Efficacy of high-volume injections with and without corticosteroid compared with sham for Achilles tendinopathy: a protocol for a randomised controlled trial

IntroductionAchilles tendinopathy (AT) is a common and disabling musculoskeletal condition. First-line management involving Achilles tendon loading exercise with, or without, other modalities may not resolve the problem in up to 44% of cases. Many people receive injections. Yet there are no injection treatments with demonstrated long-term efficacy. The aim of the trial is to examine the 12-month efficacy of high-volume injection (HVI) with corticosteroid and HVI without corticosteroid versus sham injection among individuals with AT.Methods and analysisThe trial is a three-arm, parallel group, double-blind, superiority randomised controlled trial that will assess the efficacy of HVI with and without corticosteroid versus sham up to 12 months. We will block-randomise 192 participants to one of the three groups with a 1:1:1 ratio, and both participants and outcome assessors will be blinded to treatment allocation. All participants will receive an identical evidence-based education and exercise intervention. The primary outcome measure will be the Victorian Institute of Sport Assessment – Achilles (VISA-A) at 12 months post-randomisation, a validated, reliable and disease-specific measure of pain and function. Choice of secondary outcomes was informed by core outcome domains for tendinopathy. Data will be analysed using the intention-to-treat principle.Ethics and disseminationEthics approval was obtained via the Monash University Human Ethics Committee (no: 13138). The study is expected to be completed in 2024 and disseminated via peer review publication and conference presentations.Trial registration numberAustralia and New Zealand Clinical trials registry (ACTRN12619001455156)

Developmental potency of goat embryos produced by intra cytoplasmic sperm injection and in vitro fertilization.

The objective of this study was to standardize novel intracytoplasmic sperm injection (ICSI) technique, production of goat embryos by ICSI, in vitro fertilization (IVF) and comparison of their developmental potency. Immobilized sperm from epididymal semen with breaking tail were injected to mature metaphase ii oocytes by sharp micropipette of 5 µm diameter, as well as in vitro fertilization was carried out. Icsi and IVF derived zygotes were cultured in rvcl-blast-bsa media after chemical activation with ionomycin, chx and 6-dmap. Sham injection was used as a control group. Results suggest that immobilized sperm with breaking tail microinjected by sharp injection pipette after chemical activation is an efficient approach for goat embryo production by ICSI. Satisfactory survival rate (83.2%) was found by using sharp injection pipette of 5 µm diameter. Chemical activation with ionomycin, chx and 6-dmap was found effective with activation rate of 63.33%. Developmental rate of 2 cell, 4–8 cell, 8–16 cell, morula, blastocyst in ICSI and IVF group was 74.44%, 63.33%, 44.44%, 23.33%, 14.44% and 65.16%, 57.42%, 49.03%, 38.71%, 23.23%, respectively. Upon comparison, significantly higher (p < 0.05) percentage of cleavage was found in ICSI group than IVF (73.40 ± 3.12% vs. 64.06 ± 2.44%, respectively). However, morula and blastocyst percentage was significantly higher (p < 0.05) in IVF group than ICSI (23.20 ± 2.73% vs. 37.90 ± 3.15% and 14.56 ± 1.75% vs. 21.05 ± 2.09%). It can be concluded that ICSI with sharp micropipette of 5 µm diameter can be applied to assisted reproduction for in vitro goat embryo production.

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject’s right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4–treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of −0.308 LogMAR (+15 ETDRS letters). A mean improvement of −0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

Intravitreal Use of a Bone Marrow Mononuclear Fraction (BMMF) Containing CD34+ Cells in Patients with Stargardt Type Macular Dystrophy

To assess the therapeutic potential and the safety of intravitreous use of a bone marrow mononuclear fraction (BMMF) containing CD34+ cells in patients with Stargardt type macular dystrophy. The study was conducted on 10 patients with Stargardt dystrophy with worse eye visual acuity ≤ 20 / 125 . A bone marrow aspirate was obtained from all patients, and after processing in the cell therapy center (CTC), 0.1 ml of the intravitreous BMMF suspension was injected into the eye with worse visual acuity. A sham injection was performed in the contralateral eye. The patients were evaluated at baseline and one, three, and six months after the injection. All of them were submitted to measurement of best corrected visual acuity (BCVA), microperimetry, multifocal electroretinography (mfERG) and full field electroretinography (ffERG), autofluorescence (AF), and optical coherence tomography (OCT). Fluorescein angiography was also performed before and six months after the injection. All patients completed the six-month period of evaluation. Mean visual acuity of the treated eye was 1.1 logMAR (20/250) before intravitreous (IV) injection, 0.96 logMAR (20/200+2) one month after injection, and 0.92 logMAR (20/160-1) 3 months after injection. In the untreated eye, mean VA was 1.0 logMAR (20/200) at baseline and 0.96 logMAR (20/200+2) and 0.94 logMAR (20/160-2) one and three months after injection, respectively. In the treated group, VA at baseline ranged from best acuity of 20/125-1 to worst acuity of 20/640+2, going through 20/100+2 and 20/400 during the first month. In the untreated group, BCVA ranged from 20/100+2 to 20/400 at baseline and from 20/100 to 20/400 after one month. The results for the treated group differed significantly at all follow-up times, whereas no significant difference was observed in the untreated group. Regarding the mean sensitivity of microperimetry, although there was improvement throughout all months, a significant difference occurred only during the first month. In the untreated eye, there was no significant difference in any analysis. Angiofluoresceinography did not reveal neovessel formation or tumor growth. The remaining exams were used in order to aid the diagnosis. The results indicate that the use of intravitreous BMMF in patients with Stargardt dystrophy is safe and is associated with a discrete improvement of BCVA and microperimetry in the treated eye compared to the untreated one.

Effectiveness of Platelet-Rich Plasma Injection in Rotator Cuff Tendinopathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: To investigate the effectiveness of platelet-rich plasma (PRP) injection among patients with rotator cuff tendinopathy in comparison with sham injection, no injection, or physiotherapy alone. Methods: From the earliest records to November 1, 2018, all published or unpublished randomized controlled trial (RCTs) comparing PRP injection with a control group (sham injection, no injection, or physiotherapy alone) in patients with rotator cuff tendinopathy were included. Eligible trials were included from the search results of electronic databases including PubMed, EMBASE, Scopus, The Cochrane Library, as well as the bibliographies of relevant trials. Five RCTs were enrolled in our meta-analysis. Two authors independently assessed the quality of RCTs with the Cochrane risk of bias tool. We designated pain reduction as the primary outcome and functional improvement as the secondary outcome. Standardized mean difference (SMD) was applied for random-effect meta-analysis. Results: In the short term (3–6 weeks) and medium term (12 weeks), the effectiveness of PRP injection and control group was indistinguishable in terms of both outcomes (pain reduction and functional improvement). Nevertheless, PRP injection led to significant long-term (>24 weeks) pain relief (SMD: 0.42, 95% confidence interval (CI): 0.12–0.72, without heterogeneity). For functional improvement in the long term, PRP injection was not more effective than the control group (SMD: 1.20, 95% CI: −0.20–2.59, with heterogeneity). Conclusions: PRP injection may provide benefit over the control group (sham injection, no injection, or physiotherapy alone) in reducing pain at long-term follow-up for patients with rotator cuff tendinopathy.