The Hinge Region of the Israeli Acute Paralysis Virus Internal Ribosome Entry Site Directs Ribosomal Positioning, Translational Activity, and Virus Infection.

All viruses must usurp host ribosomes for viral protein synthesis. Dicistroviruses utilize an intergenic region internal ribosome entry site (IGR IRES) to directly recruit ribosomes and mediate translation initiation from a non-AUG start codon. The IGR IRES adopts a three-pseudoknot structure that comprises a ribosome binding domain of pseudoknot II and III (PKII and PKIII), and a tRNA-like anticodon domain (PKI) connected via a short, one to three nucleotide hinge region. Recent cryo-EM structural analysis of the dicistrovirus Taura syndrome virus (TSV) IGR IRES bound to the ribosome suggests that the hinge region may facilitate translocation of the IRES from the ribosomal A to P site. In this study, we provide mechanistic and functional insights into the role of the hinge region in IGR IRES translation. Using the honeybee dicistrovirus, Israeli acute paralysis virus (IAPV), as a model, we demonstrate that mutations of the hinge region resulted in decreased IRES-dependent translation in vitro. Toeprinting primer extension analysis of mutant IRESs bound to purified ribosomes and in rabbit reticulocyte lysates showed defects in the initial ribosome positioning on the IRES. Finally, using a hybrid dicistrovirus clone, mutations in the hinge region of the IAPV IRES resulted in decreased viral yield. Our work reveals an unexpected role of the hinge region of the dicistrovirus IGR IRES coordinating the two independently folded domains of the IRES to properly position the ribosome to start translation. IMPORTANCE Viruses must use the host cell machinery to direct viral protein expression for productive infection. One such mechanism is an internal ribosome entry site that can directly recruit host cell machinery. In this study, we have identified a novel sequence in an IRES that provides insight into the mechanism of viral gene expression. Specifically, this novel sequence promotes viral IRES activity by directly guiding the host cell machinery to start gene expression at a specific site.

Meniscal allograft transplantation: undersizing grafts can lead to increased rates of clinical and mechanical failure.

PURPOSE: To assess mid-term survivorship of meniscal allograft transplantation (MAT) and determine the effect that pre-operative meniscal sizing has upon functional outcome and mechanical survivorship. METHODS: A prospectively collected database of patients receiving MAT from 2001 to 2017 was analysed. Data include demographics; sizing measurements, complications, further surgery, and patient-reported outcome measures (PROMs). Allografts were fresh frozen, non-irradiated, and sized using the Pollard technique. RESULTS: Seventy-three MATs were performed in 67 patients; mean age at MAT was 34 years (range 14-52 years). 56% were male and 62% were medial. The mean follow-up was 75 months (6.25 years). Mechanical survival at 5 and 10 years was 96% and 89.4%, respectively. There were statistically significant improvements in all PROMs; mean Lysholm score improved by 17.5 points [95% confidence interval (CI) 22.2-12.9, p < 0.001]; mean IKDC score improved significantly by 13.3 points (CI 19.3-7.4, p < 0.001); mean OKS improved by 5.6 points (CI 9.2-2.2, p < 0.002); and the median Tegner improved by 1 point. Forty-one MATs (56%) were undersized for width (range 1-11 mm). Seven MATs (10%) were undersized for length (range 1-4 mm). There was no statistically significant difference in mechanical survivorship or clinical outcomes between undersized, matched, or oversized grafts overall; however, sub-group analysis demonstrated increased failure when allografts were undersized by more than 5 mm in width. CONCLUSIONS: MAT is an effective treatment to improve function and alleviate pain with excellent survivorship in this series. Accepting an allograft that is more than 5 mm smaller in width than pre-operative templating increases the likelihood of clinical and mechanical failure. We, therefore, urge surgeons to be familiar with the measuring process used by their individual tissue bank provider to avoid graft-host mismatch that could affect outcome.

The use of allograft tendons in primary ACL reconstruction.

PURPOSE: Graft choice in primary anterior cruciate ligament (ACL) reconstruction remains controversial. The use of allograft has risen exponentially in recent years with the attraction of absent donor site morbidity, reduced surgical time and reliable graft size. However, the published evidence examining their clinical effectiveness over autograft tendons has been unclear. The aim of this paper is to provide a current review of the clinical evidence available to help guide surgeons through the decision-making process for the use of allografts in primary ACL reconstruction. METHODS: The literature in relation to allograft healing, storage, sterilisation, differences in surgical technique and rehabilitation have been reviewed in addition to recent comparative studies and all clinical systematic reviews and meta-analyses. RESULTS: Early reviews have indicated a higher risk of failure with allografts due to association with irradiation for sterilisation and where rehabilitation programs and post-operative loading may ignore the slower incorporation of allografts. More recent analysis indicates a similar low failure rate for allograft and autograft methods of reconstruction when using non-irradiated allografts that have not undergone chemically processing and where rehabilitation has been slower. However, inferior outcomes with allografts have been reported in young (< 25 years) highly active patients, and also when irradiated or chemically processed grafts are used. CONCLUSION: When considering use of allografts in primary ACL reconstruction, use of irradiation, chemical processing and rehabilitation programs suited to autograft are important negative factors. Allografts, when used for primary ACL reconstruction, should be fresh frozen and non-irradiated. Quantification of the risk of use of allograft in the young requires further evaluation. LEVELS OF EVIDENCE: III.

Patient-Centred Outcomes in Anaemia and Renal Disease: A Systematic Review.

BACKGROUND: Anaemia is a nearly universal complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) have been demonstrated to improve clinical outcomes and quality of life (QOL) in renal patients with anaemia. Patient-reported outcome measures (PROMs) are increasingly being used to evaluate the patient-centred impact of medical therapy. Here, we describe a systematic review of studies that evaluated patient-centred outcomes (PCOs) in renal patients undergoing anaemia treatment. METHODS: We conducted a search of Medline (Ovid), EMBASE (Ovid), PsychINFO, and CINAHL databases for studies published until March 2018 that investigated an intervention to treat anaemia in renal patients and used at least one PROM. We also performed a quality assessment for all included studies. Statistical analyses characterized each study, PROMs used, the quality of PCO reporting, and the association between haematological outcomes and PCOs. RESULTS: Of the 3,533 studies identified in the database search, 21 met all eligibility criteria. Fourteen (67%) of the studies were randomized-controlled trials. Most studies (81%) investigated CKD patients, 14% investigated post-renal transplant patients and 5% assessed patients with heart disease on haemodialysis. The most common anaemia intervention, used in 95% of studies, was ESAs. Forty-three percent of studies utilized one PROM, most commonly the SF-36, a measure of QOL not specifically created for use in nephrology patients. About a third of studies selectively reported PROM subscales, rather than reporting all subscales. Notable biases among included studies included lack of blinding, selective outcome reporting, and lack of power estimates for PCOs. We did not find a statistically significant association between improvements in haemoglobin and QOL. CONCLUSIONS: Future studies employing anaemia and nephrology-specific PROMs and conducted with greater rigour, standardization in the research methods, and reporting of PCOs in renal populations will improve understanding of PCOs in this patient group and hopefully improve patient outcomes and experiences.

Patient-Centered Outcomes in the Management of Anemia: A Scoping Review.

Anemia is a frequently diagnosed condition that may be a symptom of or complication of many illnesses affecting patients of all demographics. Anemia can lead to both worsened clinical outcomes and reduced quality of life. Patient-reported outcome measures (PROMs) are methodological tools used to capture the impact of disease on patient well-being. Use of PROMs in medical research is becoming more common as it is increasingly recognized that disease outcomes of interest to researchers and clinicians are not always consistent with patients' greatest concerns related to their diseases. We conducted a scoping review to characterize the studies that have evaluated patient-centered outcomes using PROMs in patients undergoing treatment for anemia. We conducted a search of Medline (Ovid), EMBASE (Ovid), PsychINFO, and CINAHL databases for studies published until January 2017 that investigated an intervention to treat anemia in any patient population and used at least 1 PROM to evaluate patient-centered outcomes. A descriptive synthesis was performed to characterize the PROMs used and to evaluate the quality of patient-centered outcome (PCO) reporting. Of the 3224 studies identified in the initial search, 130 met all eligibility criteria. We found that the population most frequently studied was oncology patients (46.2% of studies). The therapy for anemia evaluated in the most studies was erythropoietin-stimulating agents (77.7% of studies). The most commonly used PROM was the Functional Assessment of Cancer Therapy/Functional Assessment of Chronic Illness Therapy tool (46.9%), and the majority of studies used only 1 PROM tool (53.1%). We found significant variability in the quality of PCO reporting across all included studies. Improved methodologic rigor in the assessment of PCOs in anemia management is needed in future studies.

Minimal Incision Total Hip Arthroplasty: A Concise Follow-up Report on Functional and Radiographic Outcomes at 10 Years.

In 2005, we conducted a prospective randomized controlled trial that demonstrated that, compared with a standard incision, a minimal incision technique did not improve early outcomes of total hip arthroplasty (THA). There was concern that reduced exposure could compromise long-term outcome. For the current study, all surviving participants were invited to return for 10-year radiographic and clinical evaluation. Outcome scores were available for 152 patients (69.4%) from the original cohort, and radiographs were available for 126 (57.5%). The median duration of follow-up was 124 months. We did not find significant differences in functional status or radiographic outcome between the minimal and standard incision groups at 10 years. The 10-year implant survival rate was 99.1% (95% confidence interval [CI] = 97.3% to 100%) in the standard incision group and 97.9% (95% CI = 95.1% to 100%) in the minimal incision group (p = 0.57). We concluded that minimal incision THA performed by a high-volume surgeon does not compromise long-term results but offers no benefit over a standard incision. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.