HIV-1 Glycan Density Drives the Persistence of the Mannose Patch within an Infected Individual.

The HIV envelope glycoprotein (Env) is extensively modified with host-derived N-linked glycans. The high density of glycosylation on the viral spike limits enzymatic processing, resulting in numerous underprocessed oligomannose-type glycans. This extensive glycosylation not only shields conserved regions of the protein from the immune system but also acts as a target for anti-HIV broadly neutralizing antibodies (bnAbs). In response to the host immune system, the HIV glycan shield is constantly evolving through mutations affecting both the positions and numbers of potential N-linked glycosylation sites (PNGSs). Here, using longitudinal Env sequences from a clade C-infected individual (CAP256), we measured the impact of the shifting glycan shield during HIV infection on the abundance of oligomannose-type glycans. By analyzing the intrinsic mannose patch from a panel of recombinant CAP256 gp120s displaying high protein sequence variability and changes in PNGS number and positioning, we show that the intrinsic mannose patch persists throughout the course of HIV infection and correlates with the number of PNGSs. This effect of the glycan density on the processing state was also supported by the analysis of a cross-clade panel of recombinant gp120 glycoproteins. Together, these observations underscore the importance of glycan clustering for the generation of carbohydrate epitopes for anti-HIV bnAbs. The persistence of the intrinsic mannose patch over the course of HIV infection further highlights this epitope as an important target for HIV vaccine strategies. IMPORTANCE: Development of an HIV vaccine is critical for control of the HIV pandemic, and elicitation of broadly neutralizing antibodies (bnAbs) is likely to be a key component of a successful vaccine response. The HIV envelope glycoprotein (Env) is covered in an array of host-derived N-linked glycans often referred to as the glycan shield. This glycan shield is a target for many of the recently isolated anti-HIV bnAbs and is therefore under constant pressure from the host immune system, leading to changes in both glycan site frequency and location. This study aimed to determine whether these genetic changes impacted the eventual processing of glycans on the HIV Env and the susceptibility of the virus to neutralization. We show that despite this variation in glycan site positioning and frequency over the course of HIV infection, the mannose patch is a conserved feature throughout, making it a stable target for HIV vaccine design.

Reamed intramedullary nailing versus circular frame external fixation for segmental tibial fractures (STIFF-F): a mixed methods feasibility study.

BACKGROUND: Segmental tibial fractures are fractures in two or more areas of the tibial diaphysis resulting in a separate intercalary segment of the bone. Surgical fixation is recommended for patients with segmental tibial fractures as non-operative treatment outcomes are poor. The most common surgical interventions are intramedullary nailing (IMN) and circular frame external fixation (CFEF), but evidence about which is better is of poor quality. An adequately powered randomised controlled trial (RCT) to determine optimum treatment is required. STIFF-F aimed to assess the feasibility of a multicentre RCT comparing IMN with CFEF for segmental tibial fracture. METHODS: STIFF-F was a mixed-methods feasibility study comprising a pilot RCT conducted at six UK Major Trauma Centres, qualitative interviews drawing on Phenomenology and an online survey of rehabilitation. The primary outcome was recruitment rate. Patients, 16 years and over, with a segmental tibial fracture (open or closed) deemed suitable for IMN or CFEF were eligible to participate. Randomisation was stratified by site using random permuted blocks of varying sizes. Participant or assessor blinding was not possible. Interviews were undertaken with patients about their experience of injury, treatment, recovery and participation. Staff were interviewed to identify contextual factors affecting trial processes, their experience of recruitment and the treatment pathway. An online survey was developed to understand the rehabilitation context of the treatments. RESULTS: Eleven patients were screened and three recruited to the pilot RCT. Nineteen staff and four patients participated in interviews, and 11 physiotherapists responded to the survey. This study found the following: (i) segmental tibial fractures were rarer than anticipated, (ii) the complexity of the injury, study setup times and surgeon treatment preferences impeded recruitment, (iii) recovery from a segmental tibial fracture is challenging, and rehabilitation protocols are inconsistent and (iv) despite the difficulty recruiting, staff valued this research question and strived to find a way forward. CONCLUSION: The proposed multicentre RCT comparing IMN with CFEF is not feasible. This study highlighted the difficulty of recruiting patients to an RCT of a complex rare injury over a short time period. TRIAL REGISTRATION: The study was registered with the International Standard Randomised Controlled Trials Number Registry: ISRCTN11229660.

Findings from the patch augmented rotator cuff surgery (PARCS) feasibility study.

BACKGROUND: A rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The patch augmented rotator cuff surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible. METHODS: A mixed methods feasibility study of conducing a subsequent RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder Society's (BESS) surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. RESULTS: The BESS surgeons' survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting. CONCLUSIONS: Randomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders.

Patch augmentation surgery for rotator cuff repair: the PARCS mixed-methods feasibility study.

BACKGROUND: A rotator cuff tear is a common, disabling shoulder problem. Symptoms may include pain, weakness, lack of shoulder mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a need to improve the outcome of rotator cuff surgery, and the use of patch augmentation (on-lay or bridging) to provide support to the healing process and improve patient outcomes holds promise. Patches have been made using different materials (e.g. human/animal skin or tissue and synthetic materials) and processes (e.g. woven or mesh). OBJECTIVES: The aim of the Patch Augmented Rotator Cuff Surgery (PARCS) feasibility study was to determine the design of a definitive randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible. DESIGN: A mixed-methods feasibility study of a randomised controlled trial. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Library databases were searched between April 2006 and August 2018. METHODS: The project involved six stages: a systematic review of clinical evidence, a survey of the British Elbow and Shoulder Society's surgical membership, a survey of surgeon triallists, focus groups and interviews with stakeholders, a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. The various stakeholders (including patients, surgeons and industry representatives) were involved in stages 2-6. RESULTS: The systematic review comprised 52 studies; only 15 were comparative and, of these, 11 were observational (search conducted in August 2018). These studies were typically small (median number of participants 26, range 5-152 participants). There was some evidence to support the use of patches, although most comparative studies were at a serious risk of bias. Little to no published clinical evidence was available for a number of patches in clinical use. The membership survey of British Elbow and Shoulder surgeons [105 (21%) responses received] identified a variety of patches in use. Twenty-four surgeons (77%) completed the triallist survey relating to trial design. Four focus groups were conducted, involving 24 stakeholders. Differing views were held on a number of aspects of trial design, including the appropriate patient population (e.g. patient age) to participate. Agreement on the key research questions and the outline of two potential randomised controlled trials were achieved through the Delphi study [29 (67%)] and the consensus meeting that 22 participants attended. LIMITATIONS: The main limitation was that the findings were influenced by the participants, who are not necessarily representative of the views of the relevant stakeholder groups. CONCLUSION: The need for further clinical studies was clear, particularly given the range and number of different patches available. FUTURE WORK: Randomised comparisons of on-lay patch use for completed rotator cuff repairs and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. These elements are included in the trial designs proposed in this study. STUDY REGISTRATION: The systematic review is registered as PROSPERO CRD42017057908. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 13. See the NIHR Journals Library website for further project information.

Shoulder muscles and tendons allow us to move our arms to carry out daily activities, work and play sports. Disease and injury of these tendons can cause significant long-term disability. Early treatment of these tendon problems usually involves painkillers, injections and physiotherapy. However, many patients whose symptoms do not improve may need surgery to repair these tendons. Unfortunately, around 40% of surgical tendon repairs fail within 12 months. As such, these operations need to be improved. A promising approach is to use a patch to support the repair while the tendon heals; this patch is often used in a similar way to a plaster. However, it is not yet clear whether or not using a patch improves patient health and, if so, whether or not it makes enough of a difference to justify the additional cost to the NHS. A scientific study called a randomised controlled trial is needed to fairly assess the value of surgery with a patch in people requiring a tendon repair. This study must be carefully designed so that it is acceptable to patients and surgeons, among others, and feasible to run. We conducted a multistage study to explore whether or not a potential trial design could be achieved. We searched the scientific literature for previous research that had studied using patches for repairing shoulder tendons. We surveyed shoulder surgeons, including those who had previously been involved shoulder randomised controlled trials. We conducted four focus groups with stakeholders. Initial agreement on the best way to run a randomised controlled trial of patches in shoulder surgery was achieved using online questionnaires. Finally, we held a 2-day meeting to scrutinise the study findings and the relevant issues. Two potential studies were recommended, as was the need for closer monitoring of patch safety.