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Objectives: The aim of this study was to show how the US government could save approximately 47 000 patients with chronic kidney failure each year from suffering on dialysis and premature death by compensating living kidney donors enough to completely end the kidney shortage.Methods: Supply and demand analysis was used to estimate the number of donated kidneys needed to end the kidney shortage and the level of compensation required to encourage this number of donations. These results were then input into a detailed cost-benefit analysis to estimate the economic value of kidney transplantation to (1) the average kidney recipient and their caregiver, (2) taxpayers, and (3) society in general.Results: We estimate half of patients diagnosed with kidney failure each year-approximately 62 000 patients-could be saved from suffering on dialysis and premature death if they could receive an average of 1½ kidney transplants. However, currently there are only enough donated kidneys to save approximately 15 000 patients. To encourage sufficient donations to save the other 47 000 patients, the government would have to compensate living kidney donors approximately $77 000 (±50%) per donor. The value of transplantation to an average kidney recipient (and caregiver) would be approximately $1.5 million, and the savings from the recipient not needing expensive dialysis treatments would be approximately $1.2 million.Conclusions: This analysis reveals the huge benefit that compensating living kidney donors would provide to patients with kidney failure and their caregivers and, conversely, the huge cost that is being imposed on these patients and their families by the current legal prohibition against such compensation. [ABSTRACT FROM AUTHOR]

Regulation of p53 tumor suppressor gene is discussed in the contexts of the Mdm2 and Ras genes which show opposing effects on p53. Research reveals that the Ras-driven Raf/MEK/MAP kinase pathway suppresses p53 during tumor development through Raf's activation of the Mdm2's inhibitor p19(sup)ARF.

Abnormalities in the the cytoskeletons of affected cells in the Wiskott-Aldrich syndrome led to the observation that this disease may be caused by a disfunction in the formation of actin cytoskeletons. The syndrome may be caused by the absence of the Wiskott-Aldrich Syndrome protein (WASP) which normally serves in organizing polymerized actin. WASP has a structure with parts similar to other actin organizer proteins, and is inhibited specifically by the guanosine triphosphatase CDC42Hs.

The formation of stress fibers in response to epidermal growth factor (EGF) induced stress is controlled by Rac and Rho proteins and takes place through the lipoxygenase pathway of the arachidonic acid metabolism. Leukotrienes are needed for some EGF-induced changes in the cytoskeleton which include membrane ruffling followed by the formation of the stress fibers in Swiss 3T3 cells. Rac is necessary for the formation of leukotrienes which in turn activates Rho.

Brefeldin A is a toxin that can wreak havoc on mammalian cells. Within minutes, the toxin causes the Golgi complex to disassemble and redistribute into the endoplasmic reticulum. This collapse of the Golgi apparatus is believed to be caused by the inhibition of exchange factors linked to the ADP-ribosylation factor (ARF). While the molecular mechanism of Brefeldin A's action is not known, it is theorized to be due to the trapping of the exchange reaction in a dead-end complex. Further research could prove to be very useful in the development of drugs that target other small G proteins.

Purpose: To evaluate the surgical outcomes of a primary subpectoral biceps tenodesis for long head of the biceps tendon (LHBT) pathology in a large cohort of prospectively, serially collected, patients in a young active population that has known high physical demands and requirements of their shoulder to perform their vocation.Methods: A retrospective review of prospectively collected data from an active military personnel with a diagnosis of a Type II SLAP tear or biceps tenosynovitis was performed. Outcomes were evaluated at a minimum follow-up time of 18 months based on preoperative and postoperative assessments of the Single Assessment Numeric Evaluation, Western Ontario Rotator Cuff index, biceps position, and return to active duty. Inclusion criteria were (1) SLAP tears on magnetic resonance arthrogram (classified into SLAP group), and (2) no SLAP tear but examination findings of biceps tendonitis (placed in the LHBT tendonitis group). Patients were excluded for full-thickness rotator cuff tears, high-grade partial thickness tears requiring repair, acromioclavicular joint pathology, and labral pathology outside of the SLAP lesion. Patients from both groups subsequently were treated with open, subpectoral tenodesis.Results: Over a 6-year period at a mean follow-up of 2.75 years (range 1.5-5.7 years), 125 active-duty military personnel with mean age of 42.6 years (range 26.3-56.5) were enrolled. A total of 101 of 125 patients (81%) completed study requirements at a mean of 2.75 years (range 1.5-5.7 years). In total, 40 patients were diagnosed with type II SLAP tears (39.6%) and 61 with biceps tendonitis without SLAP tear (60.4%). Following open, subpectoral tenodesis, there was a significant improvement in patient outcomes (Western Ontario Rotator Cuff = 54% preoperative vs 89% postoperative, Single Assessment Numeric Evaluation = 58 preoperative vs 89.5 postoperative, P < .01). In total, 82% of patients returned to full activity at a mean of 4.1 months. The biceps muscle measured relative to the antecubital fossa of operative (mean 3.20 cm) versus nonoperative (3.11 cm) was not clinically different (P = .57). There was an 8% complication rate, including 3 requiring revision, 2 superficial infections, and 3 transient neurapraxias.Conclusions: Primary subpectoral open biceps tenodesis for SLAP tears or pathology of the LHBT provides significant improvement in shoulder outcomes with a reliable return to activity level with low risk for complications.Level Of Evidence: Level IV (Case series). [ABSTRACT FROM AUTHOR]

Background Clinical examination of the shoulder joint has gained attention as clinicians aim to use an evidence-based examination of the biceps tendon, with the desire for a proper diagnosis while minimizing costly imaging procedures. The purpose of this study is to create a decision tree analysis that enables the development of a clinical algorithm for diagnosing long head of biceps (LHB) pathology. Methods A literature review of Level I and II diagnostic studies was conducted to extract characteristics of clinical tests for LHB pathology through a systematic review of PubMed, Medline, Ovid, and Cochrane Review databases. Tests were combined in series and parallel to determine sensitivities and specificities, and positive and negative likelihood ratios were determined for each combination using a subjective pretest probability. The “gold standard” for diagnosis in all included studies was arthroscopy or arthrotomy. Results The optimal testing modality was use of the uppercut test combined with the tenderness to palpation of the biceps tendon test. This combination achieved a sensitivity of 88.4% when performed in parallel and a specificity of 93.8% when performed in series. These tests used in combination optimize post-test probability accuracy greater than any single individual test. Conclusion Performing the uppercut test and biceps groove tenderness to palpation test together has the highest sensitivity and specificity of known physical examinations maneuvers to aid in the diagnosis of LHB pathology compared with diagnostic arthroscopy (practical, evidence-based, comprehensive examination). A decision tree analysis aides in the practical, evidence-based, comprehensive examination diagnostic accuracy post-testing based on the ordinal scale pretest probability. [ABSTRACT FROM AUTHOR]

The human cDNA with a structure analogous to DNA expressing p62 protein in other organisms was found to express a a protein with a structure similar to p62. This protein, Sam68, is also identified by antibodies that are specific for p62. However, they have different functions in the cell. Sam68 is involved in the interphase stage of mitosis, while p62 is typically associated with the RasGAP protein.

Purpose: The purpose of this study was to evaluate how patient satisfaction after surgical femoroacetabular impingement (FAI) treatment is measured and reported in the current evidence base.Methods: A review of the MEDLINE database was performed. Clinical outcome studies of FAI that reported a measure of patient satisfaction were included. Patient demographics, clinical outcome scores, and patient satisfaction measures were extracted. The NewCastle Ottawa Scale (NOS) was used to grade quality. Statistical analysis was primarily descriptive.Results: Twenty-six studies met inclusion criteria; the mean NOS score among included studies was 5.7. Most studies were level 3 or 4 (n = 25, 96.1%). A 0 to 10 numeric scale, described by some studies as a visual analog scale, was the most commonly used method to assess satisfaction (n = 21; 80.8%), and mean reported scores ranged from 6.8 to 9.2 out of 10. Four studies (15.4%) used an ordinal scale, and 1 study (3.8%) used willingness to undergo surgery again as the measure of satisfaction. None of the included studies assessed preoperative satisfaction or patient expectation. Pooled cohort analysis was limited by significant overlapping study populations. Predictors of patients' satisfaction identified in included studies were presence of arthritis and postoperative outcome scores.Conclusions: Patient satisfaction was not uniformly assessed in the literature. Most studies used a 0- to 10-point satisfaction scale, but none distinguished between the process of care and the outcome of care. Although satisfaction scores were generally high, the quality of the methodologies in the studies that reported satisfaction was low, and the studies likely included overlapping patient populations. More work needs to be done to develop standardized ways for assessing patient satisfaction after arthroscopic hip surgery and other procedures in orthopaedic sports medicine.Level Of Evidence: Level III, systematic review of Level III studies. [ABSTRACT FROM AUTHOR]

Background Shoulder hemiarthroplasty (HA) has been the standard treatment for complex proximal humerus fractures in the elderly requiring surgery but not amenable to fixation. Reverse total shoulder arthroplasty (RTSA) has also emerged as a costly albeit highly effective alternative. The purpose of this study was to compare the cost-effectiveness of nonoperative fracture care, HA, and RTSA for complex proximal humerus fractures from the perspective of both U.S. payors and hospitals. Methods A Markov model was constructed for the treatment alternatives. Costs were expressed in 2013 U.S. dollars and effectiveness in quality-adjusted life-years (QALYs). The principal outcome measure was incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to evaluate model assumptions. Results In the base case, from the payor perspective, RTSA was associated with an ICER of $8100/QALY; HA was eliminated from payor analysis as a cost-ineffective strategy. From the hospital perspective, however, HA was not cost-ineffective and the ICER for HA was $36,700/QALY, with RTSA providing incremental effectiveness at $57,400/QALY. RTSA was the optimal strategy in 61% and 54% of payor and hospital probabilistic sensitivity analyses, respectively. The preferred strategy was dependent on associated QALY gains, primary RTSA cost, and failure rates for RTSA. Conclusions RTSA can be a cost-effective intervention in the surgical treatment of complex proximal humerus fractures. HA can also be a cost-effective intervention, depending on the cost perspective (cost-ineffective for payor but cost-effective for the hospital). This analysis highlights the opportunities for increased cost-sharing strategies to alleviate the cost burden on hospitals. [ABSTRACT FROM AUTHOR]

Purpose: To use population-level data to (1) evaluate the conversion rate of total hip arthroplasty (THA) within 2 years of hip arthroscopy and (2) assess the influence of age, arthritis, and obesity on the rate of conversion to THA.Methods: We used the State Ambulatory Surgery Databases and State Inpatient Databases for California and Florida from 2005 through 2012, which contain 100% of patient visits. Hip arthroscopy patients were tracked for subsequent primary THA within 2 years. Out-of-state patients and patients with less than 2 years follow-up were excluded. Multivariate analysis identified risks for subsequent hip arthroplasty after arthroscopy.Results: We identified 7,351 patients who underwent hip arthroscopy with 2 years follow-up. The mean age was 43.9 ± 13.7 years, and 58.8% were female patients. Overall, 11.7% of patients underwent THA conversion within 2 years. The conversion rate was lowest in patients aged younger than 40 years (3.0%) and highest in the 60- to 69-year-old group (35.0%) (P < .001). We found an increased risk of THA conversion in older patients and in patients with osteoarthritis or obesity at the time of hip arthroscopy. Patients treated at high-volume hip arthroscopy centers had a lower THA conversion rate than those treated at low-volume centers (15.1% v 9.7%, P < .001).Conclusions: Hip arthroscopy is performed in patients of various ages, including middle-aged and elderly patients. Older patients have a higher rate of conversion to THA, as do patients with osteoarthritis or obesity.Level Of Evidence: Level III, retrospective comparative study. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to investigate the incidence of meniscal allograft transplantation (MAT) in the United States from 2007 to 2011 and to analyze trends in MAT using a large database of privately insured non-Medicare patients. Methods Patients who underwent MAT (Current Procedural Terminology [CPT] code 29868) from 2007 to 2011 were identified using the PearlDiver Private Payer Database. Demographic and use data available in the database were extracted for patients who underwent MAT. Statistical analysis involved Student t tests, χ-square tests, and linear regression analyses, with statistical significance set at P < .05. Results The PearlDiver database allowed analysis of approximately 25.4 million patients per year during the years 2007 to 2011 (approximately 9% of the US population younger than 65 years). From 2007 to 2011, there were a total of 302 MAT procedures, for an incidence of 0.24 MAT procedures per year per 100,000 patients. There was no statistically significant increase in MAT procedures over time ( P = .36). There was a higher incidence of MAT in male patients (0.26) than in female patients (0.19) ( P = .001). There was a higher incidence of MAT in patients aged 25 to 34 years (0.40) and in those younger than 25 years (0.30) compared with older patients ( P < .001), with 9.7% of MAT procedures being performed in patients younger than age 35 years. Conclusions MAT was an uncommon procedure, with no change in its incidence from 2007 to 2011. MAT procedures were performed more commonly in patients younger than 35 years and in male patients. Level of Evidence Level IV, descriptive epidemiology study. [ABSTRACT FROM AUTHOR]

Selection and management of a postoperative rotator cuff repair rehabilitation protocol is a vital component in achieving pain control in patients, a reliable return to activities and preinjury level, retear risk management, and overall surgical outcome. Optimal treatment approaches require a team effort; open communication between the surgeon, the therapist, and the patient; continual reassessment; and a stepwise staged protocol progression. Much work has been done to identify high-level evidence-based rotator cuff rehabilitation protocols and identify risk factors for complications and tendon failure. The orthopedic surgeon is best positioned to identify predictive factors at the time of treatment that influence overall outcome and may direct and customize early rehabilitation based on these assessments. In addition, the surgeon is overall responsible for much of the postoperative decision making: ensuring an optimal environment for tendon healing, avoidance of postoperative stiffness, return to work or activity pressures, postoperative pain management, cost constraints of therapy, avoidance of revision surgery, and optimization of long-term outcome. Thus, a comprehensive understanding of the rotator cuff repair rehabilitation protocol is requisite. This article aims to review patient and surgical factors to consider in customizing the postoperative rehabilitation protocol, present postoperative assessments to guide surgical recovery and rehabilitation, and provide our current evidence-based rehabilitation protocol. [ABSTRACT FROM AUTHOR]

Summary Despite the development of potent RAF/mitogen-activated protein kinase (MAPK) pathway inhibitors, only a fraction of BRAF -mutant patients benefit from treatment with these drugs. Using a combined chemogenomics and chemoproteomics approach, we identify drug-induced RAS-RAF-MEK complex formation in a subset of BRAF -mutant cancer cells characterized by primary resistance to vemurafenib. In these cells, autocrine interleukin-6 (IL-6) secretion may contribute to the primary resistance phenotype via induction of JAK/STAT3 and MAPK signaling. In a subset of cell lines, combined IL-6/MAPK inhibition is able to overcome primary resistance to BRAF-targeted therapy. Overall, we show that the signaling plasticity exerted by primary resistant BRAF -mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy that we term “oncogene mimicry.” This model may guide future strategies for overcoming primary resistance observed in these tumors. [ABSTRACT FROM AUTHOR]

Both unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) produce satisfactory outcomes in the management of unicompartmental knee osteoarthritis (OA). The purpose of this study is to compare UKA and HTO practice patterns in a large US private payer insurance database. Utilization data for UKA and HTO were captured from the database between 2007 and 2011. Chi square analysis, parametric testing and Poisson regressions were performed where appropriate. Between 2007 and 2011, the compound annual growth rate in utilization of UKA was + 4.7%, while that for HTO was - 3.9%. Utilization of UKA and HTO were inversely correlated (P = 0.001). UKA utilization is increasing, while HTO utilization is decreasing in the management of OA. More work is required to understand specific indications and outcomes. [ABSTRACT FROM AUTHOR]

Summary: Virus infections trigger metabolic changes in host cells that support the bioenergetic and biosynthetic demands of viral replication. Although recent studies have characterized virus-induced changes in host cell metabolism (Munger et al., 2008; Terry et al., 2012), the molecular mechanisms by which viruses reprogram cellular metabolism have remained elusive. Here, we show that the gene product of adenovirus E4ORF1 is necessary for adenovirus-induced upregulation of host cell glucose metabolism and sufficient to promote enhanced glycolysis in cultured epithelial cells by activation of MYC. E4ORF1 localizes to the nucleus, binds to MYC, and enhances MYC binding to glycolytic target genes, resulting in elevated expression of specific glycolytic enzymes. E4ORF1 activation of MYC promotes increased nucleotide biosynthesis from glucose intermediates and enables optimal adenovirus replication in primary lung epithelial cells. Our findings show how a viral protein exploits host cell machinery to reprogram cellular metabolism and promote optimal progeny virion generation. [Copyright &y& Elsevier]

Minced articular cartilage techniques are viable one-stage, off-the-shelf cartilage repair procedures for treatment of focal chondral defects in the knee. In the United States, DeNovo natural tissue (NT) is the only particulated juvenile allograft one-stage articular cartilage technique currently available that does not violate the subchondral bone. DeNovo NT is composed of 1mm3 fragments of juvenile (donor age is less than 13 years) articular cartilage, embedded within fibrin adhesive at the time of implantation. DeNovo NT is a chondroconductive, chondroinductive, and chondrogenic product. Given that it is “minimally manipulated,” it does not require US Food and Drug Administration premarket approval. DeNovo NT has been available in the United States since May 2007, and approximately 7500 cases have been performed to date. The basic science and clinical outcome literature supporting minced articular cartilage techniques in treatment of focal chondral defects of the knee is early and short term, but nonetheless promising. Juvenile cells are advantageous over adult cells in that they have a greater migration and proliferation capacity without immunogenicity. Clinical outcomes, at up to 2.5 years of follow-up, have demonstrated a significant improvement in validated cartilage outcome scores, reductions in pain, and improvements in function and activity in patients with both patellofemoral and tibiofemoral lesions treated with DeNovo NT. [Copyright &y& Elsevier]

Purpose: The purpose of this investigation is to determine the proportion of sports medicine studies that are labeled as Level I Evidence in 5 journals and compare the quality of surgical and nonsurgical studies using simple quality assessment tools (Consolidated Standards of Reporting Trials [CONSORT] and Jadad). Methods: By use of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines over the prior 2 years in the top 5 (citation and impact factor based) sports medicine journals, only Level I Evidence studies were eligible for inclusion and were analyzed. All study types (therapeutic, prognostic, diagnostic, and economic) were analyzed. Study quality was assessed with the level of evidence, Jadad score, and CONSORT 2010 guidelines. Study demographic data were compared among journals and between surgical and nonsurgical studies by use of χ2, 1-way analysis of variance, and 2-sample Z tests. Results: We analyzed 190 Level I Evidence studies (10% of eligible studies) (119 randomized controlled trials [RCTs]). Therapeutic, nonsurgical, single-center studies from the United States were the most common studies published. Sixty-two percent of studies reported a financial conflict of interest. The knee was the most common body part studied, and track-and-field/endurance sports were the most common sports analyzed. Significant differences (P < .05) were shown in Jadad and CONSORT scores among the journals reviewed. Overall, the Jadad and CONSORT scores were 2.71 and 77%, respectively. No differences (P > .05) were shown among journals based on the proportion of Level I studies or appropriate randomization. Significant strengths and limitations of RCTs were identified. Conclusions: This study showed that Level I Evidence and RCTs comprise 10% and 6% of contemporary sports medicine literature, respectively. Therapeutic, nonsurgical, single-center studies are the most common publications with Level I Evidence. Significant differences across sports medicine journals were found in study quality. Surgical studies appropriately described randomization, blinding, and patient enrollment significantly more than nonsurgical studies. Level of Evidence: Level I, systematic review of Level I studies. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to quantify the current trends in knee cartilage surgical techniques performed in the United States from 2004 through 2011 using a large private-payer database. A secondary objective was to identify salient demographic factors associated with these procedures. Methods: We performed a retrospective database review using a large private-payer medical record database within the PearlDiver database. The PearlDiver database is a publicly available, Health Insurance Portability and Accountability Act–compliant national database compiled from a collection of private insurer records. A search was performed for surgical techniques in cartilage palliation (chondroplasty), repair (microfracture/drilling), and restoration (arthroscopic osteochondral autograft, arthroscopic osteochondral allograft, autologous chondrocyte implantation, open osteochondral allograft, and open osteochondral autograft). The incidence, growth, and demographic factors associated with the surgical procedures were assessed. Results: From 2004 through 2011, 198,876,000 patients were analyzed. A surgical procedure addressing a cartilage defect was performed in 1,959,007 patients, for a mean annual incidence of 90 surgeries per 10,000 patients. Across all cartilage procedures, there was a 5.0% annual incidence growth (palliative, 3.7%; repair, 0%; and restorative, 3.1%) (P = .027). Palliative techniques (chondroplasty) were more common (>2:1 ratio for repair [marrow-stimulation techniques] and 50:1 ratio for restoration [autologous chondrocyte implantation and osteochondral autograft and allograft]). Palliative surgical approaches were the most common technique, regardless of age, sex, or region. Conclusions: Articular cartilage surgical procedures in the knee are common in the United States, with an annual incidence growth of 5%. Surgical techniques aimed at palliation are more common than cartilage repair and restoration techniques regardless of age, sex, or region. Level of Evidence: Level IV, retrospective database analysis. [Copyright &y& Elsevier]

Background: Body mass index (BMI) is an independent predictor of complications after hip and knee arthroplasty. Whether similar trends apply to patients undergoing reverse total shoulder arthroplasty (RTSA) is unknown. Methods: A retrospective review of primary RTSAs with a minimum 90-day follow-up were included. Complications were classified as major or minor and medical or surgical. Patients were classified into 3 groups: normal BMI (BMI <25 kg/m2), overweight or mildly obese (BMI 25-35 kg/m2), and moderately or severely obese (BMI >35 kg/m2). Results: Of the 119 patients met our inclusion criteria, 30 (25%) had a BMI of less than 25 kg/m2; 65 (55%) had a BMI of 25 to 35 kg/m2, and 24 (20%) had BMI exceeding 35 kg/m2. Complications occurred in 30 patients (25%), comprising major in 11 (9%), minor in 19 (16%), surgical in 21 (18%), and medical in 14 (12%). The most common surgical complications were acute blood loss anemia requiring transfusion (8.4%) and dislocation (4.2%). The most common medical complications were atelectasis (2.5%) and acute renal insufficiency (2.5%). Patients with a BMI exceeding 35 kg/m2 had a significantly higher overall complication rate (P < .05) and intraoperative blood loss (P = .05) than the other groups. Patients with BMI of less than 25 kg/m2 had a greater overall complication rate than those with a BMI of 25 to 35 kg/m2 (P < .05). Multivariate regression analysis demonstrated BMI was the only significant determinant of overall complication rates and medical complication rates (P < .05). Conclusion: Patients with a BMI exceeding 35 kg/m2 (severely obese) or a BMI of less than 25 kg/m2 have higher rates of complication after RTSA. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to assess the surgical outcomes of endoscopically repaired full-thickness abductor tendon tears using validated outcome measures. Methods: After institutional review board approval was obtained, clinical outcome data were retrospectively collected from patients who underwent endoscopic gluteus medius and/or minimus repair by a single surgeon between August 2009 and September 2011. With a minimum follow-up of 1 year, patients were evaluated using the modified Harris Hip Score and the validated Hip Outcome Score (HOS). The HOS questionnaire included 2 subsections: HOS–Activities of Daily Living and HOS-Sports. Physical examination data were gathered during routine clinic visits, 1 year postoperatively. Statistical analysis was descriptive. The change in strength testing postoperatively was assessed with the Wilcoxon signed rank test, with significance set at P ≤ .05. Results: Twelve patients were identified, 1 of whom was excluded; 10 of 11 patients (91%) completed the study requirements. The mean patient age was 65.9 years (range, 60 to 74 years), 70% were women, and the mean follow-up period was 23 months (range, 13 to 38 months). The mean postoperative scores were 84.7 (SD, 14.5) for the modified Harris Hip Score and 89.1 (SD, 11.3) for the HOS–Activities of Daily Living, with 90% patient satisfaction. All patients had clinically and statistically improved abductor tendon strength (P = .004). Patients with good to excellent outcomes were younger (P < .001). There were no complications identified. Conclusions: In our small series, endoscopic abductor tendon repair was an effective surgical intervention after failed conservative management at short-term follow-up. Patients had reliably good to excellent outcomes with improved strength during hip abduction, were at low risk of complications, and were satisfied with the outcome. In addition, younger patients achieved better outcomes. Level of Evidence: Level IV, therapeutic case series. [Copyright &y& Elsevier]

Background: The AAOS’s Clinical Practice Guideline on “Optimizing Care of Rotator Cuff Problems” suggested a lack of high-quality data. Our purpose is to quantify the quality of randomized controlled trials of rotator cuff disorders via the Jadad score, and to apply the 2010 Consolidated Standards of Reporting Trials CONSORT Criteria to determine factors associated with high Jadad scores and areas for improvement. Methods: A systematic review using PRISMA guidelines was performed. Utilizing an iterative search strategy of the top 6 impact factor orthopaedic journals from 2001 to 2011, all randomized controlled studies involving rotator cuff disorders were identified and scored in a systematic, blinded fashion. Each study received a Jadad score. Adherence to CONSORT criteria was quantified and linked to the Jadad score via linear regression. Common deficiencies were described. Results: A total of 129 manuscripts were identified; 54 met inclusion criteria: total patients n = 4099; mean patients per article = 76; range, 16-660. The mean Jadad score was 3.0. Sixty-six percent (35/53) of studies were high quality (high quality: >3). Among these, the majority (63%, 22/35) were nonoperative trials. Adherence to CONSORT Criteria was associated with higher Jadad scores (R2 = 0.3). The most common deficient CONSORT Criteria were: trial design descriptions (66%; 36/54 studies), descriptions of randomization type (65%; 35/54), and power analysis (46%; 25/54). Conclusion: The majority of randomized controlled trials of rotator cuff pathology are high-quality studies based on the Jadad score. Adherence to CONSORT criteria is linked to high-quality scores. Future studies should use full CONSORT Criteria. [Copyright &y& Elsevier]

Purpose: The purposes of this study were (1) to analyze long-term outcomes in patients who have undergone open or arthroscopic Bankart repair and (2) to evaluate study methodologic quality through validated tools. Methods: We performed a systematic review of Level I to IV Evidence using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical outcome studies after open or arthroscopic Bankart repair with a minimum of 5 years'' follow-up were analyzed. Clinical and radiographic outcomes were extracted and reported. Study methodologic quality was evaluated with Modified Coleman Methodology Scores and Quality Appraisal Tool scores. Results: We analyzed 26 studies (1,781 patients). All but 2 studies were Level III or IV Evidence with low Modified Coleman Methodology Scores and Quality Appraisal Tool scores. Patients analyzed were young (mean age, 28 years) male patients (81%) with unilateral dominant shoulder (61%), post-traumatic recurrent (mean of 11 dislocations before surgery) anterior shoulder instability without significant glenoid bone loss. The mean length of clinical follow-up was 11 years. There was no significant difference in recurrence of instability with arthroscopic (11%) versus open (8%) techniques (P = .06). There was no significant difference in instability recurrence with arthroscopic suture anchor versus open Bankart repair (8.5% v 8%, P = .82). There was a significant difference in rate of return to sport between open (89%) and arthroscopic (74%) techniques (P < .01), whereas no significant difference was observed between arthroscopic suture anchor (87%) and open repair (89%) (P = .43). There was no significant difference in the rate of postoperative osteoarthritis between arthroscopic suture anchor and open Bankart repair (26% and 33%, respectively; P = .059). There was no significant difference in Rowe or Constant scores between groups (P > .05). Conclusions: Surgical treatment of anterior shoulder instability using arthroscopic suture anchor and open Bankart techniques yields similar long-term clinical outcomes, with no significant difference in the rate of recurrent instability, clinical outcome scores, or rate of return to sport. No significant difference was shown in the incidence of postoperative osteoarthritis with open versus arthroscopic suture anchor repair. Study methodologic quality was poor, with most studies having Level III or IV Evidence. Level of Evidence: Level IV, systematic review of studies with Level I through IV Evidence. [Copyright &y& Elsevier]

Purpose: To determine the prevalence of complications and reoperations during and after hip arthroscopy. Methods: A systematic review of multiple medical databases was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist. All clinical outcome studies that reported the presence or absence of complications and/or reoperations were eligible for inclusion. Length of follow-up was not an exclusion criterion. Complication and reoperation rates were extracted from each study. Duplicate patient populations within separate distinct publications were analyzed and reported only once. Results: Ninety-two studies (6,134 participants) were included. Most were Level IV evidence studies (88%) with short-term follow-up (mean 2.0 years). Labral tears and femoroacetabular impingement (FAI) were the 2 most common diagnoses treated, and labral treatment and acetabuloplasty/femoral osteochondroplasty were the 2 most common surgical techniques reported. Overall, major and minor complication rates were 0.58% and 7.5%, respectively. Iatrogenic chondrolabral injury and temporary neuropraxia were the 2 most common minor complications. The overall reoperation rate was 6.3%, occurring at a mean of 16 months. Total hip arthroplasty (THA) was the most common reoperation. The conversion rate to THA was 2.9%. Conclusions: The rate of major complications was 0.58% after hip arthroscopy. The reoperation rate was 6.3%, and the most common reason for reoperation was conversion to THA. Minor complications and the reoperation rate are directly related to the learning curve of hip arthroscopy. As surgical indications evolve, patient selection should limit the number of cases that would have been converted to THA. Similarly, the number of minor complications is directly related to technical aspects of the procedure and therefore will decrease with surgeon experience and improvement in instrumentation. Level of Evidence: Level IV, a systematic review of Level I to IV studies. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to determine operating parameters for joint fluid lavage using radiofrequency (RF) in maintaining intra-articular temperatures ≤50°C in the hip joint and to then quantify the influence of flow rate on maintaining safe intra-articular temperatures. Methods: Fiberoptic intra-articular thermometers at radial distance intervals of 1, 2, 5, and 10 mm, spanning cross-sectional areas of 3.14, 12.56, 78.5, and 314.1 mm2, respectively, from the RF probe were used in 3 human hip cadaveric specimens at room temperature, with 9 trials per variable, using a 3-portal technique with a capsule release. Using a new Dyonics RF System continuously at the superior capsulolabral junction for 90 seconds, continuous temperatures were recorded at 50 mm Hg inflow and variable outflow intervals: no flow and 5, 15, and 30 seconds. Lavages were 1 second in duration on suction. Statistical comparison was through multivariate regression analysis and a logistic model. Results: Temperatures reached ≥50°C at 5-mm radial distance from the probe in all but the 5-second pulse lavage group. Elevated temperatures were reached within 1 to 2 seconds locally (1- to 2-mm radial distance) and at a radial distance of 5 mm in the 15-, 30-, and 0-second lavage groups. Logistic regression revealed a reduction in the odds that temperatures ≥50°C will occur as flow frequency increases every 30 (odds ratio = 0.68, P = .086); 15 (odds ratio = −1.22, P = .0067); and 5 (odds ratio = −4.26, P < .0001) seconds. Conclusions: Increasing-interval pulsed irrigation is effective in maintaining intra-articular temperature profiles below 50°C during use of continuous RF ablation. Five-second-interval pulsed lavage is the longest flow interval identified during which fluid 5 mm radially from the RF device never reached temperatures >50°C. Clinical Relevance: Clinical guidelines for using the RF ablation include: meticulous technique, intermittent use, good inflow and outflow, and pulsed lavage at frequent intervals. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to perform a retrospective case-control outcome analysis at a minimum 2-year follow-up using a validated hip arthroscopy outcome measure to determine whether arthritis or age is predictive of outcomes after hip arthroscopy for labral pathology. Methods: We identified 176 consecutive patients undergoing hip arthroscopy for labral tears performed between 2001 and 2009 to complete the Modified Harris Hip Score (MHHS) and Hip Outcome Score questionnaires. Patients who underwent additional surgeries or reported an MHHS of less than 80 were compared with the control group of patients who achieved good to excellent surgical results on the MHHS (>80) to calculate odds ratios with 95% confidence intervals by use of the independent variables of patient age of 40 years or older and age below 40 years and the presence of grade 4 Outerbridge changes found at arthroscopy. Results: Of 176 patients, 125 (71%) were contacted: 27 patients had undergone additional surgery in the follow-up period, and 98 completed questionnaires. The mean patient age at surgery was 40.9 years (range, 17.3 to 62.8 years) at a mean follow-up of 4.3 years (range, 2 to 10.4 years). Of 98 respondents, 71 (72%) obtained a good to excellent surgical outcome, with 84% reporting satisfaction. The presence of osteoarthritic changes at the time of arthroscopy was predictive of worse outcome scores compared with the nonarthritic cohort (odds ratio, 2.5; 95% confidence interval, 1.2 to 5.3; P = .02). Youth (age <40 years) is predictive of good to excellent results (odds ratio, 7; 95% confidence interval, 2.9 to 16.9; P < .0001). Conclusions: Of the 98 patients who completed the questionnaires in this study, 71 (72%) obtained good to excellent outcome scores. Overall satisfaction among patients undergoing hip arthroscopy was high (84%). Patients aged younger than 40 years did better than older patients, and arthroscopically identified arthritis was predictive of worse surgical outcomes. Level of Evidence: Level III, case-control study. [Copyright &y& Elsevier]

The article discusses stress fractures, a common cause of injury in runners, occurring due to excess strain placed on weight bearing lower extremity bones. It highlights Identifying high-risk fractures as they are associated with increased risk of complications, and insidious onset of focal bone tenderness with regimen change in athlete. Also presented are beneficial prevention measures, including, orthotics, cushioned sneakers, interval training, and vitamin and calcium supplements.

Mutant onco-proteins play a direct, causal role in cancer and are therefore considered attractive drug targets. Clinical experience has supported this view, with some exceptions. However, clinical benefit has often been restricted by rapid emergence of drug-resistant clones through several distinct mechanisms. This problem can, in principle, be addressed through cocktails containing several drugs. However, the number of tumors whose survival is dependent on a single, druggable mutant onco-protein is currently unknown. The majority of tumors may be driven either by single drivers that are un-druggable, or by combinations of drivers. In both cases, new approaches will be necessary. Development of systemic RNA interference may be a solution to these problems. [ABSTRACT FROM AUTHOR]

Summary: Uptake of the anticancer drug cisplatin is mediated by the copper transporter CTR1 in cultured cells. Here we show in human ovarian tumors that low levels of Ctr1 mRNA are associated with poor clinical response to platinum-based therapy. Using a mouse model of human cervical cancer, we demonstrate that combined treatment with a copper chelator and cisplatin increases cisplatin-DNA adduct levels in cancerous but not in normal tissues, impairs angiogenesis, and improves therapeutic efficacy. The copper chelator also enhances the killing of cultured human cervical and ovarian cancer cells with cisplatin. Our results identify the copper transporter as a therapeutic target, which can be manipulated with copper chelating drugs to selectively enhance the benefits of platinum-containing chemotherapeutic agents. [Copyright &y& Elsevier]

More than 25 years have passed since activating mutations in Ras genes were identified in DNA from human tumors. In this time, it has been established beyond doubt that these mutations play a direct role in causing cancer, and do so in collaboration with a number of other oncogenes and tumor suppressors. Oncogenic mutant Ras proteins are resistant to downregulation by GAP‐mediated hydrolysis of bound GTP, and therefore signal persistently. Efforts to develop therapies that block Ras oncoprotein function directly have failed. The high affinity of Ras proteins for GTP has discouraged attempts to identify GTP‐analogs. Ras processing enzymes have been targeted, but unfortunately, K‐Ras, the Ras protein that plays the major role in human cancer, has proven refractory to these approaches. Further progress has been made with drugs that block downstream signaling: the approved drug Sorafenib inhibits Raf kinase, and its clinical benefits in liver cancer are greatest in patients in which the mitogen activated protein kinase (MAPK) signaling pathway is hyperactive. Other Raf kinase inhibitors, as well as drugs that block mitogen-activated protein kinase / extracellular signal-regulated kinase kinase (MEK) and various steps in the PI 3′ kinase pathway, are under development. Here we will discuss the complexities of Ras signaling and their effects on targeting the Ras pathway in the future. [Copyright &y& Elsevier]

Purpose: To describe anatomic measurements of the rotator interval (RI) on magnetic resonance arthrogram (MRA) images and to assess the relationship between increased dimensions of the RI and instability conditions of the shoulder. Methods: Three groups of patients with clinical instability were treated arthroscopically (anterior [A = 19 patients], posterior [P = 14 patients], and multidirectional [M = 13 patients]), and a group of 10 control patients without clinical instability were also identified. The MRAs of all groups were randomized, and 5 blinded reviewers recorded RI anatomic measurements of: (1) sagittal measures of the distance between the subscapularis (SSc) and supraspinatus (SS) tendons at 3 anatomic landmarks across the RI, and (2) the sagittal position of the long head of the biceps (LHB) relative to the most anterior aspect of the SS. Results: The rotator interval distance between the SS and SSc tendons was nearly identical for all groups of instability, and was also not different from control groups. On the sagittal oblique sequences, the distance from the LHB tendon to the anterior edge of the SS tendon was significantly increased in posterior (7.4 mm) instability versus both the control group (2.4 mm; P = .025) and those with anterior instability (4.5 mm; P = .041), with the LHB in a consistent anterior position. The remainder of the measures was not statistically different between the groups. Conclusions: The distance between the SS and SSc and the overall size of the RI was well preserved in all instability patterns and control conditions. The LHB tendon assumes a more anterior position relative to the supraspinatus tendon in patients with posterior instability versus those patients with anterior instability or those without clinical instability. Additional work is necessary to further define objective radiographic evidence of RI insufficiency in patients with shoulder instability. Level of Evidence: Level III, prognostic case-control study. [Copyright &y& Elsevier]

We have investigated the contribution of CDK4 and CDK2 inhibition to G1 arrest in colon cancers following inhibition of the MEK/MAP kinase pathway. CDK4 inhibition is sufficient to cause arrest, but inhibition of CDK2 by p27 Kip1 redistribution or ectopic expression has no effect on proliferation. Likewise, inhibition of CDK2 through expression of dominant-negative (DN) CDK2 or antisense oligonucleotides did not prevent cell proliferation in these cells. We therefore tested whether CDK2 activity is dispensable in other cells. Surprisingly, osteosarcomas and Rb-negative cervical cancers continued to proliferate after depletion of CDK2 through antisense oligonucleotides or small interfering (si) RNA. Here we report of sustained cell proliferation in the absence of CDK2, and we suggest that CDK2 is not a suitable target for cancer therapy. [Copyright &y& Elsevier]

The life history of cancer cells encompasses a series of genetic missteps in which normal cells are progressively transformed into tumor cells that invade surrounding tissues and become malignant. Most prominent among the regulators disrupted in cancer cells are two tumor suppressors, the retinoblastoma protein (RB) and the p53 transcription factor. Here, we discuss interconnecting signaling pathways controlled by RB and p53, attempting to explain their potentially universal involvement in the etiology of cancer. Pinpointing the various ways by which the functions of RB and p53 are subverted in individual tumors should provide a rational basis for developing more refined tumor-specific therapies. [Copyright &y& Elsevier]

Examines the effect of stepwise accumulation of mutations, which causes cancer, on discrete signalling pathways. Information on the Ras pathways and adenomatous polyposis coli pathway; Complexities and relevance of these pathways in biological systems; Implications of the interdependence of pathways for stepwise model.

Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use 31P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5'-[(β,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor. [ABSTRACT FROM AUTHOR]

Ras proteins mediate PI3K activation through direct binding to p110 catalytic subunits. However, it is unclear when and where this interaction occurs. In this issue of Cancer Cell, Castellano and colleagues report that KRAS-driven lung cancers require the Ras-p110α interaction for full activation of PI3K and tumor maintenance. [Copyright &y& Elsevier]

H-Ras, N-Ras, and K-Ras proteins have distinct biological properties, despite ubiquitous expression and similar affinities for regulators and effectors. C-terminal hypervariable regions that distinguish H-Ras, N-Ras, and K-Ras proteins direct them to distinct membrane compartments, where they may encounter regulators and effectors at different local concentrations. Jura and coworkers now report that these membrane-targeting domains direct differential ubiquitination of Ras proteins and so provide a molecular mechanism to explain the sorting process and, perhaps, some of the dramatic differences in biological potency among H-Ras, N-Ras, and K-Ras proteins. [Copyright &y& Elsevier]

Ras proteins send signals through multiple effector pathways. The Raf/MEK/MAPK and PI 3′ kinase pathways are well-validated Ras effectors in human cancers, but many other candidate pathways could be equally important. RalGDS is such a candidate: in a new paper from Chris Marshall’s group, an important role for RalGDS in Ras transformation in vivo has been established for the first time. Mice lacking RalGDS are defective in tumor formation, possibly because of increased apoptosis in Ras-driven tumors. The hunt for a clear role for RalGDS activation in human cancer is on. [Copyright &y& Elsevier]

The acetabular labrum plays an important role in hip joint stability and articular cartilage maintenance. As such, reconstitution of the labral complex is ideal. In cases in which the labrum is too degenerative to allow adequate reconstruction with current repair techniques, a capsular augmentation is a novel technique that can be used to restore the labral structure. Use of capsular augmentation enables preservation of the donor-tissue blood supply with local tissue transfer, without adding significant complexity to the procedure or significant donor-site morbidity. [ABSTRACT FROM AUTHOR]

Background Long head of the biceps (LHB) deformity after surgical tenotomy or auto-rupture may result from attrition or injury. The purpose of this study was to describe the surgical outcomes of biceps tenodesis after failed surgical tenotomy or auto-rupture of the LHB tendon in a population of active patients. Methods During a 5-year period, 11 patients with a mean age of 43.3 years (range, 33-56 years) presented with symptoms of biceps cramping with activity (100%), deformity (100%), or pain (36%) at a mean of 8 months (range, 0.5-22 months) from a tenotomy (6 of 11) or an auto-rupture (5 of 11). All patients underwent a mini-open subpectoral biceps tenodesis with interference screw fixation. Patients were independently evaluated by patient-reported outcome measures (Single Assessment Numeric Evaluation [SANE] and Western Ontario Rotator Cuff Index [WORC]) and a biceps position examination. Results Of the 11 patients, 10 (91%) completed the study requirements at a mean of 2.6 years (range, 1.6-4.2 years). A total of 9 of the 10 patients (90%) returned to full activity. The mean preoperative SANE score was 61.1 (standard deviation [SD], 8.8), and the mean preoperative WORC score was 53.2 (SD, 9.2), which improved postoperatively to a SANE score of 84.2 (SD, 7.1) and a WORC score of 86 (SD, 8.2). There were no differences in LHB muscle position relative to the antecubital fossa (3.17 cm preoperatively to 3.25 cm postoperatively; P = .35). Deformity was resolved in all patients; 9 of 10 patients reported full resolution of cramping, and pain was resolved in 8 of 10. Conclusions LHB tenodesis after auto-rupture or surgical tenotomy improved symptoms and allowed predictable return to activity and patient satisfaction. Additional work is necessary to determine the optimal treatment of primary biceps lesions. [ABSTRACT FROM AUTHOR]