Variations in Trochlear Morphology of Contemporary and Legacy Total Knee Arthroplasty Prostheses: A Review of 22 Designs.

BACKGROUND: The morphology of the trochlear compartment of total knee arthroplasty (TKA) prostheses is a major determinant of postoperative patello-femoral kinematics, particularly with unresurfaced patellae. The objective of this study was to quantify and compare the trochlear morphology of a large series of contemporary and legacy TKA designs. METHODS: The 3-dimensional surface models of 22 femoral components (13 contemporary and 9 legacy) were created using high-resolution laser scanning. The trochlear profile of each component was analyzed from proximal to distal in 15° increments around the trochlear axis. In each profile, the following variables were measured: sulcus angle, medio-lateral deviation of the sulcus, the height and width of the facets, and the trochlear groove orientation. RESULTS: In the contemporary group, the sulcus angle decreased progressively along the trochlear arc to varying degrees, except for 2 symmetrical designs, whereas the sulcus angle of the legacy designs showed considerable variability. The height of the medial facet was very strongly correlated with that of the lateral facet in the contemporary group (R2 = 0.89), whereas the correlation was weak for the legacy designs (R2 = 0.36). Moreover, the trochlear sulcus deviated laterally from distal to proximal in 10 contemporary designs and 7 legacy designs, resulting in a trochlear groove orientation of 4.2 to 11.1° and 4.3 to 10.5°, respectively. In the remaining 5 designs (3 contemporary and 2 legacy), the sulcus was vertical. CONCLUSIONS: There is more consistency in trochlear morphology of contemporary TKA designs compared to that of legacy designs, yet there are still large variations between different designs.

Application of Locked Nucleic Acid Oligonucleotides for siRNA Preclinical Bioanalytics.

Despite the exquisite potential of siRNA as a therapeutic, the mechanism(s) responsible for the robust indirect exposure-response relationships have not been fully elucidated. To understand the siRNA properties linked to potent activity, requires the disposition of siRNA to be characterized. A technical challenge in the characterization is the detection and quantitation of siRNA from biological samples. Described herein, a Locked Nucleic Acid (LNA) Hybridization-Ligation ECL ELISA was designed for ultra-sensitive quantification of both sense and antisense strands of siRNA independent of structural modifica-tions. This assay was applied to measure siRNA in serum and tissue homogenate in preclinical species. We observed rapid clearance of siRNA from the systemic circulation which contrasted the prolonged accumulation within the tissue. The assay was also able to distinguish and quantify free siRNA from RNA-induced silencing complex (RISC) and Argonaute 2 (Ago2) associated with therapeutic siRNA. We utilized an orthogonal method, LC-MS, to investigate 3' exonuclease activity toward the antisense strand metabolism. Taken together, we have demonstrated that the LNA Hybridization-Ligation ECL ELISA is arobust analytical method with direct application to measuring the exposure of siRNA therapeutics seamlessly across biological matrices.

The voting experience and beliefs about ballot secrecy.

New democracies go to great lengths to implement institutional protections of the electoral process. However, in this paper we present evidence that shows that even in the United States-where the secret ballot has been in place for generations-doubts about the secrecy of the voting process are surprisingly prevalent. Many say that their cast ballot can be matched to their name or that others could observe their vote choices while they were voting. We find that people who have not previously voted are particularly likely to harbor doubts about the secrecy of voters' ballots. Those who vote by mail in the privacy of their own homes also feel that others are able to discover their vote choices. Taken together, these findings suggest an important divergence between public perceptions about and the institutional status of the secret ballot in the United States, a divergence that may affect patterns of voting behavior and political participation.

Does Capsular Laxity Lead to Microinstability of the Native Hip?

BACKGROUND: Hip "microinstability" is commonly cited as the cause of symptoms that occur in the presence of translation of the femoral head away from conformity with the acetabular fossa. However, there is still no consistent objective criteria defining its presence and biomechanical basis. One hypothesis is that abnormal motion of the articular surfaces occurs because of capsular laxity, ultimately leading to clinical symptoms. PURPOSE: To determine the relationship between capsular laxity and abnormal rotation and translation of the hip. STUDY DESIGN: Controlled laboratory study. METHODS: Eight cadaveric hips were dissected down to the capsule and mounted in a customized multiaxial hip activity simulator. Each specimen was loaded with 5 N·m of internal and external rotational torque in full extension and 0°, 30°, 60°, and 90° of flexion. During testing, the relative position and rotation of the femur and the pelvis were monitored in real time with a 6-camera motion analysis system. The testing was repeated after capsular laxity was generated by placing a regular array of incisions ("pie crusting") in the iliofemoral, pubofemoral, and ischiofemoral ligaments. Joint rotation and femoral head translation were calculated with specimen-specific models. A hip microinstability index was defined as the ratio between the length of the locus of the femoral head center and the radius of the femoral head during rotation from extension to 90° of flexion. RESULTS: In intact hips, the components of femoral head translation were within 0.5 mm in positions close to neutral (<30° of flexion). Capsular modification led to significant increases in internal and external rotation ( P < .01) and in the translation of the femoral head center at different positions ( P < .05). Compared with intact hips, the femoral head was inferiorly displaced during external rotation and anteroinferiorly during internal rotation. The length of the locus of the femoral head center increased from 3.61 ± 1.30 mm to 5.35 ± 1.83 mm for external rotation ( P < .05) and from 6.24 ± 1.48 mm to 8.21 ± 1.42 mm for internal rotation ( P < .01). The correlations between rotational laxity and the total translation of the femoral head were not significant, with coefficients of 0.093 and 0.006 in external and internal rotation, respectively. In addition, the hip microinstability index increased from 0.40 ± 0.08 for intact hips to 0.55 ± 0.09 for modified hips ( P < .01). CONCLUSION: The native hip approximates a concentric ball-and-socket joint within 30° of flexion; however, beyond 30° of flexion, the femoral head translation reached as high as 4 mm. Capsular laxity leads to microinstability of the hip, as indicated by significantly increased joint rotations and femoral head translations and an abnormal movement path of the femoral head center. However, there was no correlation between rotational laxity and the increase in femoral head translation. CLINICAL RELEVANCE: Capsular laxity alters normal kinematics (joint rotation and femoral head translation) of the hip, potentially leading to abnormal femoral-acetabular contact and joint degeneration.

Meniscal Root Tears: Identification and Repair.

Intact menisci are capable of converting the axial load of tibiofemoral contact into hoop stress that protects the knee joint. Total meniscectomy leads to rapid degeneration of the knee. Strong clinical and biomechanical data show meniscal root tears and avulsions are the functional equivalent of total meniscectomy. Lateral root tears commonly occur with knee ligament sprains and tears. Medial root tears are generally more chronic, and can be caused by preexisting knee arthritis. Meniscal root repair is indicated when there is identification of a meniscal root tear in a knee with minimal to no arthritis. Chronic root tears in the setting of osteoarthritis are treated conservatively. Meniscal root tears can acutely occur with cruciate ligament tears, can exaggerate symptoms of instability, and will have negative ramifications on outcomes of anterior cruciate ligament reconstruction if not addressed concomitantly. In this review, we describe the importance of the menisci for knee joint longevity through anatomy and biomechanics, the diagnostic workup, and ultimately a transosseous technique for repair of meniscal root tears and avulsions.

Clinical pharmacology of AMG 181, a gut-specific human anti-α4ß7 monoclonal antibody, for treating inflammatory bowel diseases.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Doctor knows best: physician endorsements, public opinion, and the politics of comparative effectiveness research.

The Obama administration has made a major investment in comparative effectiveness research (CER) to learn what treatments work best for which patients. CER has the potential to reduce wasteful medical spending and improve patient outcomes, but the political sustainability of this initiative remains unclear because of concerns that it will threaten the doctor-patient relationship. An unresolved question is whether it is possible to boost public support for the use of CER as a cost-control strategy. We investigate one potential source of public support: Americans' trust in physicians as faithful agents of patient interests. We conducted two national surveys to explore the public's confidence in doctors compared to other groups. We find that doctors are viewed as harder workers, more trustworthy, and more caring than other professionals. Through survey experiments, we demonstrate that the support of doctors' groups for proposals to control costs and use CER have a greater influence on aggregate public opinion than do cues from political actors including congressional Democrats, Republicans, and a bipartisan commission. Our survey results suggest that the medical profession's stance will be an important factor in shaping the political viability of efforts to use CER as a tool for health care cost control.

The public wants information, not board mandates, from comparative effectiveness research.

We conducted two national surveys of public opinion about comparative effectiveness research and the integration of findings from the research into clinical practice. The first survey found broad support for using research results to provide information, but less support for using them to allocate government resources or mandate treatment decisions. In addition, the public is willing to consider the use of financial incentives to encourage patients to choose cheaper treatments, if research demonstrates that they work as well as more expensive ones. The second survey found that support for comparative effectiveness research dropped in response to general debates about its consequences but that arguments against the research could be effectively countered by specific, targeted rebuttals.

A national survey reveals public skepticism about research-based treatment guidelines.

Using research to develop treatment guidelines is one way to lower medical costs and improve care. However, findings from a national survey show that the public is skeptical about this approach. Specifically, the public finds arguments against establishing research-based treatment guidelines more convincing than arguments in favor of it. Our findings suggest that for evidence-based treatment guidelines to win public acceptance, the public needs to be reassured that guidelines would not lead to the limiting of access to beneficial care.

"Fit-for-purpose" method validation and application of a biomarker (C-terminal telopeptides of type 1 collagen) in denosumab clinical studies.

Biomarkers are used to study drug effects, exposure-response relationships, and facilitate early decision making during development. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, profoundly inhibits bone resorption. C-terminal telopeptides of type I collagen (CTx), a bone resorption biomarker, provides early indications of denosumab effectiveness and informs protracted clinical outcomes (e.g., bone mineral density). Because of the dynamic relationship between denosumab and CTx, a precise and robust assay was desired. Thus, we adopted a fit-for-purpose approach to modify and validate a commercial CTx diagnostic kit to meet the intended applications of a quantitative pharmacodynamic biomarker for denosumab development. Seven standards were prepared to replace five calibrators provided in the kit. Three quality controls (QC) and two sample controls were used to characterize and monitor assay performance. Robotic workstations were used for standard and QC preparation and assay execution. Method validation experiments were conducted with rigor and procedures similar to those used for drug bioanalysis. The method demonstrated a linear range of 0.0490-2.34 ng/mL with four-parameter logistic regression. Inter-assay total error of validation samples in serum was < or = 26.7%. Extensive tests were conducted on selectivity in sera from target populations, specificity, stability, parallelism, and dilutional linearity. Applications to samples from numerous clinical studies confirmed that the CTx method was reliable, robust, and fit for use as an early indicator of denosumab effectiveness. Refinement supported the confidence for use in pharmacokinetic/pharmacodynamic modeling, dose selections, correlation to clinical effects, and formulation bioequivalence work.

Peer-reviewed, evidence-based analysis of vitamin D and primary hyperparathyroidism.

BACKGROUND: Research into the actions of vitamin D on the human body has been increasing at an exponential rate, as has understanding of the impact of vitamin D on various aspects of the endocrine system. Primary hyperparathyroidism (PHPT) is a disease of the endocrine system that can result in debility if not diagnosed. New understanding about the effect of vitamin D on parathyroid hormone regulation may provide an opportunity to better understand the coexistence of PHPT and vitamin D deficiency. METHODS: An evidence-based literature review was based on a PubMed search for research involving vitamin D and primary hyperparathyroidism, and evaluating existing research on vitamin D. The PubMed search included English-language articles published between 1977 and 2008, with a focus on research and analysis completed between 2005 and the present. This study examined recent developments in understanding the relationship between vitamin D and PHPT. This review of existing literature examined the impact of vitamin D insufficiency and deficiency, including the impact on diagnosis of vitamin D insufficiency/deficiency, diagnosis and management of PHPT, and the impact on overall health. The level of evidence was determined according to criteria proposed by Sackett et al. and the grade of recommendation according to the criteria proposed by Heinrich et al. RESULTS: Level III and level IV evidence predominates the vitamin D/PHPT based literature, with several notable Heinrich grade A, B, and C studies available. Additional evaluation of studies' review is provided by reference and by section. CONCLUSIONS: Vitamin D metabolism plays an important role in PHPT etiology, diagnosis, and management. Care of both conditions may have an important impact on overall health in humans.

Improvement of sleep disturbance and neurocognitive function after parathyroidectomy in patients with primary hyperparathyroidism.

OBJECTIVE: To investigate the frequency of the nontraditional symptoms of sleep disturbance and impaired cognitive functioning in patients with primary hyper-parathyroidism (PHPT) and to assess changes in such patients after parathyroidectomy. METHODS: In this study, we used formal neurocognitive assessment of patients undergoing parathyroidectomy for PHPT. The Brief Sleep Disturbance Inventory assessed sleep disturbance, and Stroop tests evaluated for cognitive impairment. Study patients underwent preoperative and postoperative neurocognitive testing. RESULTS: Fifty-five patients underwent neurocognitive evaluation; the 43 women and 12 men had a mean age of 63 years. Sleep disturbance was assessed in all 55 patients, whereas evaluation for cognitive impairment was performed in 47. Sleep disturbance was identified preoperatively in 24 (44%) of the 55 patients. This disorder affected 17 (31%) of 55 patients postoperatively (P<0.01). Impaired executive functioning was found at baseline in 6 (13%) of 47 patients and decreased to 1 (2%) of 47 post-operatively (P<0.01), whereas impaired cognitive processing speed was detected in 12 (26%) of 47 patients at baseline and decreased to 3 (6%) of 47 after parathyroidectomy (P<0.01). Eight patients did not meet the National Institutes of Health consensus statement criteria for parathyroidectomy; 4 of these patients had preoperative impairment of sleep or cognitive functioning, 3 of whom showed improvement postoperatively. CONCLUSION: Sleep disturbance and neurocognitive impairment occur in patients with PHPT, and these disorders improve after parathyroidectomy. Further objective evaluation of nontraditional symptoms in patients diagnosed as having PHPT is warranted.

Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography.

BACKGROUND: Four-dimensional computed tomography (4D-CT) provides both functional and highly detailed anatomic information about parathyroid tumors. The purpose of this study was to compare 4D-CT with sestamibi imaging and ultrasonography as methods for the accurate preoperative localization of hyperfunctioning parathyroid glands before parathyroidectomy. METHODS: A study of 75 patients with primary hyperparathyroidism was performed at a tertiary-care institution. Sestamibi imaging, ultrasonography, and 4D-CT were performed on each patient preoperatively. Results of the imaging studies were compared with operative findings, pathologic data, and biochemical measurements to assess the sensitivity and specificity of each of the imaging modalities. RESULTS: 4D-CT demonstrated improved sensitivity (88%) over sestamibi imaging (65%) and ultrasonography (57%), when the imaging studies were used to localize (lateralize) hyperfunctioning parathyroid glands to 1 side of the neck. Moreover, when used to localize parathyroid tumors to the correct quadrant of the neck (ie, right inferior, right superior, left inferior, or left superior), the sensitivity of 4D-CT (70%) was significantly higher than sestamibi imaging (33%) and ultrasonography (29%). CONCLUSION: 4D-CT provides significantly greater sensitivity than sestamibi imaging and ultrasonography for precise (quadrant) localization of hyperfunctioning parathyroid glands. This allows improved preoperative planning, particularly for the case of reoperation. In addition to the data that are provided, we present a novel classification scheme for use in parathyroid localization.