The effect of shoulder prosthesis stem length on failure due to torsional loading. A biomechanical study in composite humeri.

Background: Shoulder arthroplasty is becoming increasingly common. With evolving implant designs, multiple humeral stem options exist for the surgeon to choose from. New stemless and short-stem systems are modular, remove less native bone stock, and better adapt to patient anatomy. It has been suggested that shorter stem implants may be protective against periprosthetic fracture; however, this has not been mechanistically evaluated. Therefore, this study aimed to biomechanically test synthetic humeri with long-stem, short-stem, and stemless arthroplasty components in a torsional manner to evaluate their response to loading and characterize failure. Methods: Twenty-four synthetic humeri were implanted with long stem, short stem, or stemless uncemented prosthesis, 8 in each group. Humeri were mounted in a custom testing jig with a morse taper interfacing with a mechanical testing system. After a 20N axial force, specimens were torsionally loaded to failure at 15 degrees/sec, with 50 Hz collection. Torque vs. rotation curves were generated for each specimen, and stiffness, yield, ultimate strength, and failure load were measured. ANOVA and post hoc pairwise comparisons were used to assess effect of stem type on mechanical test variable. The association of the stem type with fracture type was analyzed by a Fisher's Exact test. Statistical significance was set at P < .05. Results: During torsional loading, long-stem implants were significantly stiffer than short or stemless implants. The angle of implant yielding was similar across stem designs; however, stemless implants had a lower yield torque. This correlated with a decreased yield energy in stemless compared to short stems as well. Maximum torque and failure torque was also significantly higher in short-stem and long-stem implants compared to stemless. Discussion: Periprosthetic fractures in shoulder arthroplasty are a concern in low-energy trauma, and stem design likely plays a significant role in early implant-bone failure. Our results suggest stemless implants under torsional load fail at lower stress and are less stiff than stemmed implants. The failure mechanism of stemless implants through metaphyseal cancellous bone emphasizes the effect bone quality has on implant fixation. There is likely a balance of torsional stability to survive physiologic loads while minimizing diaphyseal stress and risk of diaphyseal periprosthetic fracture. This combined with revision and fixation options represent decisions the surgeon is faced with when performing shoulder arthroplasty.

Management of irreparable massive rotator cuff tears: a systematic review and meta-analysis of patient-reported outcomes, reoperation rates, and treatment response.

BACKGROUND: There is no consensus on the treatment of irreparable massive rotator cuff tears. The goal of this systematic review and meta-analysis was to (1) compare patient-reported outcome scores, (2) define failure and reoperation rates, and (3) quantify the magnitude of patient response across treatment strategies. METHODS: The MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and Scopus databases were searched for studies including physical therapy and operative treatment of massive rotator cuff tears. The criteria of the Methodological Index for Non-randomized Studies were used to assess study quality. Primary outcome measures were patient-reported outcome scores as well as failure, complication, and reoperation rates. To quantify patient response to treatment, we compared changes in the Constant-Murley score and American Shoulder and Elbow Surgeons (ASES) score with previously reported minimal clinically important difference (MCID) thresholds. RESULTS: No level I or II studies that met the inclusion and exclusion criteria were found. Physical therapy was associated with a 30% failure rate among the included patients, and another 30% went on to undergo surgery. Partial repair was associated with a 45% retear rate and 10% reoperation rate. Only graft interposition was associated with a weighted average change that exceeded the MCID for both the Constant-Murley score and ASES score. Latissimus tendon transfer techniques using humeral bone tunnel fixation were associated with a 77% failure rate. Superior capsular reconstruction with fascia lata autograft was associated with a weighted average change that exceeded the MCID for the ASES score. Reverse arthroplasty was associated with a 10% prosthesis failure rate and 8% reoperation rate. CONCLUSION: There is a lack of high-quality comparative studies to guide treatment recommendations. Compared with surgery, physical therapy is associated with less improvement in perceived functional outcomes and a higher clinical failure rate.

Identification and characterization of dysregulated P-element induced wimpy testis-interacting RNAs in head and neck squamous cell carcinoma.

It is clear that alcohol consumption is a major risk factor in the pathogenesis of head and neck squamous cell carcinoma (HNSCC); however, the molecular mechanism underlying the pathogenesis of alcohol-associated HNSCC remains poorly understood. The aim of the present study was to identify and characterize P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) and PIWI proteins dysregulated in alcohol-associated HNSCC to elucidate their function in the development of this cancer. Using next generation RNA-sequencing (RNA-seq) data obtained from 40 HNSCC patients, the piRNA and PIWI protein expression of HNSCC samples was compared between alcohol drinkers and non-drinkers. A separate piRNA expression RNA-seq analysis of 18 non-smoker HNSCC patients was also conducted. To verify piRNA expression, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed on the most differentially expressed alcohol-associated piRNAs in ethanol and acetaldehyde-treated normal oral keratinocytes. The correlation between piRNA expression and patient survival was analyzed using Kaplan-Meier estimators and multivariate Cox proportional hazard models. A comparison between alcohol drinking and non-drinking HNSCC patients demonstrated that a panel of 3,223 piRNA transcripts were consistently detected and differentially expressed. RNA-seq analysis and in vitro RT-qPCR verification revealed that 4 of these piRNAs, piR-35373, piR-266308, piR-58510 and piR-38034, were significantly dysregulated between drinking and non-drinking cohorts. Of these four piRNAs, low expression of piR-58510 and piR-35373 significantly correlated with improved patient survival. Furthermore, human PIWI-like protein 4 was consistently upregulated in ethanol and acetaldehyde-treated normal oral keratinocytes. These results demonstrate that alcohol consumption may cause dysregulation of piRNA expression in HNSCC and in vitro verifications identified 4 piRNAs that may be involved in the pathogenesis of alcohol-associated HNSCC.

Performance of PROMIS Global-10 to Legacy Instruments in Patients With Lateral Epicondylitis.

PURPOSE: To validate the Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 for patients who have lateral epicondylitis requiring surgical treatment in comparison with other gold standard patient-reported outcomes. METHODS: Sixty-two patients with lateral epicondylitis of the elbow were prospectively enrolled before arthroscopic treatment. Inclusion criteria were patients 18 years of age or older with a diagnosis of lateral epicondylitis. Each patient completed the PROMIS Global-10, EuroQol 5 Dimension (EQ-5D), American Shoulder and Elbow Surgeons (ASES) assessment form, Mayo Elbow Performance Score (MEPS), and Quick Disabilities of the Arm, Shoulder and Hand Score (QuickDASH). Spearman correlations were calculated. Bland-Altman agreement tests were conducted between estimated EQ-5D scores from the PROMIS-10 and actual EQ-5D scores. RESULTS: Correlation between the PROMIS-10 and the EQ-5D was excellent (0.72, P < .0001). Bland-Altman 95% limits of agreement for estimated EQ-5D scores ranged from 0.33 below to 0.21 above actual EQ-5D scores. Correlation of the PROMIS-10 physical score was good to excellent with MEPS (0.61, P < .0001) and QuickDASH scores (0.64, P < .0001) and good with the ASES (0.58, P < .0001). Correlation of the PROMIS mental scores was good with QuickDASH (0.50, P < .0001) and poor with ASES (0.26, P = .0492) and MEPS (0.37, P = .0038). CONCLUSIONS: The PROMIS Global-10 physical scores showed good to excellent correlation with gold standard patient-reported outcome instruments, demonstrating it is a reliable tool for outcome assessment in populations with lateral epicondylitis. Despite the excellent correlation with the EQ-5D, the 95% limit of agreement and high variability among the estimated EQ-5D scores derived from the PROMIS-10 suggests that the PROMIS-10 cannot be used as a substitute for actual EQ-5D scores to derive quality-adjusted life years for economic evaluations and cost-effectiveness research. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria on the basis of consecutive patients.

Performance of PROMIS Global-10 compared with legacy instruments in patients with shoulder arthritis.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 measures physical and mental health and provides an estimated EuroQol-5 Dimension (EQ-5D) score. The purpose of this study was to determine the correlation between the PROMIS Global-10 and several gold-standard legacy measures to validate its overall performance and usefulness in patients with shoulder arthritis. METHODS: The study prospectively enrolled 161 patients with shoulder arthritis before treatment. Each patient completed the PROMIS, EQ-5D, American Shoulder and Elbow Surgeons (ASES) Assessment Form, Single Assessment Numeric Evaluation (SANE), and Western Ontario Osteoarthritis of the Shoulder (WOOS) Index. Spearman correlations were calculated, and Bland-Altman agreement tests were conducted between estimated EQ-5D scores from the PROMIS and actual EQ-5D scores. Ceiling and floor effects were determined. RESULTS: Correlation between the PROMIS and EQ-5D was excellent (0.72, P < .001). However, agreement for estimated EQ-5D ranged from 0.37 below to 0.36 above actual EQ-5D scores. Correlation of the PROMIS physical score was good with the ASES score (0.57, P < .001) and poor with the SANE score (0.23, P = .0045) and WOOS score (0.11, P = .3743). Correlation of the PROMIS mental score was poor when compared with all patient-reported outcome instruments investigated (ASES score, 0.26 [P = .0012]; SANE score, 0.13 [P = .1004]; and WOOS score, 0.09 [P = .4311]). No floor or ceiling effects were observed. CONCLUSION: PROMIS Global-10 physical scores show excellent correlation with the EQ-5D. However, the PROMIS Global-10 cannot replace actual EQ-5D scores for cost-effectiveness assessment in this population because of the large variance in agreement between actual and PROMIS Global-10-estimated EQ-5D scores. PROMIS Global-10 physical scores showed good correlation with the ASES score but poor correlation with other gold-standard patient-reported outcome instruments, suggesting that it is an inappropriate instrument for outcome measurement in populations with shoulder arthritis.

Alcohol-dysregulated microRNAs in hepatitis B virus-related hepatocellular carcinoma.

Alcohol consumption and chronic hepatitis B virus (HBV) infection are two well-established risk factors for Hepatocellular carcinoma (HCC); however, there remains a limited understanding of the molecular pathway behind the pathogenesis and progression behind HCC, and how alcohol promotes carcinogenesis in the context of HBV+ HCC. Using next-generation sequencing data from 130 HCC patients and 50 normal liver tissues, we identified a panel of microRNAs that are significantly dysregulated by alcohol consumption in HBV+ patients. In particular, two microRNAs, miR-944 and miR-223-3p, showed remarkable correlation with clinical indication and genomic alterations. We confirmed the dysregulation of these two microRNAs in liver cell lines treated by alcohol and acetaldehyde, and showed that manipulation of miR-223-3p and miR-944 expression induces significant changes in cellular proliferation, sensitivity to doxorubicin, and the expression of both direct-binding and downstream mRNA targets. Together, the results of this study suggest that alcohol consumption in HBV+ HCCs regulates microRNAs that likely play previously uncharacterized roles in the alcohol-associated carcinogenesis of HCC, and future studies of these microRNAs may be valuable for furthering the understanding and treatment of alcohol and HBV-associated HCC.

The non-coding landscape of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease marked by frequent recurrence and metastasis and stagnant survival rates. To enhance molecular knowledge of HNSCC and define a non-coding RNA (ncRNA) landscape of the disease, we profiled the transcriptome-wide dysregulation of long non-coding RNA (lncRNA), microRNA (miRNA), and PIWI-interacting RNA (piRNA) using RNA-sequencing data from 422 HNSCC patients in The Cancer Genome Atlas (TCGA). 307 non-coding transcripts differentially expressed in HNSCC were significantly correlated with patient survival, and associated with mutations in TP53, CDKN2A, CASP8, PRDM9, and FBXW7 and copy number variations in chromosomes 3, 5, 7, and 18. We also observed widespread ncRNA correlation to concurrent TP53 and chromosome 3p loss, a compelling predictor of poor prognosis in HNSCCs. Three selected ncRNAs were additionally associated with tumor stage, HPV status, and other clinical characteristics, and modulation of their expression in vitro reveals differential regulation of genes involved in epithelial-mesenchymal transition and apoptotic response. This comprehensive characterization of the HNSCC non-coding transcriptome introduces new layers of understanding for the disease, and nominates a novel panel of transcripts with potential utility as prognostic markers or therapeutic targets.

Alcohol-dysregulated miR-30a and miR-934 in head and neck squamous cell carcinoma.

BACKGROUND: Alcohol consumption is a well-established risk factor for head and neck squamous cell carcinoma (HNSCC); however, the molecular mechanisms by which alcohol promotes HNSCC pathogenesis and progression remain poorly understood. Our study sought to identify microRNAs that are dysregulated in alcohol-associated HNSCC and investigate their contribution to the malignant phenotype. METHOD: Using RNA-sequencing data from 136 HNSCC patients, we compared the expression levels of 1,046 microRNAs between drinking and non-drinking cohorts. Dysregulated microRNAs were verified by qRT-PCR in normal oral keratinocytes treated with biologically relevant doses of ethanol and acetaldehyde. The most promising microRNA candidates were investigated for their effects on cellular proliferation and invasion, sensitivity to cisplatin, and expression of cancer stem cell genes. Finally, putative target genes were identified and evaluated in vitro to further establish roles for these miRNAs in alcohol-associated HNSCC. RESULTS: From RNA-sequencing analysis we identified 8 miRNAs to be significantly upregulated in alcohol-associated HNSCCs. qRT-PCR experiments determined that among these candidates, miR-30a and miR-934 were the most highly upregulated in vitro by alcohol and acetaldehyde. Overexpression of miR-30a and miR-934 in normal and HNSCC cell lines produced up to a 2-fold increase in cellular proliferation, as well as induction of the anti-apoptotic gene BCL-2. Upon inhibition of these miRNAs, HNSCC cell lines exhibited increased sensitivity to cisplatin and reduced matrigel invasion. miRNA knockdown also indicated direct targeting of several tumor suppressor genes by miR-30a and miR-934. CONCLUSIONS: Alcohol induces the dysregulation of miR-30a and miR-934, which may play crucial roles in HNSCC pathogenesis and progression. Future investigation of the alcohol-mediated pathways effecting these transformations will prove valuable for furthering the understanding and treatment of alcohol-associated HNSCC.

Transcriptome sequencing uncovers novel long noncoding and small nucleolar RNAs dysregulated in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma persists as one of the most common and deadly malignancies, with early detection and effective treatment still posing formidable challenges. To expand our currently sparse knowledge of the noncoding alterations involved in the disease and identify potential biomarkers and therapeutic targets, we globally profiled the dysregulation of small nucleolar and long noncoding RNAs in head and neck tumors. Using next-generation RNA-sequencing data from 40 pairs of tumor and matched normal tissues, we found 2808 long noncoding RNA (lncRNA) transcripts significantly differentially expressed by a fold change magnitude ≥2. Meanwhile, RNA-sequencing analysis of 31 tumor-normal pairs yielded 33 significantly dysregulated small nucleolar RNAs (snoRNA). In particular, we identified two dramatically down-regulated lncRNAs and one down-regulated snoRNA whose expression levels correlated significantly with overall patient survival, suggesting their functional significance and clinical relevance in head and neck cancer pathogenesis. We confirmed the dysregulation of these noncoding RNAs in head and neck cancer cell lines derived from different anatomic sites, and determined that ectopic expression of the two lncRNAs inhibited key EMT and stem cell genes and reduced cellular proliferation and migration. As a whole, noncoding RNAs are pervasively dysregulated in head and squamous cell carcinoma. The precise molecular roles of the three transcripts identified warrants further characterization, but our data suggest that they are likely to play substantial roles in head and neck cancer pathogenesis and are significantly associated with patient survival.