Research Spotlight

Baumgarten, H., J. J. Squiers, M. Arsalan, M. John and M. J. Dimaio (2016). “Defining the clinical need and indications: Who are the right patients for transcatheter mitral valve replacement.” J Cardiovasc Surg (Torino) 57(3): 352-359.

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Mitral regurgitation (MR) can be divided into two major etiologies, primary and secondary MR. Primary MR, also termed degenerative or organic MR, is a disease of the valve itself and is treated routinely by surgical repair in all but prohibitive risk patients. In these patients, transcatheter repair techniques, including edge to edge repair with the MitraClip device have been largely successful and widely adopted. Transcatheter placement of artificial chords has also been performed. The potential role for transcatheter mitral valve replacement (TMVR) in primary MR will likely be quite limited. Secondary or functional MR is due to a disease of the left ventricle and not the valve itself. The MR is a result of dilation of the left ventricle causing distraction of the papillary muscles with tethering of the mitral leaflets and lack of leaflet coaptation. Medical therapy is the mainstay treatment, with resynchronization used in appropriate patients. Surgical repair, usually with an undersized annuloplasty, is used in a limited number of patients. Transcatheter edge to edge repair is used extensively outside the US in secondary MR and is the subject of a pivotal trial in the US. However, it is in this group of patients with secondary MR that there is the largest clinical unmet need and, hence, the greatest potential opportunity for TMVR. At least ten TMVR platforms are in early feasibility, first in human, or preclinical trial stages. Four devices have cumulative early human experience in <100 patients. In this article, we discuss those patients most likely to benefit from TMVR and detail lessons learned from the first human studies regarding patient selection.

Wolford, L., R. Movahed, M. Teschke, R. Fimmers, D. Havard and E. Schneiderman (2016). “Temporomandibular joint ankylosis can be successfully treated with tmj concepts patient-fitted total joint prosthesis and autogenous fat grafts.” J Oral Maxillofac Surg 74(6): 1215-1227.

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PURPOSE: To measure and identify factors associated with treatment outcomes for patients with temporomandibular joint (TMJ) ankylosis treated with TMJ Concepts patient-fitted total joint prostheses and autogenous fat grafts. PATIENTS AND METHODS: This retrospective cohort study evaluated records of patients with TMJ ankylosis from a single private practice, treated from 1992 to 2011, who met the following inclusion criteria: 1) radiographic evidence of bony ankylosis, 2) limited incisal opening, 3) minimum of 12 months’ follow-up, and 4) treatment with TMJ Concepts (Ventura, CA)/Techmedica (Camarillo, CA) total joint prostheses and fat grafts. For each patient, the number of previous TMJ surgical procedures, as well as the estimated age of ankylosis onset, age at surgery, and length of postoperative follow-up, was recorded. Subjective evaluations were made with Likert-like scales (from 0 to 10) for 1) TMJ pain, 2) headache and facial pain, 3) jaw function, 4) diet, and 5) disability. Objective evaluations included maximal incisal opening and excursion movements. Nonparametric statistics were used for analysis. RESULTS: There were 32 patients (22 female and 10 male patients) with 48 ankylosed TMJs (16 bilateral and 16 unilateral) in this study, with a mean age of 39 years (range, 11 to 68 years), 2 or more previous TMJ surgical procedures in 69%, and a mean follow-up period of 68 months (range, 12 to 168 months). Trauma was the major etiology of TMJ ankylosis, occurring in 17 of 32 patients (53%). The following improvements occurred: The median value for TMJ pain changed from 8.0 preoperatively to 1.5 at longest follow-up; headache, from 8 to 3.5; facial pain, from 8 to 4; jaw function, from 8 to 2.5; diet, from 7 to 3; and disability, from 7 to 1.5. The median incisal opening was 14.5 mm (interquartile range, 6.3 to 20 mm) preoperatively and 35 mm (interquartile range, 30 to 40 mm) at longest follow-up. The median left lateral excursion improved from 0.5 to 2 mm, and the median right lateral excursion improved from 1 to 1.3 mm. All of these improvements were highly significant (P < .001, Wilcoxon tests). Equally favorable outcomes were found in patients with 12 to 48 months of maximal follow-up and patients with more than 48 months of maximal follow-up. CONCLUSIONS: The treatment of TMJ ankylosis with the TMJ Concepts patient-fitted total joint prosthesis in combination with fat grafting around the articulation area of the prosthesis is a viable and predictable method for improving pain levels, function, and quality of life, as well as prevention of reankylosis of the TMJ.

Wuerz, T. H., S. H. Song, J. S. Grzybowski, H. D. Martin, R. C. Mather, 3rd, M. J. Salata, A. A. Espinoza Orias and S. J. Nho (2016). “Capsulotomy size affects hip joint kinematic stability.” Arthroscopy: May 2016 [Epub ahead of print].

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PURPOSE: To evaluate the effect of capsulotomy size and subsequent repair on the biomechanical stability of hip joint kinematics through external rotation of a cadaveric hip in neutral flexion. METHODS: Eight fresh-frozen cadaveric hip specimens were used in this study. Each hip was tested under torsional loads of 6 N.m applied by a servohydraulic frame and transmitted by a pulley system. The test conditions were (1) neutral flexion with the capsule intact, (2) neutral flexion with a 4-cm interportal capsulotomy, (3) neutral flexion with a 6-cm capsulotomy, and (4) neutral flexion with capsulotomy repair. Soft tissue was retained during all interventions. Measures indicating joint kinematics (range of motion [ROM], hysteresis area [HA], and neutral zone [NZ]) were obtained for each condition. RESULTS: For all hip specimens, the average ROM, HA, and NZ were calculated relative to the intact capsular state (100%) and expressed in terms of percentage (+/- SD). The findings for ROM were as follows: intact, 100%; 4 cm, 107.42% +/- 5.69%; 6 cm, 113.40% +/- 7.92%; and repair, 99.78% +/- 3.77%. The findings for HA were as follows: intact, 100%; 4 cm, 108.30% +/- 9.30%; 6 cm, 115.30% +/- 13.92%; and repair, 99.47% +/- 4.12%. The findings for NZ were as follows: intact, 100%; 4 cm, 139.61% +/- 62.35%; 6 cm, 169.25% +/- 78.19%; and repair, 132.03% +/- 64.38%. Statistically significant differences in ROM existed between the intact and 4-cm conditions (P = .039), the intact and 6-cm conditions (P < .0001), the 4-cm and repair conditions (P = .033), and the 6-cm and repair conditions (P < .0001). There was no statistically significant difference between the intact and repair conditions (P > .99) or between the 4- and 6-cm conditions (P = .126). CONCLUSIONS: Under laboratory-based conditions, larger-sized capsulotomies were accompanied by increases in all three measures of joint mobility: ROM, HA, and NZ at time zero. Complete capsular closure effectively restored these measures when compared with the intact condition. CLINICAL RELEVANCE: Cadaveric models consisting of the hip joint with surrounding soft tissue were used under laboratory testing conditions to investigate potential iatrogenic joint instability resulting from expansive capsulotomies, showing that complete capsular closure leads to reconstitution of original joint stability properties at time zero.

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Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1.

Bentebibel, S. E., S. Khurana, N. Schmitt, P. Kurup, C. Mueller, G. Obermoser, A. K. Palucka, R. A. Albrecht, A. Garcia-Sastre, H. Golding and H. Ueno (2016). “Icos(+)pd-1(+)cxcr3(+) t follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.” Sci Rep 6: 26494.

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The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.