness to enroll patients in 5 potential trial targets among members of the Australian Society for Otolaryngology Head and Neck Surgery (ASOHNS). STUDY DESIGN, SETTING, AND SUBJECTS: All ASOHNS members were surveyed using a multistage mail, email, Internet, and phone-based questionnaire. METHODS: Equipoise was measured for each of the scenarios using a bidirectional linear scale comparing 2 treatments. Responses were categorized into 1 of 3 groups: (A) preferred treatment 1, (B) completely undecided, and (C) preferred treatment 2. The resulting proportions are called equipoise ratios: A:B:C. Using tick boxes, the authors queried the general clinical importance and willingness to enroll patients for all scenarios. RESULTS: A total of 167 of 313 surgeons responded (53.4%). Three of the 5 trial scenarios exhibited evidence of community equipoise, but 2 scenarios, radiofrequency ablation plus uvulopalatopharyngoplasty (UPPP) versus UPPP alone and upper-airway reconstruction versus mandibular advancement splint (MAS), did not have strong support for enrolling patients. Informal feedback indicates one of these may be feasible in a smaller number of specifically trained surgeons. CONCLUSION: We suggest 2 potential RCT targets: septoplasty and turbinate reduction versus conservative measures for snoring and airway reconstruction versus MAS for OSA, where importance, clinical equipoise, and willingness all exist.

Biomechanical Response in Mandibular Bone due to Mastication Loading on 3-Unit Fixed Partial Dentures.

An understanding of functional responses in oral bone is a crucial component of dental biomechanics. The purpose of this study was to investigate the potential biological remodelling response during mastication on the mandibular pre- and post-insertion of a fixed partial denture (FPD). A series of three-dimensional (3D) finite element analysis (FEA) models were presented pre- and postextraction to determine the biomechanical responses to masticatory loading in the anterior mandible. Equivalent strains were analysed at lingual/buccal and mesial/distal areas of the premolar to molar region and quantified to anticipate bone remodelling response. Mandibular bone incorporating an FPD experienced substantially greater stress/strain magnitudes than that prior to placement of fixed prosthodontics, which is suggestive of engagements of bone remodelling. The results suggest similar outcomes to those reported clinically. Developing a simulation reflecting the outcomes of restorative treatment can provide meaningful insight into restorative treatment planning, clinical outcomes, and fixed prosthodontics designs.

Prediction of mandibular bone remodelling induced by fixed partial dentures.

Fixed partial dentures (FPD) or dental bridges have been extensively utilised in prosthodontic restoration. Despite considerable clinical success to date, there has been limited fundamental understanding of the biomechanical consequences induced by FPD treatment. It is noted that FPD construction significantly alters the biological and mechanical environment in the supporting bone region. Thus, the surrounding bones will be engaged to adapt to such a biomechanical change. This paper aims to address this critical issue by developing a new remodelling procedure induced by FPD restoration. Specifically, it relates the mechanical stimulus to the change in Hounsfield Unit (HU) value in terms of surface area density (SAD) of bony morphology, which allows direct correlation to clinical computerised tomography (CT) data. The procedure will provide prosthodontist with a new approach for assessing FPD treatment, thereby optimising FPD design for improving longevity and reliability of future FPD restoration.

Mechanical responses to orthodontic loading: a 3-dimensional finite element multi-tooth model.

INTRODUCTION: The initial mechanical response to orthodontic loading comprises biologic reactions that remain unclear, despite their clinical significance. We used a 3-dimensional finite element analysis to investigate the stress-strain responses of teeth to orthodontic loading. METHODS: The model was derived from computed tomography data, with adequate boundary conditions and tissue characterization, with orthodontic hardware to provide a more accurate reflection of events during orthodontic therapy. This study also incorporated the adjacent dentition. Two cases were analyzed: a single-tooth system with a mandibular canine, and a multi-tooth system consisting of the mandibular incisor, the canine, and the first premolar, subjected to orthodontic tipping forces. RESULTS AND CONCLUSIONS: The systems experienced elevated distortion strain energies in the alveolar crest, whereas the tensile and compressive stresses coincided with the apical sites clinically associated with root resorption. Stress levels were considerably greater in the multi-tooth system than in the single-tooth system. The results for the single-tooth model agree with those previously reported. The numeric studies show how orthodontic tooth movement develops different stress fields and how root resorption might occur as a result of hydrostatic compressive stress-induced tissue necrosis.

Influence of tooth removal on mandibular bone response to mastication.

The quantification of biomechanical response of mandibular bone to mastication is an integral component for a key in understanding the biological consequence of masticatory functions. Understanding the response of mandibular bone to external loading may also well explain the mechanisms of bone turnover. In this study, three finite element (FE) models simulating the lower second premolar, first and second molars along with their supporting structures were developed to determine stress/strain levels and distribution under different occlusal loading. The changes in stress/strain values and profiles have been investigated in three scenarios: pre-extraction of the lower first molar, post-extraction and after full healing of the extracted socket. The mastication induced equivalent strains within the supporting mandibular bone at each of these three scenarios were quantified and compared against the Frost's mechanostat theory. The results of stress/strain profiles show considerably lower magnitudes in the post-extracted and healed scenarios compared with the pre-extraction case. Following the Frost's MES hypothesis, the initial equivalent strains are related to local bone remodelling. It is found that in the extracted case the bone near the tooth socket undergoes resorption from lingual respect whilst filling the cavity, whereas in the healed case bone turnover reaches equilibrium. The results provide important data for clinical assessment of constructing dentures or other restorative devices.