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Purpose The purpose of this investigation was to systematically review the contemporary literature to determine if a lateral augmentation (LA) added to an Anterior Cruciate Ligament Reconstruction (ACLR) provides better clinical and patient reported outcomes compared to an isolated ACLR. Methods A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) criteria. Two authors independently conducted an electronic search using MEDLINE® and Embase® on February 6 th , 2021 for level I-III randomized controlled trials (RCT) and prospective cohort studies without randomization, published after 2012 and with a minimum of two year follow-up. Publications were included when they reported on the objective knee stability examination, patient reported outcome scores, return to sports or graft rupture rate of any type of primary, isolated ACLR compared to ACLR combined with any type of LA. Results A total of 11 studies that reported on a combined total of 1892 unique patients were eligible for data extraction, including five RCTs and six prospective cohort studies. In 6 studies, an Anterolateral Ligament reconstruction (ALLR) was the LA of choice, while the 5 other publications used different types of Lateral Extra-articular Tenodesis (LET). A significant reduction in graft ruptures was found in patients treated with ACLR + LA (3%) compared to isolated ACLR (12%). Rotational laxity was significantly higher in isolated ACLR (14%) compared to ACLR + LA (6%). Addition of a LA reduced anterior translation when assessed via instrumented laxity testing. No significant difference was found in the patient reported outcome scores (IKDC and Tegner) between both patient groups, except for the Lysholm Score which was significant in favour of the ACLR + LA group. Conclusion Combination of a primary ACLR with a LA can significantly reduce the risk of graft rupture and provide better rotatory stability, without jeopardizing patient reported outcomes. Level of evidence Level III, Systematic Review of Level I, II and III studies.

Purpose To identify available patient-reported outcome measures (PROMs) used to evaluate central sensitization (CS) manifestations in chronic pain conditions and evaluate the quality of psychometric properties of those instruments. Methods A comprehensive search across multiple electronic databases was conducted for relevant studies following the specification of eligibility criteria and development of key search terms. After screening and full-text review, the methodological quality of studies and psychometric properties of PROMs were assessed and summarized using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and scoring manual. The results were statistically pooled in a meta-analysis, specifically test-retest reliability, based on data availability and consistency of findings across studies. Results A total of fifty-eight studies evaluating eight instruments in adult patients with chronic pain were included. The methodological quality of the included studies was varied. Most identified PROMs have limited evidence regarding their measurement properties. The Central Sensitization Inventory (CSI) received the highest overall ratings for most measurement properties among all the instruments, followed by Pain Sensitivity Questionnaire (PSQ) and Fibromyalgia Survey Questionnaire (FSQ). Based on pooled data from available studies, the test-retest reliability of the CSI was found to be excellent, with an intra-class correlation coefficient (ICC) of 0.93 (95% CI: 0.91–0.95) for overall chronic pain, 0.90 (95% CI: 0.87–0.93) for chronic musculoskeletal pain and 0.93 (95% CI: 0.88–0.99) for chronic neck pain. PSQ also demonstrated excellent test-retest reliability, showing an ICC of 0.86 (95% CI: 0.72–0.99) for chronic pain. Conclusion Although not all properties have been studied, the CSI, which received the highest overall ratings, could serve as a reliable PROM assessing CS in chronic pain. More studies should be performed to comprehensively evaluate all measurement properties of all included instruments. Plain English summary Central sensitization (CS) is a key process in many chronic pain conditions where the central nervous system becomes overly sensitive, causing persistent pain even in the absence of clear tissue damage. To evaluate the outcome of care for pain associated with CS, healthcare providers use patient-reported outcome measures (PROMs) as outcome measurement instruments that capture the patient’s pain experience. However, the quality of these PROMs is very important to ensure they accurately reflect the patient’s experience and the outcomes they intend to measure. In this study, we evaluated and rated the psychometric properties (also referred to as measurement properties) - reliability, validity and responsiveness of eight different PROMs used to assess CS manifestation in chronic pain. Our findings revealed that most PROMs lack sufficient evidence supporting their quality. Notably, the Central Sensitization Inventory (CSI) showed promising results, but further research is needed to assess all properties. Our findings recommend more studies to fully evaluate all properties of all PROMs, which would be beneficial for both clinicians and researchers to better understand, measure the outcome of care and manage chronic pain associated with CS.

PurposeTo extensively review Patient Reported Outcome Measures (PROMs) used to assess outcomes in persons with hand fractures in terms of their psychometric properties.MethodsA COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodological review was conducted. Six electronic databases were searched (Medline, Embase, Scopus, Web of Science, PsycINFO, CINAHL) for studies evaluating the psychometric properties of PROMs assessing recovery from hand fracture. Titles and abstracts, full text review, quality assessment and data extraction were performed by two reviewers. Any disagreements were resolved after review by a third, expert reviewer. Quality assessment of included studies was performed using the COSMIN checklist.ResultsThis COSMIN review found that there were only 4 studies that fulfilled the inclusion criteria in terms of assessing measurement properties of PROMs in hand fractures. Only the construct validity of the Disabilities of the Arm, Shoulder, and Hand (DASH), the Quick DASH (QDASH) and the Duruoz Hand Index (DHI), and the responsiveness of the DASH, the Patient Specific Functional Scale (PSFS), the Patient-Rated Wrist and Hand Evaluation (PRWHE) and the Michigan Hand Outcomes Questionnaire (MHQ) were assessed in these studies. The overall rating of the studies was assessed as insufficient or indeterminate and quality of evidence was assessed as moderate, low, or very low by our team.ConclusionsThis study identified that there is a lack of evidence in the medical literature with regards to the measurement properties of PROMs in patients with hand fractures. The 4 included studies do not provide good quality data to support the use of these PROMS in patients with hand fractures. There is a need for more studies for more PROMs. This has important consequences for how outcomes will be measured in clinical studies in hand research and in clinical practice.SummaryHand fractures are some of the most common types of fractures in adults. They affect patients in the short term with everyday activities and can have a long-term impact especially on people who use their hands a lot at work and at home. The recovery from a hand fracture, with whatever treatment, can be captured by questionnaires completed by patients at frequent time intervals. We looked at whether questionnaires, which could do so for these patients, have been assessed in previous studies. Even though this is an important topic, we only found a handful of studies which have done so, and these were not very robust in their assessment. This study indicates that there needs to be more work in the field which will be very helpful for clinical practice and future research.

Background: A posterior tibial slope (PTS) >12° has been shown to correlate with failure of anterior cruciate ligament (ACL) reconstruction (ACLR). PTS-reducing osteotomy has been described to correct the PTS in patients with a deficient ACL, mostly after failure of primary ACLR. Purpose: To report radiologic indices, clinical outcomes, and postoperative complications after PTS-reducing osteotomy performed concurrently with revision ACLR (R-ACLR). Study Design: Case series; Level of evidence, 4. Methods: A review of medical records at 3 institutions was performed of patients who had undergone PTS-reducing osteotomy concurrently with R-ACLR between August 2010 and October 2020. Radiologic parameters recorded included the PTS, patellar height according to the Caton-Deschamps Index (CDI), and anterior tibial translation (ATT). Patient-reported outcomes (International Knee Documentation Committee [IKDC] and Knee injury and Osteoarthritis Outcome Score [KOOS]), reoperations, and complications were evaluated. Results: Included were 23 patients with a mean follow-up of 26.7 months (range, 6-84 months; median, 22.5 months). Statistically significant differences from preoperative to postoperative values were found in PTS (median [range], 14.0° [12°-18°] vs 4.0° [0°-15°], respectively; P < .001), CDI (median, 1.00 vs 1.10, respectively; P = .04) and ATT (median, 8.5 vs 3.6 mm, respectively; P = .001). At the final follow-up, the IKDC score was 52.4 ± 19.2 and the KOOS subscale scores were 81.5 ± 9.5 (Pain), 74 ± 21.6 (Symptoms), 88.5 ± 8 (Activities of Daily Living); 52.5 ± 21.6 (Sport and Recreation), and 48.8 ± 15.8 (Quality of Life). A traumatic ACL graft failure occurred in 2 patients (8.7%). Reoperations were necessary for 6 patients (26.1%) because of symptomatic hardware, and atraumatic recurrent knee instability was diagnosed in 1 patient (4.3%). Conclusion: Tibial slope–reducing osteotomy resulted in a significant decrease of ATT and can be considered in patients with a preoperative PTS ≥12° and ≥1 ACLR failure. In highly complex patients with multiple prior surgeries, the authors found a reasonably low graft failure rate (8.7%) when utilizing PTS-reducing osteotomy. Surgeons must be aware of potential complications in patients with multiple previous failed ACLRs.

Background: Despite the overall prevalence and success of total knee arthroplasty (TKA), a significant portion of patients are dissatisfied with their outcomes. Purpose: To assess the responsiveness and determine the minimally important difference (MID) of 2 patient-reported outcome measures (PROMs)—the Knee injury and Osteoarthritis Outcome Score–Joint Replacement (KOOS-JR) and the Patient-Reported Outcomes Measurement Information System Global–10 (PROMIS 10)—in patients after TKA. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Included were patients who underwent TKA from August 2015 through August 2019 and completed baseline and postoperative KOOS-JR and PROMIS 10 surveys. The PROMIS 10 consists of 2 domains: physical health and mental health. Estimates for the reliable change index (RCI) and MID, using anchor-based and distribution-based methods, were calculated for each PROM. Regression modeling was used to determine whether patient and clinical factors predicted MID thresholds or MID achievement. Results: A total of 1315 patients were included. Distribution-based MIDs, calculated using various methods from baseline scores, ranged from 19.3 to 31 for the KOOS-JR, and the RCI was 4.38. Of these patients, 293 (22.3%) demonstrated small or moderate improvement, and this cohort was included in the calculation of anchor-based MIDs. The anchor-based MIDs were 16.9 and 24.3 at 3-month and 1-year follow-up, respectively, and 66% of patients achieved the MID at 12 months. Higher preoperative PROM score, male sex, non-White race, and current smoker status were predictive of failing to achieve the anchor-based MID for KOOS-JR at 1 year postoperatively (P < .05). Higher preoperative PROM score and any 90-day adverse event predicted lower thresholds of important change in anchor-based MIDs. Higher baseline PROM scores, younger age, male sex, non-White ethnicity, higher American Society of Anesthesiologists classification, preoperative narcotics use, not smoking, and longer hospital stay were all associated with lower odds of achieving the MID on the KOOS-JR or either of the PROMIS 10 subscales. Conclusion: The study results demonstrated relevant values for interpretation of the KOOS-JR and PROMIS 10. While patient demographics did not accurately predict which patients would achieve the MID, some potential factors predicting successful patient-reported outcomes after TKA were identified.

Purpose:Graft failure rates following anterior cruciate ligament reconstruction (ACLR) are inadequate in young, active patients. Recently, the STABILITY 1 Study provided level 1 evidence that augmenting hamstring ACLR with a lateral extra-articular tenodesis (LET) reduces graft failure. Further evidence regarding outcomes after LET and in those with specific risk factors is required. Methods:This thesis includes three studies. In study 1, we used logistic regression to determine predictors of persistent rotatory laxity and graft failure in young, active patients two-years post-ACLR. In study 2, we investigated a subgroup of patients with lateral meniscal posterior root tears (LMPRT) at the time of ACLR to determine how the injury affected their outcome postoperative. In study 3, we performed magnetic resonance imaging on a consecutive subgroup of patients at two-years postoperative to determine whether augmenting ACLR with LET affects articular cartilage quality in the lateral compartment of the knee. Results:In study 1, adding an LET was significantly associated with 60% lower odds of graft rupture, while younger age, increased tibial slope, high-grade preoperative knee laxity, and earlier RTS were associated with higher odds of graft rupture. Adding an LET and increasing graft diameter significantly reduced persistent rotatory laxity. In study 2, we found that patients with a LMPRT have similar outcomes to patients without LMPRT, regardless of treatment performed. In study 3, we found that T1rho relaxation was slightly elevated in the lateral compartment for the ACLR + LET group. Cartilage relaxation values increased as meniscal tear size increased when the meniscus was excised, while relaxation times were relatively stable after repair. Conclusion:Our findings confirm the protective nature of the LET while identifying other predictors of clinical failure and graft rupture. Our results suggest clinicians are skilled at deciding when LMPRTs need to be repaired, and that the meniscus should be repaired, where possible, to prevent changes in cartilage relaxation. This study confirms the need for long-term follow-up of STABILITY 1 patients to determine whether the LET provides short-term stability without increasing increased risk of OA development.

The Star Excursion Balance Test (SEBT) is an eight-direction, maximal-reach balance test whose measurement properties are unknown in participants with chronic patellar instability. We designed an observational study with repeated measures to evaluate the test-retest reliability, cross-sectional and longitudinal construct validity, sensitivity to change and responsiveness of the SEBT in this population. Fifteen patients completed the SEBT and reported outcomes at baseline and two weeks and four patients completed testing three months later at the Fowler Kennedy Sports Medicine Clinic. Intra-class correlation coefficients (ICC) for the SEBT were fair to good, ranging from 0.66-0.84. The SEBT demonstrates good cross-sectional construct validity and we are unable to comment with certainty on longitudinal construct validity; correlations between SEBT reach distance and patient-reported outcomes showed agreement with our hypotheses in 93 of 126 (74%) and 46 of 108 (43%) directions. These are preliminary results of a larger continuing study; therefore definitive conclusions cannot be made.

Members of the family Coronaviridae have the largest genomes of all RNA viruses, typically in the region of 30 kilobases. Several coronaviruses, such as Severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), are of medical importance, with high mortality rates and, in the case of SARS-CoV, significant pandemic potential. Other coronaviruses, such as Porcine epidemic diarrhea virus and Avian coronavirus, are important livestock pathogens. Ribosome profiling is a technique which exploits the capacity of the translating ribosome to protect around 30 nucleotides of mRNA from ribonuclease digestion. Ribosome-protected mRNA fragments are purified, subjected to deep sequencing and mapped back to the transcriptome to give a global \"snap-shot\" of translation. Parallel RNA sequencing allows normalization by transcript abundance. Here we apply ribosome profiling to cells infected with Murine coronavirus, mouse hepatitis virus, strain A59 (MHV-A59), a model coronavirus in the same genus as SARS-CoV and MERS-CoV. The data obtained allowed us to study the kinetics of virus transcription and translation with exquisite precision. We studied the timecourse of positive and negative-sense genomic and subgenomic viral RNA production and the relative translation efficiencies of the different virus ORFs. Virus mRNAs were not found to be translated more efficiently than host mRNAs; rather, virus translation dominates host translation at later time points due to high levels of virus transcripts. Triplet phasing of the profiling data allowed precise determination of translated reading frames and revealed several translated short open reading frames upstream of, or embedded within, known virus protein-coding regions. Ribosome pause sites were identified in the virus replicase polyprotein pp1a ORF and investigated experimentally. Contrary to expectations, ribosomes were not found to pause at the ribosomal frameshift site. To our knowledge this is the first application of ribosome profiling to an RNA virus.

The loss of glomerular podocytes is a key event in the progression of chronic kidney disease resulting in proteinuria and declining function. Podocytes are slow cycling cells that are considered terminally differentiated. Here we provide the first report of the directed differentiation of induced pluripotent stem (iPS) cells to generate kidney cells with podocyte features. The iPS-derived podocytes share a morphological phenotype analogous with cultured human podocytes. Following 10 days of directed differentiation, iPS podocytes had an up-regulated expression of mRNA and protein localization for podocyte markers including synaptopodin, nephrin and Wilm's tumour protein (WT1), combined with a down-regulation of the stem cell marker OCT3/4. In contrast to human podocytes that become quiescent in culture, iPS-derived cells maintain a proliferative capacity suggestive of a more immature phenotype. The transduction of iPS podocytes with fluorescent labeled-talin that were immunostained with podocin showed a cytoplasmic contractile response to angiotensin II (AII). A permeability assay provided functional evidence of albumin uptake in the cytoplasm of iPS podocytes comparable to human podocytes. Moreover, labeled iPS-derived podocytes were found to integrate into reaggregated metanephric kidney explants where they incorporated into developing glomeruli and co-expressed WT1. This study establishes the differentiation of iPS cells to kidney podocytes that will be useful for screening new treatments, understanding podocyte pathogenesis, and offering possibilities for regenerative medicine.

Segment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a target for antiviral drugs and vaccination. Surprisingly, M2 is not essential for virus replication in a laboratory setting, although its loss attenuates the virus. To better understand how IAV might replicate without M2, we studied the reversion mechanism of an M2-null virus. Serial passage of a virus lacking the mRNA2 splice donor site identified a single nucleotide pseudoreverting mutation, which restored growth in cell culture and virulence in mice by upregulating mRNA4 synthesis rather than by reinstating mRNA2 production. We show that mRNA4 encodes a novel M2-related protein (designated M42) with an antigenically distinct ectodomain that can functionally replace M2 despite showing clear differences in intracellular localisation, being largely retained in the Golgi compartment. We also show that the expression of two distinct ion channel proteins is not unique to laboratory-adapted viruses but, most notably, was also a feature of the 1983 North American outbreak of H5N2 highly pathogenic avian influenza virus. In identifying a 14th influenza A polypeptide, our data reinforce the unexpectedly high coding capacity of the viral genome and have implications for virus evolution, as well as for understanding the role of M2 in the virus life cycle.