Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials.

BACKGROUND: Inclisiran significantly reduced low-density lipoprotein cholesterol (LDL-C) in individuals with heterozygous familial hypercholesterolaemia, established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents (type 2 diabetes, familial hypercholesterolaemia or a 10-year risk of a cardiovascular event ≥20%) in the ORION phase III clinical trials. Infrequent dosing at days 1, 90, 270 and 450 resulted in a mean LDL-C reduction of ~50%. A total of 298 participants from South Africa (SA) were enrolled. Local data are needed to support the use of inclisiran in the SA population, potentially addressing an unmet need for additional LDL-C-lowering therapies. Objectives. To analyse the ORION phase III trial data to assess the efficacy and safety of inclisiran in SA participants. Methods. ORION-9, 10 and 11 were randomised, double-blind, phase III trials. Participants were receiving maximally tolerated statins with or without other lipid-lowering therapies (excluding protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors). Participants were randomised 1:1 to inclisiran sodium 300 mg/284 mg (free acid) or placebo administered at days 1, 90, 270 and 450. The co-primary endpoints were the LDL-C percentage change from baseline to day 510 and the time-averaged percentage change in LDL-C from baseline after day 90 up to day 540. Key secondary endpoints included the absolute change in LDL-C from baseline to day 510, the time-averaged absolute change from baseline after day 90 up to day 540, and changes in other lipids and lipoproteins. Results. The mean age of the participants was 58.6 years (56% male). The mean LDL-C level at baseline was 3.6 mmol/L. At day 510, inclisiran reduced LDL-C levels by 54.2% compared with placebo (95% confidence interval (CI) -61.3 - -47.2; p<0.0001). The corresponding time-averaged reduction in LDL-C was 52.8% (95% CI -57.9 - -47.8; p<0.0001). Treatment-emergent adverse events at the injection site were more common with inclisiran compared with placebo (10.1% v. 0.7%); however, all were mild or moderate in nature and none were persistent. Conclusion. Inclisiran, given in addition to maximally tolerated standard lipid-lowering therapy, is effective and safe and results in robust reductions in LDL-C in SA patients at high cardiovascular risk.

Vestibular rehabilitation in multiple sclerosis: study protocol for a randomised controlled trial and cost-effectiveness analysis comparing customised with booklet based vestibular rehabilitation for vestibulopathy and a 12 month observational cohort study of the symptom reduction and recurrence rate following treatment for benign paroxysmal positional vertigo.

BACKGROUND: Symptoms arising from vestibular system dysfunction are observed in 49-59% of people with Multiple Sclerosis (MS). Symptoms may include vertigo, dizziness and/or imbalance. These impact on functional ability, contribute to falls and significant health and social care costs. In people with MS, vestibular dysfunction can be due to peripheral pathology that may include Benign Paroxysmal Positional Vertigo (BPPV), as well as central or combined pathology. Vestibular symptoms may be treated with vestibular rehabilitation (VR), and with repositioning manoeuvres in the case of BPPV. However, there is a paucity of evidence about the rate and degree of symptom recovery with VR for people with MS and vestibulopathy. In addition, given the multiplicity of symptoms and underpinning vestibular pathologies often seen in people with MS, a customised VR approach may be more clinically appropriate and cost effective than generic booklet-based approaches. Likewise, BPPV should be identified and treated appropriately. METHODS/ DESIGN: People with MS and symptoms of vertigo, dizziness and/or imbalance will be screened for central and/or peripheral vestibulopathy and/or BPPV. Following consent, people with BPPV will be treated with re-positioning manoeuvres over 1-3 sessions and followed up at 6 and 12 months to assess for any re-occurrence of BPPV. People with central and/or peripheral vestibulopathy will be entered into a randomised controlled trial (RCT). Trial participants will be randomly allocated (1:1) to either a 12-week generic booklet-based home programme with telephone support or a 12-week VR programme consisting of customised treatment including 12 face-to-face sessions and a home exercise programme. Customised or booklet-based interventions will start 2 weeks after randomisation and all trial participants will be followed up 14 and 26 weeks from randomisation. The primary clinical outcome is the Dizziness Handicap Inventory at 26 weeks and the primary economic endpoint is quality-adjusted life-years. A range of secondary outcomes associated with vestibular function will be used. DISCUSSION: If customised VR is demonstrated to be clinically and cost-effective compared to generic booklet-based VR this will inform practice guidelines and the development of training packages for therapists in the diagnosis and treatment of vestibulopathy in people with MS. TRIAL REGISTRATION: ISRCTN Number: 27374299 Date of Registration 24/09/2018 Protocol Version 15 25/09/2019.

Patellar complications in single versus double tunnel medial patellofemoral ligament reconstruction.

PURPOSE: Hamstring graft fixation on the patellar side during medial patellofemoral ligament (MPFL) reconstruction is usually with transosseous tunnels and can frequently lead to further problems. The aim of our study was to compare and analyse patellar complications in single patellar tunnel versus double tunnel hamstring graft fixation. METHODS: Twenty-nine knees with MPFL reconstructions (group S) in which the hamstring tendon graft was transfixed using a suspensory fixation method in a single tunnel drilled across the patella were analysed in comparison with 29 knees (group D) with interference fixation of the graft through two tunnels drilled up to a predetermined depth in the patella. Primary outcome measured was any patellar complication like anterior knee pain and patella fracture. Secondary outcomes assessed were future functional instability and failure of reconstruction. RESULTS: Anterior knee pain was noted in six patients in group S, of which three patients had removal of the irritating metalwork on the patella. In all, nine surgical interventions were needed in six patients in this group. Three patients in group D complained of knee pain, but no one in this group needed any further surgical interventions ( p value 0.02). Symptomatic instability requiring revision surgery or realignment surgery was required in two patients in the group S and none in group D. No patellar fractures were seen in either group. CONCLUSION: Our study showed increasing problems with single tunnel patellar fixation, with more reoperation and failure rates compared to double tunnel fixation. The evidence supports the move towards anatomical double bundle MPFL reconstructions.

The MMP3 gene in musculoskeletal soft tissue injury risk profiling: A study in two independent sample groups.

Matrix metalloproteinase-3 (MMP3) is a mediator of matrix remodelling and a proposed susceptibility locus in the genetic profile of musculoskeletal soft tissue injuries. Therefore, this study aimed to validate the MMP3 gene as a risk marker for these injuries by conducting a case control genetic association study in two independent samples groups. Three previously investigated MMP3 variants (rs679620, rs591058 and rs650108) in addition to the functional promoter variant (rs3025058) were genotyped in 195 Australian control participants and 79 Australian individuals with chronic Achilles tendinopathy. Similarly, 234 South African individuals with acute anterior cruciate ligament ruptures and 232 matched control participants were also analysed. Based on high linkage with the previously associated MMP3 variant rs679620, rs3025058 was inferred and found to be associated with increased risk for Achilles tendinopathy within the South African group (P = 0.012; OR: 2.88; 95% CI: 1.4 to 6.1). Lastly, the 6A-G-C-G haplotype, constructed from the investigated variants, was significantly associated with reduced risk for Achilles tendinopathy (29% CON vs. 20% TEN, P = 0.037) in the Australian group. In conclusion, a signal surrounding MMP3 is apparent with respect to Achilles tendinopathy. However, whether the investigated variants are contributing to injury susceptibility or whether they are merely linked to the risk conferring variants mapping elsewhere within the MMP gene cluster on chromosome 11, still requires refining.

Rehabilitation goals of people with spinal cord injuries can be classified against the International Classification of Functioning, Disability and Health Core Set for spinal cord injuries.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To establish whether inter-professional rehabilitation goals from people with non-traumatic spinal cord injury (SCI) can be classified against the International Classification of Functioning, Disability and Health (ICF) SCI Comprehensive and Brief Core Sets early postacute situation. SETTING: Neurological rehabilitation unit. METHODS: Rehabilitation goals of 119 patients with mainly incomplete and non-traumatic SCIs were classified against the ICF SCI Core Sets following established linking rules. RESULTS: A total of 119 patients generated 1509 goals with a mean (and s.d.) of 10.5 (9.1) goals per patient during the course of their inpatient rehabilitation stay. Classifying the 1509 rehabilitation goals against the Comprehensive ICF Core Set generated 2909 ICF codes. Only 69 goals (4.6%) were classified as 'not definable (ND)'. Classifying the 1509 goals against the Brief ICF Core Set generated 2076 ICF codes. However, 751(49.8%) of these goals were classified as 'ND'. In the majority of goals (95.7%), the ICF code description was not comprehensive enough to fully express the goals set in rehabilitation. In particular, the notion of quality of movement or specificity and measurability aspects of a goal (usually described with the criteria and acronyms SMART) could not be expressed through the ICF codes. CONCLUSION: Inter-professional rehabilitation goals can be broadly described by the ICF Comprehensive Core Set for SCI but not the Brief Core Set.

Observer agreement in the reporting of knee and lumbar spine magnetic resonance (MR) imaging examinations: selectively trained MR radiographers and consultant radiologists compared with an index radiologist.

PURPOSE: To assess agreement between trained radiographers and consultant radiologists compared with an index radiologist when reporting on magnetic resonance imaging (MRI) examinations of the knee and lumbar spine and to examine the subsequent effect of discordant reports on patient management and outcome. METHODS: At York Hospital two MR radiographers, two consultant radiologists and an index radiologist reported on a prospective, random sample of 326 MRI examinations. The radiographers reported in clinical practice conditions and the radiologists during clinical practice. An independent consultant radiologist compared these reports with the index radiologist report for agreement. Orthopaedic surgeons then assessed whether the discordance between reports was clinically important. RESULTS: Overall observer agreement with the index radiologist was comparable between observers and ranged from 54% to 58%; for the knee it was 46-57% and for the lumbar spine was 56-66%. There was a very small observed difference of 0.6% (95% CI -11.9 to 13.0) in mean agreement between the radiographers and radiologists (P=0.860). For the knee, lumbar spine and overall, radiographers' discordant reports, when compared with the index radiologist, were less likely to have a clinically important effect on patient outcome than the radiologists' discordant reports. Less than 10% of observer's reports were sufficiently discordant with the index radiologist's reports to be clinically important. CONCLUSION: Carefully selected MR radiographers with postgraduate education and training reported in clinical practice conditions on specific MRI examinations of the knee and lumbar spine to a level of agreement comparable with non-musculoskeletal consultant radiologists.

The effect of waiting times from general practitioner referral to MRI or orthopaedic consultation for the knee on patient-based outcomes.

OBJECTIVES: The purpose of this study was to test for the effect of waiting time from general practitioner (GP) referral to MRI or to orthopaedic consultation on outcomes of patients with knee problems, and to test whether any characteristics of trial participants predicted waiting time to MRI or orthopaedics. METHODS: We undertook secondary analyses of data on 553 participants from a randomised trial who were recruited from 163 general practices during November 2002 to October 2004. RESULTS: Of the patients allocated to MRI, 263 (94%) had an MRI, and of those referred to orthopaedics, 236 (86%) had an orthopaedic consultation. The median (interquartile range) waiting time in days from randomisation to MRI was 41.0 (21.0-71.0) and to orthopaedic appointment was 78.5 (54.5-167.5). Waiting time was found to have no significant effect on patient outcome for both the Short Form 36-item (SF-36) physical functioning score (p=0.570) and the Knee Quality of Life 26-item (KQoL-26) physical functioning score (p=0.268). There was weak evidence that males waited less time for their MRI (p=0.049) and older patients waited longer for their orthopaedic referral (p=0.049). For patients who resided in the catchment areas of some centres there were significantly longer waiting times for both MRI and orthopaedic appointment. CONCLUSION: Where patients reside is a strong predictor of waiting time for access to services such as MRI or orthopaedics. There is no evidence to suggest, however, that this has a significant effect on physical well-being in the short term for patients with knee problems.

Isolated rupture of the popliteus tendon in a professional soccer player.

We report an unusual case of an isolated intra-substance rupture of the popliteus tendon in a professional soccer player. The injury, sustained in a soccer tackle, was diagnosed on magnetic resonance imaging and subsequently confirmed on arthroscopic examination of the knee. The impinging proximal stump was debrided and the patient returned to playing competitive soccer within 6 weeks of surgery.

Impingement fracture of the anteromedial tibial margin: a radiographic sign of combined posterolateral complex and posterior cruciate ligament disruption.

Marginal fractures of the tibial plateau are associated with a high incidence of soft tissue injuries to the stabilising structures of the knee joint. Injuries to the anterior cruciate ligament are associated with the Segond fracture and impingement fractures of the posteromedial tibial plateau. Recognition of these fractures aids diagnosis of these injuries. Marginal fractures of the tibial plateau associated with posterior cruciate ligament injuries are less common, though recently a "reverse" Segond fracture has been recognised. We describe a fracture of the anteromedial tibial plateau associated with complete disruption of the posterior cruciate ligament and posterolateral complex.

Kneeling ability after total knee arthroplasty. Perception and reality.

Kneeling as one of the knee's capabilities required for many activities of daily living has not been examined in detail after total knee replacement. The purpose of the present study was to question the patients' ability to kneel and their perception of factors affecting this ability after total knee arthroplasty, and to objectively assess their kneeling ability. Seventy patients with 100 total knee arthroplasties were asked to comment on their ability to kneel. Thirty-one patients with 44 knees said they could kneel easily, 29 patients with 41 knees said they were able to kneel but avoided doing so, and 10 patients with 15 knees said they were unable to kneel. Regarding observed kneeling ability, all patients were able to kneel under supervision: 56 patients with 82 knees knelt easily and got up easily from this position, 11 patients with 14 knees showed slight difficulties in kneeling or in getting up, and three patients with four knees had marked difficulties with kneeling. The patients' perceived ability to kneel after total knee arthroplasty was less than their observed ability. Fear of harming the prosthesis and lack of information prevented kneeling in 49% of the patients (27 of 56 knees) with perceived inability to kneel. Of those patients with observed difficulty in kneeling, scar pain and back related problems seemed to be major factors in limiting the kneeling ability. Kneeling, as an important function of the knee, should be given additional consideration in relation to the functional results of total knee arthroplasty. Patients should be counseled regarding factors affecting future ability to kneel.

Synovial cyst of the proximal tibiofibular joint with peroneal nerve compression after total knee arthroplasty.

Synovial or ganglion cysts of the proximal tibiofibular joint are less common than synovial cysts of the knee joint but may present in a similar manner and may be difficult to diagnose clinically. Although synovial cysts arising from the knee joint after prosthetic arthroplasty have already been described, we report a case in which a lateral knee mass compressing the peroneal nerve was found to be a synovial cyst arising from the tibiofibular joint.

Horizontal pelvic osteotomies for bladder exstrophy. A preliminary report.

We have treated 11 patients aged three days to 15 years with bladder exstrophy by horizontal osteotomies of the innominate bones. The operation was originally used for older patients with severe deformity or failed previous surgery but is now applied as a primary procedure in the first week of life. The osteotomies enable the complex malformations to be corrected in a single operation without turning the patient: the pubic bones can be brought together, the abdominal wall repaired and the bladder closed with reconstruction of the urethra and external genitalia. The early results have been very satisfactory in all cases with only minor complications; we felt that a preliminary report should be made, despite a mean follow-up of only seven months.

Seasonal variation in anthelmintic response by cattle to dermally applied levamisole.

Four experiments in 1978-79, and 2 in 1982 designed to define the optimum dose rate of dermally applied formulations of levamisole are described. These experiments showed that the absorption of levamisole with resultant blood levels and anthelmintic activity is strongly influenced by temperature. In warm to hot conditions percutaneous absorption is rapid and high blood levels with high anthelmintic activity against Haemonchus placei, Ostertagi sp, Trichostrongylus sp, Cooperia sp, Oesophagostomum radiatum, O. venulosum and Dictyocaulus viviparus result from dose rates of 10 mg/kg or more. In cold weather the high efficacy against H. placei, Cooperia sp, and Oesophagostomum sp is unchanged, but efficacy against Ostertagia sp, T. axei and D. viviparus decreases to the extent that a mean dose rate of 20 mg/kg (range 15 to 25 mg/kg) is necessary if the anthelmintic activity of dermally applied levamisole is to match that of either parenterally or orally administered material. These anthelmintic data are supported by the levamisole blood profile which in winter months, peaks at a figure of one quarter or less of that obtained from a similar dose rate in warm conditions. The implications of this variability in action are discussed.