Discovery and molecular basis of subtype-selective cyclophilin inhibitors.

Although cyclophilins are attractive targets for probing biology and therapeutic intervention, no subtype-selective cyclophilin inhibitors have been described. We discovered novel cyclophilin inhibitors from the in vitro selection of a DNA-templated library of 256,000 drug-like macrocycles for cyclophilin D (CypD) affinity. Iterated macrocycle engineering guided by ten X-ray co-crystal structures yielded potent and selective inhibitors (half maximal inhibitory concentration (IC50) = 10 nM) that bind the active site of CypD and also make novel interactions with non-conserved residues in the S2 pocket, an adjacent exo-site. The resulting macrocycles inhibit CypD activity with 21- to >10,000-fold selectivity over other cyclophilins and inhibit mitochondrial permeability transition pore opening in isolated mitochondria. We further exploited S2 pocket interactions to develop the first cyclophilin E (CypE)-selective inhibitor, which forms a reversible covalent bond with a CypE S2 pocket lysine, and exhibits 30- to >4,000-fold selectivity over other cyclophilins. These findings reveal a strategy to generate isoform-selective small-molecule cyclophilin modulators, advancing their suitability as targets for biological investigation and therapeutic development.

Differences in Prosthetic Prescription Between Men and Women Veterans After Transtibial or Transfemoral Lower-Extremity Amputation: A Longitudinal Cohort Study (2005-2018).

OBJECTIVE: To evaluate whether prosthetic prescription differed by gender and the extent to which differences were mediated by measured factors. DESIGN: Retrospective longitudinal cohort study using data from Veterans Health Administration (VHA) administrative databases. SETTING: VHA patients throughout the United States. PARTICIPANTS: The sample included 20,889 men and 324 women who had an incident transtibial or transfemoral amputation between 2005 and 2018. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Time to prosthetic prescription (up to 1 year). We used parametric survival analysis (an accelerated failure time model) to assess gender differences. We estimated mediation effects of amputation level, pain comorbidity burden, medical comorbidities, depression, and marital status on time to prescription. RESULTS: In the 1 year after amputation, the proportion of women (54.3%) and men (55.7%) prescribed a prosthesis was similar. However, after we controlled for age, race, ethnicity, enrollment priority, VHA region, and service-connected disability, the time to prosthetic prescription was significantly faster among men compared with women (acceleration factor=0.73; 95% confidence interval, 0.61-0.87). The difference in time to prosthetic prescription between men and women was significantly mediated by amputation level (23%), pain comorbidity burden (-14%), and marital status (5%) but not medical comorbidities or depression. CONCLUSIONS: Although the proportion of patients with prosthetic prescription at 1-year postamputation was similar between men and women, women received prosthetic prescriptions more slowly than men, suggesting that more work is needed to understand barriers to timely prosthetic prescriptions among women, and how to intervene to reduce those barriers.

Early Convalescent Plasma Therapy and Mortality Among US Veterans Hospitalized With Nonsevere COVID-19: An Observational Analysis Emulating a Target Trial.

BACKGROUND: Early convalescent plasma transfusion may reduce mortality in patients with nonsevere coronavirus disease 2019 (COVID-19). METHODS: This study emulates a (hypothetical) target trial using observational data from a cohort of US veterans admitted to a Department of Veterans Affairs (VA) facility between 1 May and 17 November 2020 with nonsevere COVID-19. The intervention was convalescent plasma initiated within 2 days of eligibility. Thirty-day mortality was compared using cumulative incidence curves, risk differences, and hazard ratios estimated from pooled logistic models with inverse probability weighting to adjust for confounding. RESULTS: Of 11 269 eligible person-trials contributed by 4755 patients, 402 trials were assigned to the convalescent plasma group. Forty and 671 deaths occurred within the plasma and nonplasma groups, respectively. The estimated 30-day mortality risk was 6.5% (95% confidence interval [CI], 4.0%-9.7%) in the plasma group and 6.2% (95% CI, 5.6%-7.0%) in the nonplasma group. The associated risk difference was 0.30% (95% CI, -2.30% to 3.60%) and the hazard ratio was 1.04 (95% CI, .64-1.62). CONCLUSIONS: Our target trial emulation estimated no meaningful differences in 30-day mortality between nonsevere COVID-19 patients treated and untreated with convalescent plasma. Clinical Trials Registration. NCT04545047.

Practical application of microsphere samples for benchmarking a quantitative phase imaging system.

Quantitative phase imaging (QPI) provides an approach for monitoring the dry mass of individual cells by measuring the optical pathlength of visible light as it passes through cells. A distinct advantage of QPI is that the measurements result in optical path length quantities that are, in principle, instrument independent. Reference materials that induce a well-defined optical pathlength shift and are compatible with QPI imaging systems will be valuable in assuring the accuracy of such measurements on different instruments. In this study, we evaluate seven combinations of microspheres embedded in index refraction matching media as candidate reference materials for benchmarking the performance of a QPI system and as calibration standards for the optical pathlength measurement. Poly(methyl metharylate) microspheres and mineral oil were used to evaluate the range of illumination apertures, signal-to-noise ratios, and focus positions that allow an accurate quantitative optical pathlength measurement. The microsphere-based reference material can be used to verify settings on an instrument that are suitable for obtaining an accurate pathlength measurement from biological cells. The microsphere/media reference material is applied to QPI-based dry mass measurements of a population of HEK293 cells to benchmark and provide evidence that the QPI image data are accurate.

Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 3-year outcomes.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up. METHODS: TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life. RESULTS: Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed. CONCLUSION: TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.

Targeted lung denervation in sheep: durability of denervation and long-term histologic effects on bronchial wall and peribronchial structures.

BACKGROUND: Targeted lung denervation (TLD), a novel bronchoscopic procedure which attenuates pulmonary nerve input to the lung to reduce the clinical consequences of neural hyperactivity, may be an important emerging treatment for COPD. While procedural safety and impact on clinical outcomes have recently been reported, the mechanism of action has not been reported. We explored the long-term pathologic and histopathologic effects in a sheep model of ablation of bronchial branches of the vagus nerve using a novel dual-cooled radiofrequency ablation catheter. METHODS: Nineteen sheep underwent circumferential ablation of both main bronchi with simultaneous balloon surface cooling using a targeted lung denervation system (Nuvaira, Inc., USA). Animals were followed over an extended time course (30, 365, and 640 days post procedure). At each time point, lung denervation (axonal staining in bronchial nerves), and effect on peribronchial structures near the treatment site (histopathology of bronchial epithelium, bronchial cartilage, smooth muscle, alveolar parenchyma, and esophagus) were quantified. One way analysis of variance (ANOVA) was performed to reveal differences between group means on normal data. Non-parametric analysis using Kruskal-Wallis Test was employed on non-normal data sets. RESULTS: No adverse clinical effects were observed in any sheep. Nerve axon staining distal to the ablation site was decreased by 60% at 30 days after TLD and efferent axon staining was decreased by >70% at 365 and 640 days. All treated airways exhibited 100% epithelial integrity. Effect on peribronchial structures was strictly limited to lung tissue immediately adjacent to the ablation site. Tissue structure 1 cm proximal and distal to the treatment area remained normal, and the pulmonary veins, pulmonary arteries, and esophagus were unaffected. CONCLUSIONS: The denervation of efferent axons induced by TLD therapy is durable and likely a contributing mechanism through which targeted lung denervation impacts clinical outcomes. Further, long term lung denervation did not alter the anatomy of the bronchioles or lung, as evaluated from both a gross and histologic perspective.

Posterior shoulder tightness can be a risk factor of scapular malposition: a cadaveric biomechanical study.

BACKGROUND: Scapular malposition and posterior shoulder tightness are key pathologic processes in the shoulder of throwing athletes. The objective of this study was to investigate the effects of posterior capsule tightness, posterior rotator cuff muscle tightness, or both on scapular position. METHODS: Ten shoulders from 5 fresh frozen cadaveric male torsos were tested in maximum internal, neutral, and maximum external shoulder rotations at 0°, 45°, and 90° of shoulder abduction. Scapular rotation-namely, upward and downward rotation, internal and external rotation, and anterior and posterior tilt-and the scapula-spine distance were measured by using a MicroScribe digitizer (Revware, Raleigh, NC, USA). Each shoulder underwent 4 experimental stages: intact; isolated posterior rotator cuff muscle (infraspinatus and teres minor) tightness; both posterior rotator cuff muscle and capsule tightness; and isolated posterior capsule tightness. RESULTS: Posterior muscle tightness significantly decreased upward rotation (P< .05) only in maximum shoulder internal rotation at 45° or 90° of shoulder abduction, whereas posterior capsule tightness did not affect upward rotation (P= .09 to .96). Posterior capsule tightness significantly increased scapular internal rotation (P< .01), but posterior muscle tightness did not change scapular internal rotation (P= .62 to .89). Posterior capsule tightness significantly increased both the superior and inferior scapula-spine distance (ie, caused scapular protraction) in maximum shoulder external rotation at 90° of abduction (P< .01). CONCLUSION: Posterior shoulder tightness resulted in scapular malposition. However, the muscular and capsular components of that tightness affected the scapular position differently. For the treatment of scapula malposition, stretching of the posterior shoulder capsule and muscles is recommended.

Respiratory Sinus Arrhythmia Attenuation via Targeted Lung Denervation in Sheep and Humans.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. OBJECTIVE: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. METHODS: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu-vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). RESULTS: HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. CONCLUSIONS: TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.

Psychometric validation of the Stoma-QOL questionnaire in a Canadian cross-sectional sample of colostomy and ileostomy patients.

OBJECTIVES: The Stoma-QOL questionnaire is a patient-reported outcome (PRO) used to measure quality of life in patients with ileostomy or colostomy. This study assesses the Stoma-QOL's overall and item-level psychometric characteristics in patients with temporary stomas, and whether stoma-related quality of life differs by demographic characteristics. MATERIALS AND METHODS: Analysis of cross-sectional observational PRO data from hospitals in Vancouver, Canada. Patients registered for elective ileostomy or colostomy closure, over the age of 18, and able to read English were eligible for participation. Emergent and cancer-related cases were excluded. One-way analysis of variance was used to test for demographic differences in Stoma-QOL scores. Cronbach's alpha was used for reliability, and Rasch item-response theory was used to assess overall and item characteristics. RESULTS: 120 patients were included. No statistically significant difference in Stoma-QOL scores was found by age, sex, or socioeconomic status. Reliability was 0.93. Mean item responses ranged from 1.77 to 3.55 and item-total correlation ranged from 0.51 to 0.77. The Rasch item-response theory model demonstrated significant misfit, likely due to the misfit of item 9, which asks about sexuality, and high residual correlations between item pairs 6 and 8 about fatigue, and items 16 and 17 about social relationships. CONCLUSIONS: The Stoma-QOL questionnaire is a well-designed PRO for measuring stoma-related quality of life. Demographic variables do not appear to have a strong influence on Stoma-QOL scores. Item 9 demonstrated misfit but removal likely does not improve the instrument. Future research should focus on revising items 6, 8, 16, and 17.

Agglomeration of Escherichia coli with Positively Charged Nanoparticles Can Lead to Artifacts in a Standard Caenorhabditis elegans Toxicity Assay.

The increased use and incorporation of engineered nanoparticles (ENPs) in consumer products requires a robust assessment of their potential environmental implications. However, a lack of standardized methods for nanotoxicity testing has yielded results that are sometimes contradictory. Standard ecotoxicity assays may work appropriately for some ENPs with minimal modification but produce artifactual results for others. Therefore, understanding the robustness of assays for a range of ENPs is critical. In this study, we evaluated the performance of a standard Caenorhabditis elegans ( C. elegans) toxicity assay containing an Escherichia coli ( E. coli) food supply with silicon, polystyrene, and gold ENPs with different charged coatings and sizes. Of all the ENPs tested, only those with a positively charged coating caused growth inhibition. However, the positively charged ENPs were observed to heteroagglomerate with E. coli cells, suggesting that the ENPs impacted the ability of nematodes to feed, leading to a false positive toxic effect on C. elegans growth and reproduction. When the ENPs were tested in two alternate C. elegans assays that did not contain E. coli, we found greatly reduced toxicity of ENPs. This study illustrates a key unexpected artifact that may occur during nanotoxicity assays.

Evaluating the 8-item overactive bladder questionnaire (OAB-v8) using item response theory.

AIMS: The OAB-v8 is a patient-reported outcome questionnaire used to screen for overactive bladder and measure symptom bother. This study uses modern validation methods to assess the item and test characteristics of the OAB-v8, and determine whether it should be scored differently for men and women. METHODS: A secondary analysis of data from patients with lower urinary tract symptoms prospectively recruited from a urology clinic in Calgary, Canada. Item-response theory (IRT) was used to evaluate the dimensionality, reliability, and validity of the OAB-v8, and differential functioning analysis (DIF) was used to determine whether the OAB-v8 should be scored differently for men and women. RESULTS: A total of 1128 patients were included for analysis, of which 28% were female. Mean OAB-v8 scores indicated meaningful levels of symptom bother, and women scored 2 points higher, on average, than men (P = 0.005). Reliability was high (Cronbach's alpha = 0.901) for a wide range of patients (between -2 and 2.5 standard deviations of the mean). Samejima's graded response model best fit the data, and the scale demonstrated essential unidimensionality. Items #5 and #6 were excessively correlated. There was no evidence of differential functioning. CONCLUSIONS: OAB-v8 demonstrated high reliability and would be appropriate for a wide range of patients. Items #5 and #6 may need to be re-worded. The OAB-v8 should not be scored differently for men and women, although women do appear to experience higher average levels of symptom bother from OAB than men.

Evaluation of the Fecal Incontinence Quality of Life Scale (FIQL) using item response theory reveals limitations and suggests revisions.

PURPOSE: The Fecal Incontinence Quality of Life Scale (FIQL) is a commonly used patient-reported outcome measure for fecal incontinence, often used in clinical trials, yet has not been validated in English since its initial development. This study uses modern methods to thoroughly evaluate the psychometric characteristics of the FIQL and its potential for differential functioning by gender. METHODS: This study analyzed prospectively collected patient-reported outcome data from a sample of patients prior to colorectal surgery. Patients were recruited from 14 general and colorectal surgeons in Vancouver Coastal Health hospitals in Vancouver, Canada. Confirmatory factor analysis was used to assess construct validity. Item response theory was used to evaluate test reliability, describe item-level characteristics, identify local item dependence, and test for differential functioning by gender. RESULTS: 236 patients were included for analysis, with mean age 58 and approximately half female. Factor analysis failed to identify the lifestyle, coping, depression, and embarrassment domains, suggesting lack of construct validity. Items demonstrated low difficulty, indicating that the test has the highest reliability among individuals who have low quality of life. Five items are suggested for removal or replacement. Differential test functioning was minimal. CONCLUSIONS: This study has identified specific improvements that can be made to each domain of the Fecal Incontinence Quality of Life Scale and to the instrument overall. Formatting, scoring, and instructions may be simplified, and items with higher difficulty developed. The lifestyle domain can be used as is. The embarrassment domain should be significantly revised before use.

Knotless Transosseous-Equivalent Rotator Cuff Repair Improves Biomechanical Self-reinforcement Without Diminishing Footprint Contact Compared With Medial Knotted Repair.

PURPOSE: To assess the effect of medial-row knots on self-reinforcement and footprint contact characteristics for transosseous-equivalent repair compared with the same construct without knots. METHODS: In 8 fresh-frozen human shoulders, transosseous-equivalent repairs with and without medial-row mattress knots were performed in each specimen. A pressure sensor was fixed at the tendon-footprint interface for all repairs. Parameters measured included footprint contact area, force, and pressure. The supraspinatus tendon was loaded sequentially from 0 to 60 N at 0° and 30° of abduction. RESULTS: Both repairs provided a linear progression (slope) of footprint force and pressure as increasing tendon loads were applied. However, the knotless repair had a significantly higher progression ("self-reinforcement" effect) than the knotted repair at both abduction angles (P = .006 at 0° and P = .021 at 30°). The addition of medial-row knots did not significantly change the footprint contact area (in square millimeters), contact force (in newtons), contact pressure (in kilopascals), or peak pressure (in kilopascals) at each load tested, as well as at both abduction angles. For a given repair, only the knotless repair had significant decreases in contact area, contact force, contact pressure, and peak pressure with increasing abduction angles from 0° to 30° (P = .004 and P = .048). CONCLUSIONS: Knotless transosseous-equivalent repair shows an improved self-reinforcement effect, without diminishing footprint contact, compared with the same repair with medial knots. Although knotless repair itself can show diminished footprint contact with abduction, medial knots show an adverse biomechanical effect by inhibiting self-reinforcement, without improving contact characteristics compared with knotless repair at each abduction angle tested. Clinical outcomes with specific indications, on the basis of these findings, require further investigation. CLINICAL RELEVANCE: This study biomechanically helps to validate studies that have shown clinical success with knotless transosseous-equivalent repair. The inhibition of self-reinforcement may provide a quantified biomechanical rationale for medial tear patterns seen with knotted repairs.

Partial-thickness tears involving the rotator cable lead to abnormal glenohumeral kinematics.

HYPOTHESIS: The objective of this study was to determine the biomechanical function of the rotator cable when a partial-thickness (>50%) tear is present. We compared intact specimens with partial tears of the anterior cable followed by partial anterior and posterior tears in regard to glenohumeral kinematics and translation. The hypothesis was that partial-thickness tears will lead to abnormal glenohumeral biomechanics, including glenohumeral translation and path of glenohumeral articulation. METHODS: Five fresh frozen cadaveric shoulders with intact labrum, rotator cuff, and humerus were tested using a custom shoulder testing system in the scapular plane. Glenohumeral translation was measured after applying an anterior load of 30 N at different angles of external rotation. The path of glenohumeral articulation was measured by calculating the humeral head center with respect to the glenoid articular surface at 30°, 60°, 90°, and 120° of external rotation. RESULTS: With an anterior force of 30 N, there was a significant increase in anterior and total translation at 30° of external rotation after the anterior cable was cut (P < .05). When the tear was extended to the posterior cable, there was a significant increase in anterior, inferior, and total translation at 30° and 120° of external rotation (P < .05). With respect to the path of glenohumeral articulation , the humeral head apex was shifted superiorly at 90° and 120° of external rotation after the posterior cable was cut (P < .05). CONCLUSION: Partial-thickness articular-sided rotator cuff tears with a thickness >50% involving the rotator cable increased glenohumeral translation and changed kinematics in our cadaveric biomechanical model.

A biomechanical cadaveric study comparing superior capsule reconstruction using fascia lata allograft with human dermal allograft for irreparable rotator cuff tear.

BACKGROUND: Biomechanical and clinical success of the superior capsule reconstruction (SCR) using fascia lata (FL) grafts has been reported. In the United States, human dermal (HD) allograft has been used successfully for SCRs; however, the biomechanical characteristics have not been reported. METHODS: Eight cadaveric shoulders were tested in 5 conditions: (1) intact; (2) irreparable supraspinatus tear; (3) SCR using FL allograft with anterior and posterior suturing; (4) SCR using HD allograft with anterior and posterior suturing; and (5) SCR using HD allograft with posterior suturing. Rotational range of motion, superior translation, glenohumeral joint force, and subacromial contact were measured at 0°, 30°, and 60° of glenohumeral abduction in the scapular plane. Graft dimensions before and after testing were also recorded. Biomechanical parameters were compared using a repeated-measures analysis of variance with Tukey post hoc test, and graft dimensions were compared using a Student t-test (P < .05). RESULTS: Irreparable supraspinatus tear significantly increased superior translation, superior glenohumeral joint force, and subacromial contact pressure, which were completely restored with the SCR FL allografts. Both SCR HD allograft repairs partially restored superior translation and completely restored subacromial contact and superior glenohumeral joint force. The HD allografts significantly elongated by 15% during testing, whereas the FL allograft lengths were unchanged. CONCLUSIONS: Single-layered HD SCR allografts partially restored superior glenohumeral stability, whereas FL allograft SCR completely restored the superior glenohumeral stability. This may be due to the greater flexibility of the HD allograft, and the SCR procedure used was developed on the basis of FL grafts.

High resolution surface plasmon resonance imaging for single cells.

BACKGROUND: Surface plasmon resonance imaging (SPRI) is a label-free technique that can image refractive index changes at an interface. We have previously used SPRI to study the dynamics of cell-substratum interactions. However, characterization of spatial resolution in 3 dimensions is necessary to quantitatively interpret SPR images. Spatial resolution is complicated by the asymmetric propagation length of surface plasmons in the x and y dimensions leading to image degradation in one direction. Inferring the distance of intracellular organelles and other subcellular features from the interface by SPRI is complicated by uncertainties regarding the detection of the evanescent wave decay into cells. This study provides an experimental basis for characterizing the resolution of an SPR imaging system in the lateral and distal dimensions and demonstrates a novel approach for resolving sub-micrometer cellular structures by SPRI. The SPRI resolution here is distinct in its ability to visualize subcellular structures that are in proximity to a surface, which is comparable with that of total internal reflection fluorescence (TIRF) microscopy but has the advantage of no fluorescent labels. RESULTS: An SPR imaging system was designed that uses a high numerical aperture objective lens to image cells and a digital light projector to pattern the angle of the incident excitation on the sample. Cellular components such as focal adhesions, nucleus, and cellular secretions are visualized. The point spread function of polymeric nanoparticle beads indicates near-diffraction limited spatial resolution. To characterize the z-axis response, we used micrometer scale polymeric beads with a refractive index similar to cells as reference materials to determine the detection limit of the SPR field as a function of distance from the substrate. Multi-wavelength measurements of these microspheres show that it is possible to tailor the effective depth of penetration of the evanescent wave into the cellular environment. CONCLUSION: We describe how the use of patterned incident light provides SPRI at high spatial resolution, and we characterize a finite limit of detection for penetration depth. We demonstrate the application of a novel technique that allows unprecedented subcellular detail for SPRI, and enables a quantitative interpretation of SPRI for subcellular imaging.

The relation between knee flexion angle and anterior cruciate ligament femoral tunnel characteristics: a cadaveric study comparing a standard and a far anteromedial portal.

PURPOSE: The purpose of this study was to compare the anterior cruciate ligament (ACL) femoral tunnel characteristics between 2 common arthroscopic portals used for ACL reconstruction, a standard anteromedial portal and a far anteromedial portal. METHODS: Seven cadaveric knees were used. A 1.25-mm Kirschner wire was drilled through the center of the ACL femoral footprint and through the distal femur from the standard anteromedial and far anteromedial portals at knee flexion angles of 100°, 120°, and 140°. No formal tunnels were drilled. Each tunnel exit point was marked with a colored pin. After all tunnels were created, the specimens were digitized with a MicroScribe device (Revware, Raleigh, NC) to measure the tunnel length; distance to the posterior femoral cortical wall (posterior cortical margin); and tunnel orientation in the sagittal, coronal, and axial planes. RESULTS: The standard anteromedial portal resulted in a longer tunnel length, a less horizontal tunnel in the coronal plane, and a greater posterior cortical margin compared with the far anteromedial portal at all knee flexion angles. For both portal locations, the tunnel length and posterior cortical margin increased, and the tunnel position became more horizontal in the coronal plane, more anterior in the sagittal plane, and less horizontal in the transverse plane as knee flexion increased. CONCLUSIONS: Portal position affects femoral tunnel characteristics, with results favoring the more laterally positioned standard anteromedial portal at all flexion angles. Increasing the knee flexion angle leads to a longer femoral tunnel length and posterior femoral cortical margin with either portal position. CLINICAL RELEVANCE: Understanding how portal positioning and knee flexion angle affect femoral tunnel orientation and characteristics may lead to improved surgical outcomes after ACL reconstruction.

Biomechanical effects of a 2 suture-pass medial inter-implant mattress on transosseous-equivalent rotator cuff repair and considerations for a "technical efficiency ratio".

BACKGROUND: Rotator cuff repair involving fewer tendon suture passes without compromising biomechanical performance would represent a technical advancement. An inter-implant "medial pulley-mattress" transosseous-equivalent (MP-TOE) repair requiring fewer tendon suture-passes was hypothesized to provide equivalent biomechanical characteristics compared to the control. METHODS: In 6 human cadaveric shoulders, a transosseous-equivalent (TOE) repair (control) was performed utilizing 2 separate medial mattresses resulting in 4 tendon-bridging sutures. In 6 matched-pairs, 2 single-loaded anchors were used to create a medial inter-implant mattress construct (all sutures shuttled in 1 tendon pass per anchor)-after knot-tying, the same tendon-bridging pattern as the control was created. A materials testing machine cyclically loaded each repair from 10-180 N for 30 cycles; each repair subsequently underwent failure testing. Gap and strain were measured with a video digitizing system. A "technical efficiency ratio" (TER) was defined as: (#knots + #suture passes + #suture limbs)/#fixation points. RESULTS: Cyclic and failure testing demonstrated no significant differences between constructs. Gap formation at cycle 30 was 5.3 ± 0.8 mm (TOE) and 5.0 ± 0.3 mm (MP-TOE) (P = .62). Cycle 30 anterior strain values were -16.0 ± 7.3% (TOE) and -15.8 ± 6.6% (MP-TOE) (P = .99). Yield loads were 208.7 ± 2.7 N (TOE) and 204.0 ± 1.3 N (MP-TOE) (P = .17). Mode of failure demonstrated less tendon cut-out with the MP-TOE repair. The MP-TOE repair has a TER of 2.0 vs 2.5 for the control. CONCLUSION: The MP-TOE repair requiring fewer tendon suture passes, yet creating an additional inter-implant mattress configuration, is biomechanically equivalent to the original TOE technique, and may limit failure with improved medial load-sharing capacity. A TER may help quantify technical ease and help standardize comparisons between repair techniques.

Gender differences in prosthesis-related outcomes among veterans: Results of a national survey of U.S. veterans.

BACKGROUND: Women with lower extremity amputations (LEAs) tend to have poorer prosthesis-related outcomes than men, although the literature is sparse. To our knowledge, there are no prior studies examining prosthesis-related outcomes of women veterans with LEAs. OBJECTIVE: To examine gender differences (overall and by type of amputation) among veterans who underwent LEAs between 2005 and 2018, received care at the Veterans Health Administration (VHA) prior to undergoing amputation, and were prescribed a prosthesis. It was hypothesized that compared to men, women would report lower satisfaction with prosthetic services, poorer prosthesis fit, lower prosthesis satisfaction, less prosthesis use, and worse self-reported mobility. Furthermore, it was hypothesized that gender differences in outcomes would be more pronounced among individuals with transfemoral than among those with transtibial amputations. DESIGN: Cross-sectional survey. Linear regressions were used to assess overall gender differences in outcomes and gender differences based on type of amputation in a national sample of veterans. SETTING: VHA medical centers. PARTICIPANTS: The sample consisted of 449 veterans who self-identified their gender (women = 165, men = 284) with transtibial (n = 236), transfemoral (n = 135), and bilateral LEAs (n = 68) including all amputation etiologies. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Orthotics and Prosthetics User's Survey, Trinity Amputation and Prosthesis Experiences Scale, and Prosthetic Limb Users Survey of Mobility-Short Form were used to assess satisfaction with prosthetic services, prosthesis fit, prosthesis satisfaction, prosthesis use, and self-reported mobility. RESULTS: Women had poorer self-reported mobility than men (d = -0.26, 95% confidence interval -0.49 to -0.02, p < .05); this difference was small. There were no statistically significant gender differences in satisfaction with prosthetic services, prosthesis fit, prosthesis satisfaction, daily hours of prosthesis use, or by amputation type. CONCLUSIONS: Contrary to the hypothesis, prosthesis-related outcomes were similar between men and women with LEAs. Minimal differences may in part be due to receiving care from the VHA's integrated Amputation System of Care.