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Lung neoplasms commonly develop in patients previously treated for head and neck carcinomas. The derivation of these tumors, either as new primary lung cancers or as metastatic head and neck cancers, is difficult to establish based on clinical or histopathologic criteria since both are squamous cell carcinomas and have identical features under light microscopy. However, this distinction has significant treatment and prognostic implications. Gene expression profiling was performed on a panel of 52 sequentially collected patients with either primary lung (n = 21) or primary head and neck (n = 31) carcinomas using the Affymetrix HG_U95Av2 high-density oligonucleotide microarray. Unsupervised hierarchical clustering with Ward linkage and the Pearson correlation metric was performed. To assess robustness, bootstrap resampling was performed with 1,000 iterations. A t test of the normalized values for each gene was used to determine the genes responsible for segregating head and neck from lung primary carcinomas, and those with the most differential expression were used for later analyses. In the absence of a large “test” set of tumors, we used a supervised leave-one-out cross-validation to test how well we could predict the tumor origin. Once a gene expression profile was established, 12 lung lesions taken from patients with previously treated head and neck cancers were similarly analyzed by gene expression profiling to determine their sites of origin. Unsupervised clustering analysis separated the study cohort into two distinct groups which reliably remained segregated with bootstrap resampling. Group 1 consisted of 30 tongue carcinomas. Group 2 consisted of 21 lung cancers and 1 tongue carcinoma. The clustering was not changed even when normal lung or tongue profiles were subtracted from the corresponding carcinomatous lesions, and a leave-one-out cross-validation showed a 98% correct prediction (see Supplementary Data 1). A minimum set of 500 genes required to distinguish these groups was established. Given the ability to segregate these lesions using molecular profiling, we analyzed the lung tumors of undetermined origin. All cases clearly clustered with either lung or tongue tumor subsets, strongly supporting our hypothesis that this technique could elucidate the tissue of origin of metastatic lesions. Although histologically similar, squamous cell carcinomas have distinct gene expression profiles based on their anatomic sites of origin. Accordingly, the application of gene expression profiling may be useful in identifying the derivation of lung nodules and consequently enhances treatment planning.

Supplementary Tables 1-3 from Squamous Cell Carcinoma Related Oncogene/DCUN1D1 Is Highly Conserved and Activated by Amplification in Squamous Cell Carcinomas

Chromosomal amplification at 3q is common to multiple human cancers, but has a specific predilection for squamous cell carcinomas (SCC) of mucosal origin. We identified and characterized a novel oncogene, SCC-related oncogene (SCCRO), which is amplified along the 3q26.3 region in human SCC. Amplification and overexpression of SCCRO in these tumors correlate with poor clinical outcome. The importance of SCCRO amplification in malignant transformation is established by the apoptotic response to short hairpin RNA against SCCRO, exclusively in cancer cell lines carrying SCCRO amplification. The oncogenic potential of SCCRO is underscored by its ability to transform fibroblasts (NIH-3T3 cells) in vitro and in vivo. We show that SCCRO regulates Gli1—a key regulator of the hedgehog (HH) pathway. Collectively, these data suggest that SCCRO is a novel component of the HH signaling pathway involved in the malignant transformation of squamous cell lineage. (Cancer Res 2006; 66(19): 9437-44)

Supplementary Figure and Table from Gene Expression Profiling Allows Distinction between Primary and Metastatic Squamous Cell Carcinomas in the Lung

Supplementary Methods from Squamous Cell Carcinoma Related Oncogene/DCUN1D1 Is Highly Conserved and Activated by Amplification in Squamous Cell Carcinomas

Supplementary Figure Legends 1-7 from Squamous Cell Carcinoma Related Oncogene/DCUN1D1 Is Highly Conserved and Activated by Amplification in Squamous Cell Carcinomas

PURPOSE Patellar dislocation is associated with a range of anatomical abnormalities affecting the trochlea, extensor mechanism and the tibia. The relationship between patellofemoral instability and rotational abnormalities of the posterior condyles, trochlear groove and proximal tibia has not been adequately determined. This study aimed to identify the frequency and severity of anatomical risk factors to determine their relative contribution to patellofemoral instability. METHODS A retrospective morphological study was undertaken comparing multiple anatomical measurements with magnetic resonance imaging of 50 patients with patellofemoral instability to an age- and gender-matched Control group (n = 50). Several techniques were assessed measuring both femoral and tibial axial asymmetry. A new measurement, tibial rotational asymmetry, comparing a line between the midpoints of the collateral ligaments to the axis between the patellar tendon and posterior cruciate ligament, was assessed for its association with patellofemoral instability. RESULTS Compared to the controls, the patellofemoral instability group demonstrated a significant difference in tibial rotational asymmetry, with a mean of 2.9° (SD 3.2°) externally rotated vs - 1.6° (SD 2.2°) in the control group. Significant differences were also demonstrated regarding the sulcus angle, tibial tubercle-trochlear groove distance, tibial tubercle-posterior cruciate ligament distance, patellar size and the Insall-Salvati ratio. There were no differences between groups regarding the lengths of the posterior condyles, the heights of the trochlear ridges or lateralisation of the trochlear groove. Further analysis of the patellofemoral instability group revealed a subgroup of males with normal anatomy (7/50) and a subgroup of females with isolated patella alta (7/50). CONCLUSION Patellofemoral instability is associated with tibial rotational asymmetry due to lateralisation of the tibial tubercle. It is also associated with patella alta and reduced trochlear groove depth. The femoral axial shape is otherwise unchanged. LEVEL OF EVIDENCE III.

A 61 year old man sustained electrical burns to hands requiring amputation of the right thumb and index finger at the metacarpophalangeal level. The thumb was reconstructed by means of on-top-plasty of the long finger. This is a reliable and safe technique in selected patients with severe, traumatic hand injuries.

Purpose The minimal important change (minimal amount of change vs. baseline that a patient recognizes as a clinical change) and minimum clinically important difference (smallest difference between two measurements that are deemed important by patients) are important values to evaluate the clinical relevance of changes over time and differences between groups. This study aims to establish these values for the KOOS-12 at 1 year postoperatively. Methods KOOS-12 scores were calculated from the full-length KOOS completed by patients undergoing primary TKA preoperatively and at 1 year follow up. Minimal important change (MIC) values were estimated using the anchor-based predictive modeling approach and adjustment for the large proportion of improved patients in the study cohort was performed. The MCID was defined as the difference in the mean change in the KOOS-12 between the ‘no improvement’ and ‘little improvement’ groups. Results A total of 352 patients (161 male:191 female) with an overall mean age of 67.9 years (standard deviation (SD) 8.2) and a mean body mass index of 31.4 kg/m2 (SD 6.3) were included: 97.1% of patients reported an important improvement, 1.1% reported being about the same and 1.7% reported being importantly worse. The MIC improvement values were 11.5 for Pain, 13.7 for Function, 5.5 for Quality of Life (QoL) and 14.9 for the total KOOS-12 score. MCID values were 13.5 for Pain, 15.2 for Function, 8.0 for QoL and 11.1 for the total KOOS-12 score. Conclusion MIC of 14.9 and MCID of 11.1 established in this study can assist clinicians and researchers in the interpretation of within-group changes (MIC) and differences between groups (MCID) at 1 year after TKA.

To investigate the validity, responsiveness and ceiling effect of the recently introduced KOOS-12 and compare its performance to the KOOS, OKS, WOMAC and UCLA activity scales.Patients from an independent multicentre study examining a medially stabilized knee system prospectively completed the KOOS, OKS, WOMAC and UCLA preoperatively and at 1 year postoperatively. KOOS-12 scores were calculated from the full length KOOS data. Construct validity was assessed using Spearman's correlation analysis. The ceiling effect was evaluated by calculating the percentage of patients with a maximum score. If the percentage exceeded 15%, a ceiling effect was considered to be present. Responsiveness was evaluated by performing paired t tests on the changes in measures and calculation of Cohen's d.A ceiling effect was present for the KOOS Pain, ADL and QoL subscales and the KOOS-JR at 1 year postoperatively. No ceiling effect was observed for the KOOS-12. Correlation of the KOOS-12 was low (0.3 r 0.5) with the UCLA, moderate (0.5 r 0.7) with the KOOS symptoms, sports and WOMAC stiffness subscales and high (r 0.7) with all other scores and subscales. Effect size of the UCLA activity scale was moderate (Cohen's d 0.2-0.8) whereas effect sizes of all other outcome measures were large (d 0.8).The KOOS-12 does not exhibit a ceiling effect, has good convergent construct validity and is responsive to changes in pain, function, QoL and knee impact between preoperatively and 1 year postoperatively.Diagnostic level III.

Pacinian corpuscle pathology is a rare clinical entity and an uncommonly reported cause of digital pain. While many prior reports implicate hand trauma, we describe a case of Pacinian hyperplasia found in a patient with Raynaud’s phenomenon and propose a potential mechanism of disease.

INTRODUCTION Limitations in insurance coverage may cause patients to turn to crowdfunding to raise money for gender-affirming procedures. In this study, we analyze the impact of Medicaid insurance coverage on gender-affirming mastectomy campaigns posted on GoFundMe.com. METHODS Between March 1 and 12, 2021, we accessed GoFundMe.com to analyze available campaigns requesting monetary contributions for gender-affirming mastectomy. Campaigns were identified using the search term "top surgery" followed by the state's name. Duplicate campaigns, campaigns whose primary goal was not gender-affirming mastectomy, and ongoing campaigns were excluded. Campaigns were then categorized according to their state's coverage of gender-affirming surgery: explicit exclusion (EE), explicit inclusion (EI), or no explicit statement of gender-affirming care. We collected data on the number of donors and shares, the fundraising goal, and the total amount raised for each campaign. Common themes within campaign narratives were identified and assessed by each reviewer. Finally, we collected data on the photographs posted by campaign creators. RESULTS Our search yielded 790 campaigns, with an overall mean of 58 ± 99 donors and 212 ± 288 shares. The mean fundraising goal and amount raised among all campaigns were $6811 ± $5027 and $2579 ± $3072, respectively. Fundraising goals were most likely to be met in an EI state than an EE state (26.3% vs 8.1%; P < 0.001). The mean amount sought was highest in EE states and lowest in EI states, whereas the mean amount raised was lowest in EE states and highest in EI states. Of the campaigns, 97.1% mentioned personal or situational characteristics in the narrative section; 16.2% of all campaigns expressed negative feelings about posting on GoFundMe.com to raise money for their surgeries. CONCLUSION Disparities in health care coverage of gender-affirming surgeries were seen between state categories, with a decreased need for crowdfunding in states explicitly including coverage of gender-affirming surgery. Many transgender patients used crowdfunding to pay for transition-related health care costs, relying on the kindness of strangers and their social network at the expense of their personal privacy. Expansion of legislative coverage of gender-affirming surgeries may alleviate some of this financial burden and reduce transgender patients' reliance on crowdfunding campaigns.

The management of phalangeal and metacarpal fractures continues to evolve. Nonoperative or less invasive techniques, limiting the need for soft tissue dissection and resultant stiffness, are being developed and becoming more popular. The competing forces of fracture stability to optimize healing and early mobilization to optimize function need careful balancing. As imaging, equipment, and techniques improve, hand surgeons can tailor individualized care to the unique needs of each patient.

CD1a-autoreactive T cells contribute to skin disease, but the identity of immunodominant self-lipid antigens and their mode of recognition are not yet solved. In most models, MHC and CD1 proteins serve as display platforms for smaller antigens. Here, we showed that CD1a tetramers without added antigen stained large T cell pools in every subject tested, accounting for approximately 1% of skin T cells. The mechanism of tetramer binding to T cells did not require any defined antigen. Binding occurred with approximately 100 lipid ligands carried by CD1a proteins, but could be tuned upward or downward with certain natural self-lipids. TCR recognition mapped to the outer A' roof of CD1a at sites remote from the antigen exit portal, explaining how TCRs can bind CD1a rather than carried lipids. Thus, a major antigenic target of CD1a T cell autoreactivity in vivo is CD1a itself. Based on their high frequency and prevalence among donors, we conclude that CD1a-specific, lipid-independent T cells are a normal component of the human skin T cell repertoire. Bypassing the need to select antigens and effector molecules, CD1a tetramers represent a simple method to track such CD1a-specific T cells from tissues and in any clinical disease.

CD1a molecules capture lipid classes that can prevent the binding of autoreactive T cell antigen receptors., CD1a-autoreactive T cells represent a significant proportion of circulating αβ T cells in humans and appear to be enriched in the skin. How their autoreactivity is regulated remains unclear. In this issue of JEM, Cotton et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20202699) show that CD1a molecules do not randomly survey cellular lipids but instead capture certain lipid classes that broadly interfere with the binding of autoreactive T cell antigen receptors to the target CD1a. These findings provide new potential therapeutic avenues for manipulating CD1a autoreactive T cell responses.

Limb transplantation is a life-changing procedure for amputees. However, limb recipients have a 6-fold greater rejection rate than solid organ transplant recipients, related in part to greater immunogenicity of the skin. Here, we report a detailed immunological and molecular characterization of individuals who underwent bilateral limb transplantation at our institution. Circulating Th17 cells are increased in limb transplant recipients over time. Molecular characterization of 770 genes in skin biopsies reveals upregulation of T cell effector immune molecules and chemokines, particularly CCL18. Skin antigen-presenting cells primarily express the chemokine CCL18, which binds to the CCR8 receptor. CCL18 treatment recruits more allo-T cells to the skin xenograft in a humanized skin transplantation model, leading to signs of accelerated graft rejection. Blockade of CCR8 remarkedly decreases CCL18-induced allo-T cell infiltration. Our results suggest that targeting the CCL18:CCR8 pathway could be a promising immunosuppressive approach in transplantation.

Supplemental Digital Content is available in the text., Background: Upper extremity transplantation (UET) is becoming increasingly common. This article attempts to collate data from cases contributing to the International Registry on Hand and Composite Tissue Transplantation (IRHCTT), define psychosocial themes perceived as predictors of success using statistical methods, and provide an objective measure for optimization and selection of candidates. Methods: The IRHCTT provided anonymous data on UET recipients. A supplementary psychosocial survey was developed focusing on themes of depression, posttraumatic stress disorder (PTSD), anxiety, interpersonal functioning and dependence, compliance, chronic pain, social support, quality of life, and patient expectations. We determined the risk of transplant loss and psychological factors associated with higher risk of transplant loss. Results: Sixty-two UET recipients reported to the IRHCTT. Forty-three psychosocial surveys (68%) were received, with 38 (88%) having intact transplants and 5 (12%) being amputated. Among recipients with a diagnosis of anxiety (N = 29, 67%), 5 (17%) reported transplant loss (P = 0.03). Among those with depression (N = 14, 33%), 2 recipients (14%) has transplant loss (P = 0.17); while 4 recipients (22%) with PTSD (N = 18, 42%) had transplant loss (P = 0.01). Of participants active in occupational therapy (N = 28, 65%), 2 (7%) reported transplant loss (P = 0.09). Of recipients with realistic functional expectations (N = 34, 79%), 2 (6%) had transplant loss versus 3 (34%) who were felt to not have realistic expectations (N = 9, 21%, P = 0.05). Recipients with strong family support (N = 33, 77%) had a lower risk of transplant loss compared with poor or fair family support (N = 10, 23%), but did not reach statistical significance (6% versus 30%, P = 0.14). Conclusion: Anxiety, depression, PTSD, participation in occupational therapy, expectations for posttransplant function, and family support are associated with postsurgical transplant status.

Animal studies are essential to biomedical research and the cornerstone is a reproducible animal model. While there are many reports on rodent peripheral nerve injury models, a large animal model is essential to confirm the effects of nerve regeneration over the longer distances of regeneration required in humans. Swine have long been used as a large animal model for other surgical and biomedical studies. This paper represents a novel neurovascular injury model in the Sus scrofa domesticus swine (American Yorkshire pig). This paper will describe our experience and recommendations with pre-operative, operative and post-operative protocols and our refinements to produce an effective model.

Purpose We performed a qualitative study to understand the psychosocial factors associated with success in upper-extremity vascularized composite allotransplantation from the perspective of transplant providers. Methods We recruited 13 providers actively involved in upper-extremity vascularized composite allotransplantation. Participants included physicians, nurses, social workers, occupational therapists, and research administrators. We conducted semistructured face-to-face focus group interviews using a guide that explored providers’ perceptions of qualities contributing to transplant outcome. Topics included social support networks and their influence on recovery, barriers to treatment compliance and successful posttransplant rehabilitation, and the process of setting patients’ expectations. We performed a thematic analysis that produced a list of themes, subthemes, and proposed hypotheses explaining how the themes related to the study’s guiding questions. Results The analysis identified numerous factors that contribute to transplant success: (1) recipients’ prior experiences modify their ability to cope and adapt after transplantation, (2) behaviors and characteristics such as positivity influence candidacy and may be predictive of successful outcomes, and (3) social support is essential for improved function and compliance. The provider care team cited difficulty in predicting recipient compliance and in setting realistic expectations. Conclusions Motivated recipients with developed coping and resiliency, a positive attitude, and stable, physically-able caregivers are perceived by providers to have greater success after transplantation. Clinical Relevance Findings from this work may help providers determine optimal candidates for upper-extremity vascularized composite allotransplantation.

We report a case of a 71-year-old female patient who sustained a severe midface soft tissue avulsion injury from a family canine. The removed tissue was recovered from the canine's digestive tract and transferred to the hospital where emergent microvascular replantation was performed. The tissue survived for 72 hours, but then developed vascular compromise. Despite aggressive revision of multiple anastomoses with extensive use of vein grafting, the replanted segment was lost. Reconstruction then proceeded along traditional lines with an acceptable cosmetic outcome and good functional outcomes.

The sulcus line (SL) is a three-dimensional landmark that corrects for individual variation in the coronal alignment of the trochlear groove in contrast to the traditional Whiteside's line (WL). Femoral rotational asymmetry (FRA) is an anatomical variation in which the posterior condyles and trochlear groove are not perpendicular to each other. This study aims to measure the SL and assess its reliability relative to WL, in addition to measuring and classifying the FRA. A retrospective analysis of a series of 191 CT scans of nonarthritic knees was performed. Measurements were taken of rotational landmarks in three-dimensional reconstructions. The variability and outlier rate of SL was less than WL (P 0.05), however it decreased the rate of change of the rotational alignment of the trochlear groove between the native knee and the prosthetic knee from 31% to 5% (P 5° in 56/191 (29%) of cases. The SL technique is more accurate than WL for determining the rotational alignment of the trochlear groove. Nonarthritic femora have a high rate of rotational asymmetry. Identifying and classifying FRA in individual cases allows the femoral component to be inserted in a position which gives the best possible match to both the native posterior condyles and trochlear groove. Clin. Anat. 31:551-559, 2018. © 2018 Wiley Periodicals, Inc.

Vascularized composite allotransplantation represents a useful addition to reconstructive options available to the plastic surgeon. Though the procedure provides beneficial functional outcomes, there remain complications, often associated with the immunosuppression necessary to maintain an allograft. We report a case of eponychial fold lesions following successful bilateral upper extremity allotransplantation.

Self-efficacy is positively associated with adherence behaviours and rehabilitation outcomes following Anterior Cruciate Ligament (ACL) reconstruction. An internet resource can be an effective way to provide information, goal setting, patient monitoring and hence support overall self-management.This study examined the feasibility of a three month 'internet-based intervention' (mobile-oriented site) to enhance recovery for patients following ACL reconstruction. The potential effect of the internet-based intervention on knee pain, function, self-efficacy and fear of pain were also assessed.This was a pilot randomised controlled trial (RCT) with pre and post intervention design (assessments at one week and three months following ACL reconstruction) comparing: (1) a control group and (2) an intervention group (internet-based intervention). A set of qualitative and quantitative assessments were included to evaluate potential improvements in self-efficacy, pain and function and perception of the internet intervention.Seventeen participants were available for analysis (n = 10 intervention and n = 7 control group). Participants reported the internet-based intervention to be a useful tool for information, reminder and reinforcement for performing their exercise rehabilitation with 30.3% (±35.3%) adherence to the internet-based intervention. No differences were observed between the groups over time on the outcome questionnaires (p 0.05). Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12616001379404.

Vascularised composite allotransplantation (VCA) represents an exciting and emerging field in plastic and reconstructive surgery. Despite the generally good functional and psychosocial outcomes, multiple complications can be associated with the procedure. The authors describe a case of avascular necrosis of the humeral head following successful upper extremity VCA.

A goal of hand and upper extremity transplantation is to return motor and sensory function to an amputee. Given the integral roles of one's hands in activities of daily living and social interaction, however, restoring psychosocial well-being should also be a priority. Based on the authors' experience, double-hand transplantation success depends significantly on strong social support, physical rehabilitation, medication adherence, and social integration. Because caregiving is demanding, tasks should be distributed among members of a patient's family and social network. This article analyzes how to respond to an overwhelmed caregiver by drawing on solid organ transplant literature about caregiver fatigue.

International audience; Background: There is unmet need for non-invasive immunomonitoring to improve diagnosis and treatment of acute rejection in vascularized composite allotransplantation (VCA). Circulating matrix metalloproteinase 3 (MMP3) was described as a candidate non-invasive biomarker to predict treatment response to acute rejection in clinical VCA. However, larger validation studies are yet to be reported to allow for more definitive conclusions. Methods: We retrospectively measured MMP3 levels using ELISA in a total of 140 longitudinal serum samples from six internal and three external face transplant recipients, as well as three internal and seven external upper extremity transplant recipients. The control groups comprised serum samples from 36 kidney transplant recipients, 14 healthy controls, and 38 patients with autoimmune skin disease. A linear mixed model was used to study the effect of rejection state (pre-transplant, no-rejection, non-severe rejection (NSR), and severe rejection) on MMP3 levels. Results: In VCA, MMP3 levels increased significantly (p < 0.001) between pre- and post-transplant no-rejection states. A further increase occurred during severe rejection (p < 0.001), while there was no difference in MMP3 levels between non-severe and no-rejection episodes. A threshold of 5-fold increase from pre-transplant levels could discriminate severe from NSR with 76% sensitivity and 81% specificity (AUC = 0.79, 95% CI = 0.65-0.92, p < 0.001). In kidney transplantation, the MMP3 levels were significantly (p < 0.001) elevated during antibody-mediated rejection but not during T-cell mediated rejection (TCMR) (p = 0.547). MMP3 levels in healthy controls and autoimmune skin disease patients were comparable with either pre-transplant or no-rejection/NSR episodes of VCA patients. Conclusion: The results of this study suggest that serum MMP3 protein is a promising marker for stratifying patients according to severity of rejection, complementary to biopsy findings.

Purpose We performed a qualitative study to understand psychosocial factors associated with perceived success of upper-extremity vascularized composite allotransplantation (VCA). We interviewed transplant recipients and their primary caregivers. Methods We recruited 4 upper-extremity VCA recipients and primary caregivers for 3 of them. We conducted semistructured face-to-face interviews using a guide that explored participants’ transplantation experiences. Topics included comparison of pretransplant and posttransplant expectations, reflections on factors contributing to the success of the transplant experience, and posttransplant rehabilitation and functioning. We performed a thematic analysis that produced a list of themes, subthemes, and proposed hypotheses explaining how the themes related to the study’s guiding questions. Results Participants described several factors as contributing to the success of the transplant experience, including developing realistic expectations about posttransplant function and lifelong immunosuppression, support from one’s community and particularly the primary caregiver, and framing the experience in a positive light. Social, aesthetic, and other values unique to the hands, as opposed to prosthetics, motivated recipients to undergo VCA despite its inherent risk and uncertainties. Conclusions Despite inherent challenges, undergoing VCA was viewed as worthwhile to regain benefits unique to hands. Participants met the challenges of the transplant process through setting realistic expectations, strong social support, and a positive perspective. Clinical relevance Findings from this work may help clinicians and prospective patients to prepare for and set appropriate expectations of VCA.

Previous studies have demonstrated that the product of the Interferon stimulated geneCh25h, 25-Hydroxycholestrol, provides an immediate and rapid mechanism for down-regulating sterol biosynthesis, through the inhibition ofHmgcrgene expression and proteolytic degradation of HMGCR protein. Further studies provide evidence that inhibition of the sterol biosynthesis pathway by 25-HC has broad antiviral effects. In this study, Influenza A virus (IAV) replication was inhibited in cells treated with Fluvastatin or whereHmgcrexpression was inhibited with an siRNA. Treatment of A549 cells with 25-HC however, resulted in a 2-fold enhancement of IAV replication despite the fact that 25-HC promotes the proteolytic degradation of HMGCR. A549 cells infected with IAV revealed a rapid loss of HMGCR protein, a reduction inHmgcrgene expression as well as an increase in the expression ofCh25h, that were all independent of the IFN pathway. Infection of both wild-type andCh25h−/−murine BMDMs with IAV also revealed a rapid loss of HMGCR abundance indicating that 25-HC independent mechanisms exist for promoting proteolytic degradation of HMGCR. These data for the human A549 cell line contrast with the induction ofCh25hand subsequent loss of HMGCR in murine cells that has been shown to be dependent on IFN signalling.ImportanceCholesterol, a lipid, is mainly produced by the liver or obtained from everyday foods. It is an essential element of the structure of cells and is vital for maintaining the normal function of human body. In cells, cholesterol can be oxidised to oxysterols by biological catalysts, known as enzymes. Certain oxysterols have recently emerged as important elements in the immune response to micro-organisms. This project studied a key enzyme, which is a component of the cholesterol metabolism, known as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). A set of experiments were designed and performed to study the behaviour of HMGCR following viral infections. This study lays the foundation for re-building a map of cholesterol metabolism and the immune response to viral infection. It will be useful for understanding the importance of cholesterol metabolism in infection and exploring novel antiviral strategies.

Joint stability is one of the goals of any joint replacement. The contribution of prosthesis design to sagittal stability in total knee arthroplasty (TKA) has emerged as an area of interest. The purpose of this study was to evaluate the sagittal stability of four prosthesis types and determine the effect on patient reported outcome measures (PROMs).A matched-cohort cross-sectional study was performed on 60 patients after TKA at 1-year follow-up. Three surgeons performed 10 medially stabilized (MS) TKA and 10 non-MS TKA. Sagittal stability was assessed by a blinded observer using a KT-1000 arthrometer, Lachman's test, and the anterior drawer test. PROMs (Oxford, Knee Injury and Osteoarthritis Outcome Score, Western Ontario and McMaster Universities Osteoarthritis Index, Forgotten joint score) and visual analog scale assessed function and satisfaction.MS TKA had significantly decreased translation on KT-1000 and improved stability compared with non-MS TKA (P.05). Increased PROMs were demonstrated in the MS TKA group compared with the non-MS TKA group (P.05). When divided based on objective stability, regardless of the prosthesis type, patients with a stable knee had superior PROMs (P.05), particularly in sport-related questions.The MS TKA had significantly greater sagittal stability, improved PROMs, and satisfaction compared with non-MS TKA. Independent of prosthesis design, patients with greater sagittal stability demonstrated improved PROMs.

Summary: Perineal wounds are one of the more challenging plastic surgical defects to reconstruct. Resections in the perineum vary in size and are frequently complicated by radiation, chemotherapy, and contamination. Furthermore, the awkward location and potential need to maintain function of the anus, urethra, and vagina and to allow comfortable sitting all contribute to the complexity of these reconstructions. In light of this complex nature, many options are available for flap coverage. In this paper, we discuss the properties of perineal defects that make each option appropriate.

Microvascular muscle transfer is the gold standard for reanimation following chronic facial nerve paralysis, however, despite the regenerative capacity of peripheral motor axons, poor reinnervation often results in sub-optimal function. We hypothesized that injection of alginate hydrogels releasing growth factors directly into donor tissue would promote reinnervation, muscle regeneration, and function. A murine model of sciatic nerve ligation and neurorrhaphy was first used to assess the ability of gel delivery of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) to promote functional reinnervation. VEGF + IGF-1 gel delivery to aged mice resulted in prolonged ability to control toe movement, increased toe spreading, and improved static sciatic index score, indicative of improved sciatic nerve and neuromuscular junction function. Further, a 26% increase in muscle fiber area, and 2.8 and 3.0-fold increases in muscle contraction force and velocity, respectively, were found compared to blank alginate in the murine model. This strategy was subsequently tested in a rabbit model of craniofacial gracilis muscle transplantation. Electromyography demonstrated a 71% increase in compound muscle action potential 9 weeks after transplantation following treatment with VEGF + IGF-1 alginate, compared to blank alginate in the rabbit model. Improving functional innervation in transplanted muscle via a hydrogel source of growth factors may enhance the therapeutic outcomes of facial palsy treatments and, more broadly, muscle transplantations.

Background Patient reported outcome measurements (PROMs) that exhibit a substantial ceiling effect show clustering of participant's scores towards the upper limit of a scale and consequently have low discriminatory power among high end scores. This study aimed to compare ceiling effects at 1 and 2 years postoperatively across commonly usedPROMs for TKA. Hypothesis We hypothesized, that the analyzed PROMs differ substantially in regards to their ceiling effect. Patients and methods Patients that underwent a primary unilateral TKA and completed pre-operative and post-operative questionnaires were included in the analysis. Participants completed the KOOS, KOOS-12, KOOS-JR, KOOS-PS, WOMAC and OKS preoperatively, and completed the KOOS, KOOS-12, KOOS-JR, KOOS-PS, WOMAC,OKS and FJS postoperatively at 1 and 2 years. Results 1-year and 2-year follow-up data was available for 380 and 193 patients, respectively. The preoperative mean age was 68.0 (8.5) and mean BMI was 31.4 kg/m2 (6.6), with a male to female ratio of 49.6% to 50.4%. At 1 year postoperatively, a ceiling effect was seen for the Pain and ADL subscales of the KOOS and the KOOS JR. The KOOS Pain, Symptoms, ADL and QoL subscales, the WOMAC Total and KOOS JR exhibited a ceiling effect at 2 years postoperatively. We found 9.0% and 14.8% of patients achieving a maximum score in the FJS at 1 and 2 years, respectively, indicating the absence of a substantial ceiling effect. Conclusion The PROMs studied differ substantially with regards to their ceiling effect and consequently their ability to detect differences between well performing groups. The KOOS Pain, Symptoms, ADL and QoL subscales, the WOMAC Total and KOOS JR exhibited a substantial ceiling effect at 2 years postoperatively. We recommend using PROMs like the FJS and KOOS-12 with a more evenly distribution of scores across the scale when studying well performing cohorts. Level of evidence III.