The dioecious and andromonoecious Solanum taxa (the "S. dioicum group") of the Australian Monsoon Tropics have been the subject of phylogenetic and taxonomic study for decades, yet much of their ...basic biology is still unknown. This is especially true for plant-animal interactions, including the influence of fruit form and calyx morphology on seed dispersal. We combine field/greenhouse observations and specimen-based study with phylogenetic analysis of seven nuclear regions obtained via a microfluidic PCR-based enrichment strategy and high-throughput sequencing, and present the first species-tree hypothesis for the S. dioicum group. Our results suggest that epizoochorous trample burr seed dispersal (strongly linked to calyx accrescence) is far more common among Australian Solanum than previously thought and support the hypothesis that the combination of large fleshy fruits and endozoochorous dispersal represents a reversal in this study group. The general lack of direct evidence related to biotic dispersal (epizoochorous or endozoochorous) may be a function of declines and/or extinctions of vertebrate dispersers. Because of this, some taxa might now rely on secondary dispersal mechanisms (e.g. shakers, tumbleweeds, rafting) as a means to maintain current populations and establish new ones.
Background Rotator cuff tears are one of the most common musculoskeletal complaints and a substantial source of morbidity in elderly patients. Chronic cuff tears are associated with muscle atrophy ...and an infiltration of fat to the area, a condition known as “fatty degeneration.” To improve the treatment of cuff tears in elderly patients, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. Methods Using a full-thickness, massive supraspinatus and infraspinatus tear model in elderly rats, we measured fiber contractility and determined changes in fiber type distribution that develop 30 days after tear. We also measured the expression of messenger RNA and micro-RNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of muscle fibers, an accumulation of type IIb fibers, and an upregulation in atrophic, fibrogenic, and inflammatory gene expression would occur in torn cuff muscles. Results Thirty days after the tear, we observed a reduction in muscle fiber force and an induction of RNA molecules that regulate atrophy, fibrosis, lipid accumulation, inflammation, and macrophage recruitment. A marked accumulation of advanced glycation end products and a significant accretion of macrophages in areas of fat accumulation were observed. Conclusions The extent of degenerative changes in old rats was greater than that observed in adults. In addition, we identified that the ectopic fat accumulation that occurs in chronic cuff tears does not occur by activation of canonical intramyocellular lipid storage and synthesis pathways.
Glenoid baseplate augments have recently been introduced as a way of managing glenoid monoplanar or biplanar abnormalities in reverse shoulder arthroplasty (RSA). The purpose of this study is to ...evaluate the difference in clinical outcomes, complications, and revision rates between augmented and standard baseplates in RSA for rotator cuff arthropathy patients with glenoid deformity.
A multicenter retrospective analysis of 171 patients with glenoid bone loss who underwent RSA with and without augmented baseplates was performed. Preoperative inclusion criteria included minimum follow-up of 2 years and preoperative retroversion of 15°-30° and/or a beta angle 70°-80°. Version and beta angle were measured on computed tomographic scans, when available, and plain radiographs. Shoulder range of motion (ROM) and patient-reported outcomes were obtained from preoperative and multiple postoperative time points.
The study consisted of 84 standard baseplate patients and 87 augmented baseplate patients. The augment cohort had greater mean preoperative glenoid retroversion (17° vs. 9°, P < .001). At >5-year follow-up, the increase in postoperative active abduction (52° vs. 31°, P = .023), forward flexion (58° vs. 35°, P = .020), and internal rotation score (2.8° vs. 1.1°, P = .001) was significantly greater in the augment cohort. Additionally, >5-year follow-up American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score (87.0 ± 16.6 vs. 75.9 ± 22.4, P = .022), Constant score (78.0 ± 9.7 vs. 64.6 ± 15.1, P < .001), and Shoulder Arthroplasty Smart score (81.2 ± 6.5 vs. 71.2 ± 13.6, P = .003) were significantly higher in the augment cohort. Revision rate was low overall, with no difference between the augment and no augment groups (0.7% vs. 3.0%, P = .151).
In comparing augments to standard nonaugment baseplates in the setting of RSA with glenoid deformity, our results demonstrate greater postoperative improvements in multiple planes of active ROM in the augment cohort. Additionally, the augment cohort demonstrated greater postoperative level and improvement in scores for multiple clinical outcome metrics up to >5 years of follow-up with no difference in complication or revision rates, supporting the use of augmented glenoid baseplates in RSA with glenoid deformity.
The purpose of this study was to compare the outcomes of primary reverse total shoulder arthroplasty (rTSA) using glenoid bone grafting (BG rTSA) with primary rTSA using augmented glenoid baseplates ...(Aug rTSA) with a minimum 2-year follow-up.
A total of 520 primary rTSA patients treated with 8° posterior glenoid augments (n = 246), 10° superior glenoid augments (n = 97), or combined 10° superior/8° posterior glenoid augments (n = 177) were compared with 47 patients undergoing glenoid bone grafting for glenoid bone insufficiency. The mean follow-up was 37.0(±16) and 53.0(±27) months, respectively. Outcomes were analyzed preoperatively and at the latest follow-up using conventional statistics and stratification by minimum clinically important difference (MCID) and substantial clinical benefit (SCB) thresholds where applicable. Radiographs were analyzed for baseplate failure, and the incidences of postoperative complications and revisions were recorded.
The glenoid Aug rTSA cohort had greater improvements in patient-reported outcome measures (PROMs) and range of motion when compared with the BG rTSA group at a minimum of 2-year follow-up, including Simple Shoulder Test, Constant score, American Shoulder and Elbow Surgeons score, University of California Los Angeles score, Shoulder Pain and Disability Index score, shoulder function, Shoulder Arthroplasty Smart score, abduction, and external rotation (P < .05). Patient satisfaction was higher in the Aug rTSA group compared with the BG rTSA group (P = .006). The utilization of an augmented glenoid component instead of glenoid bone grafting resulted in approximately 50% less total intraoperative time (P < .001), nearly 33% less intraoperative blood loss volume (P < .001), approximately 3-fold less scapular notching (P < .01), and approximately 8-fold less adverse events requiring revision (P < .01) when compared with the BG rTSA cohort. Aside from SCB for abduction, the Aug rTSA cohort achieved higher rates of exceeding MCID and SCB for every PROM compared with BG rTSA. More specifically, 77.6% and 70.2% of the Aug rTSA achieved SCB for American Shoulder and Elbow Surgeons and Shoulder Pain and Disability Index vs. 55% and 48.6% in the BG rTSA, respectively (P = .003 and P = .013).
The present midterm clinical and radiographic study demonstrates that the utilization of an augmented baseplate for insufficient glenoid bone stock is superior as judged by multiple PROMs and range of motion metrics when compared with bone graft augmentation at minimum 2-year follow-up. In addition, when analyzed according to MCID and SCB thresholds, the use of augmented baseplates outperforms the use of glenoid bone grafting. Complication and revision rates also favor the use of augmented glenoid baseplates over glenoid bone grafting. Long-term clinical and radiographic follow-up is necessary to confirm that these promising midterm results are durable.
Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of ...dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin’s association with calcium (Ca ²⁺) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal muscle fibers. Following experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive functional and structural disruption of the t-tubules that is ameliorated by reducing external Ca ²⁺ or blocking L-type Ca ²⁺ channels with diltiazem. Furthermore, we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric contraction-induced t-tubule damage, inflammation, and necrosis, which resulted in a concomitant increase in postinjury functional recovery. Our discovery of dysferlin as a t-tubule protein that stabilizes stress-induced Ca ²⁺ signaling offers a therapeutic avenue for limb girdle muscular dystrophy 2B and Miyoshi myopathy patients.
Abstract Background Currently, soft-tissue imbalance contributes to several of the foremost reasons for revision following primary TKA, including: instability, stiffness, and aseptic loosening. In ...order to decrease the incidence of soft-tissue imbalance, intraoperative sensors were developed to provide real-time, quantitative load data within the knee. This study examines the intraoperative data of a group of multicenter patients to determine how targeted ligament releases affect intra-articular loading, and to understand which types of releases are necessary to achieve quantified ligament balance. Methods A group of 129 patients received sensor-assisted TKA, as part of a multicenter study. Medial and lateral loading data was collected pre-release, during any sequential releases, and post-release. All data was collected at 10°, 45°, and 90° during range of motion testing. Ligament release type, release technique type, and resultant loading was collected. Results Loading across the joint decreased, overall, and became more symmetrical after releases were performed. On average, between 2 and 3 corrections were made (up to 8) in order to achieve ligament balance. The ligament release type and subsequent quantified change in loading was in agreement with historical, qualified sources. Conclusion Objective data from sensor output may assist surgeons in decreasing loading variability and, thereby, decreasing ligament imbalance and its associated complications.
Complications after anatomic (aTSA) and reverse (rTSA) total shoulder arthroplasty can be devastating to a patient's quality of life and require revisions that are costly to both the patient and the ...health care system. The purpose of this study is to determine the types, incidence, and timing of complications following aTSA and rTSA using an international database of patients who received a single-platform total shoulder arthroplasty system, in order to quantify the types of failure modes and the differences that occur between aTSA and rTSA.
A total of 2224 aTSA (male-female, 1090:1134) and 4158 rTSA (male-female, 1478:2680) patients were enrolled in an international database of primary shoulder arthroplasty performed by 40 different surgeons in the United States and Europe. Adverse events and revisions reported for these 6382 patients were analyzed to identify the most common failure modes associated for both aTSA and rTSA.
For the 2224 aTSA patients, 239 adverse events were reported for a complication rate of 10.7% and 124 revisions for a revision rate of 5.6%. The top 3 complications for aTSA were rotator cuff tear/subscapularis failure (n = 69; complication rate = 3.1%, revision rate = 1.9%), aseptic glenoid loosening (n = 55; complication rate = 2.5%, revision rate = 1.9%), and infection (n = 28; complication rate = 1.3%, revision rate = 0.8%). For the 4158 rTSA patients, 372 adverse events were reported for a complication rate of 8.9% and 104 revisions for a revision rate of 2.5%. The top 3 complications for rTSA were acromial/scapular fracture/pain (n = 102; complication rate = 2.5%, revision rate = 0.0%), instability (n = 60; complication rate = 1.4%, revision rate = 1.0%), and pain (n = 49; complication rate = 1.2%, revision rate = 0.2%).
This large database analysis quantified complication and revision rates for aTSA and rTSA. We found aTSA and rTSA complication rates of 10.7% and 8.9%, respectively; with revision surgery rates of 5.6% and 2.5%, respectively. The 2 most common complications for each prosthesis type (aTSA: subscapularis/rotator cuff tears, aseptic glenoid loosening; rTSA: acromial/scapular fractures, instability) were unique to each device. The rate of infection was similar for both. Future prosthesis and technique development should work to mitigate these common complication types in order to reduce their rate of occurrence.
An improved understanding of how gender differences and the natural aging process are associated with differences in clinical improvement in outcome metric scores and ROM measurements after reverse ...total shoulder arthroplasty (rTSA) may help physicians establish more accurate patient expectations for reducing postoperative pain and improving function.
(1) Is gender associated with differences in rTSA outcome scores like the Simple Shoulder Test (SST), the UCLA Shoulder score, the American Shoulder and Elbow Surgeons (ASES) Shoulder score, the Constant Shoulder score, and the Shoulder Pain and Disability Index (SPADI) and ROM? (2) Is age associated with differences in rTSA outcome scores and ROM? (3) What factors are associated with the combined interaction effect between age and gender? (4) At what time point during recovery does most clinical improvement occur, and when is full improvement reached?
We quantified and analyzed the outcomes of 660 patients (424 women and 236 men; average age, 72 ± 8 years; range, 43-95 years) with cuff tear arthropathy or osteoarthritis and rotator cuff tear who were treated with rTSA by 13 shoulder surgeons from a longitudinally maintained international database using a linear mixed effects statistical model to evaluate the relationship between clinical improvements and gender and patient age. We used five outcome scoring metrics and four ROM assessments to evaluate clinical outcome differences.
When controlling for age, men had better SST scores (mean difference MD = 1.41 points 95% confidence interval {CI}, 1.07-1.75, p < 0.001), UCLA scores (MD = 1.76 95% CI, 1.05-2.47, p < 0.001), Constant scores (MD = 6.70 95% CI, 4.80-8.59, p < 0.001), ASES scores (MD = 7.58 95% CI, 5.27-9.89, p < 0.001), SPADI scores (MD = -12.78 95% CI, -16.28 to -9.28, p < 0.001), abduction (MD = 5.79° 95% CI, 2.74-8.84, p < 0.001), forward flexion (MD = 7.68° 95% CI, 4.15-11.20, p < 0.001), and passive external rotation (MD = 2.81° 95% CI, 0.81-4.8, p = 0.006). When controlling for gender, each 1-year increase in age was associated with an improved ASES score by 0.19 points (95% CI, 0.04-0.34, p = 0.011) and an improved SPADI score by -0.29 points (95% CI, -0.46 to 0.07, p = 0.020). However, each 1-year increase in age was associated with a mean decrease in active abduction by 0.26° (95% CI, -0.46 to 0.07, p = 0.007) and a mean decrease of forward flexion by 0.39° (95% CI, -0.61 to 0.16, p = 0.001). A combined interaction effect between age and gender was found only with active external rotation: in men, younger age was associated with less active external rotation and older age was associated with more active external rotation (β0 intercept = 11.029, β1 slope for age variable = 0.281, p = 0.009). Conversely, women achieved no difference in active external rotation after rTSA, regardless of age at the time of surgery (β0 intercept = 34.135, β1 slope for age variable = -0.069, p = 0.009). Finally, 80% of patients achieved full clinical improvement as defined by a plateau in their outcome metric score and 70% of patients achieved full clinical improvement as defined by a plateau in their ROM measurements by 12 months followup regardless of gender or patient age at the time of surgery with most improvement occurring in the first 6 months after rTSA.
Gender and patient age at the time of surgery were associated with some differences in rTSA outcomes. Men had better outcome scores than did women, and older patients had better outcome scores but smaller improvements in function than did younger patients. These results demonstrate rTSA outcomes differ for men and women and for different patient ages at the time of surgery, knowledge of these differences, and also the timing of improvement plateaus in outcome metric scores and ROM measurements can both improve the effectiveness of patient counseling and better establish accurate patient expectations after rTSA.
Level III, therapeutic study.
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive ...tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
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